Professor Ronald B Geskus

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Technology Exchange: Medical statistics
Scientific Themes: Clinical Trials & Epidemiology and Immunology & Infectious Disease
Keywords: prediction models, survival analysis, longitudinal data analysis, clinical trials and infectious diseases

The biostatistics group of the Oxford University Clinical Research unit has an important role in the design and analysis of the studies that are performed in our unit. We collaborate with the other research groups, which each focus on a specific class of infectious diseases, as well as with the clinical trials unit. We contribute to the analysis of the clinical trials, and devise modern trial designs when needed. But we are also involved in observational studies, which have their own statistical challenges.

From a statistical perspective, research interests are i) the construction and validation of models for diagnosis and prediction, ii) models for the longitudinal development of markers of disease progression, iii) complex time-to-event data. At the same time, we enhance the statistical skills of our fellow researchers via both basic and advanced courses on statistical methods.

Name Department Institution Country
Professor Bridget Wills Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Jeremy Day Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Stephen Baker Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Guy Thwaites Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Louise Thwaites Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor (Ann) Sarah Walker Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Dr Thuong Thuong T Nguyen Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Hoa Thi Ngo Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Tran T Hien Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Hannah Clapham Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Buddha Basnyat Tropical Medicine Oxford University, Kathmandu Nepal
Dr Juan Carrique-Mas Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Raph Hamers Tropical Medicine Oxford University, Jakarta Indonesia
Dr Thuy Le Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Eduard Sanders Tropical Medicine Oxford University, Kilifi Kenya
Professor Cameron P Simmons Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr H Rogier van Doorn Tropical Medicine Oxford University, Hanoi Vietnam
Dat VQ, Geskus RB, Wolbers M, Loan HT, Yen LM, Binh NT, Chien LT, Mai NTH, Phu NH, Lan NPH et al. 2018. Continuous versus intermittent endotracheal cuff pressure control for the prevention of ventilator-associated respiratory infections in Vietnam: study protocol for a randomised controlled trial. Trials, 19 (1), pp. 217. | Show Abstract | Read more

BACKGROUND: Ventilator-associated respiratory infection (VARI) comprises ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT). Although their diagnostic criteria vary, together these are the most common hospital-acquired infections in intensive care units (ICUs) worldwide, responsible for a large proportion of antibiotic use within ICUs. Evidence-based strategies for the prevention of VARI in resource-limited settings are lacking. Preventing the leakage of oropharyngeal secretions into the lung using continuous endotracheal cuff pressure control is a promising strategy. The aim of this study is to investigate the efficacy of automated, continuous endotracheal cuff pressure control in preventing the development of VARI and reducing antibiotic use in ICUs in Vietnam. METHODS/DESIGN: This is an open-label randomised controlled multicentre trial. We will enrol 600 adult patients intubated for ≤ 24 h at the time of enrolment. Eligible patients will be stratified according to admission diagnosis (180 tetanus, 420 non-tetanus) and site and will be randomised in a 1:1 ratio to receive either (1) automated, continuous control of endotracheal cuff pressure or (2) intermittent measurement and control of endotracheal cuff pressure using a manual cuff pressure meter. The primary outcome is the occurrence of VARI, defined as either VAP or VAT during the ICU admission up to a maximum of 90 days after randomisation. Patients in both groups who are at risk for VARI will receive a standardised battery of investigations if their treating physician feels a new infection has occurred, the results of which will be used by an endpoint review committee, blinded to the allocated arm and independent of patient care, to determine the primary outcome. All enrolled patients will be followed for mortality and endotracheal tube cuff-related complications at 28 days and 90 days after randomisation. Other secondary outcomes include antibiotic use; days ventilated, in ICU and in hospital; inpatient mortality; costs of antibiotics in ICU; duration of ICU stay; and duration of hospital stay. DISCUSSION: This study will provide high-quality evidence concerning the use of continuous endotracheal cuff pressure control as a method to reduce VARI, antibiotic use and hospitalisation costs and to shorten stay. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02966392 . Registered on November 9, 2016. Protocol version: 2.0; issue date March 3, 2017.

Basten M, Heijne JCM, Geskus R, Daas CD, Kretzschmar M, Matser A. 2018. Sexual risk behaviour trajectories among men who have sex with menat risk for HIV in Amsterdam, the Netherlands: a 10 year follow-up study. AIDS, | Show Abstract | Read more

OBJECTIVE: Sexual risk behaviour changes during a person's life course. Insights in sexual risk behaviour trajectories of MSM may provide starting points for the timing of HIV prevention methods. We aimed to study longitudinal trajectories of sexual risk behaviour predictive of HIV acquisition from sexual debut onwards. DESIGN: A longitudinal study among 815 HIV-negative participants of the Amsterdam Cohort Studies (ACS) who completed extensive questionnaires about their sexual behaviour every 6 months between 2007 and 2017. METHODS: A comprehensive behavioural risk score predictive of HIV seroconversion was developed. On the basis of this risk score, linear trajectories of sexual risk behaviour and MSM group membership were estimated using latent class growth mixture modelling. Associations between longitudinal trajectories and demographic and psychosocial factors were examined. RESULTS: Three trajectories of sexual risk behaviour were identified, which were labelled Low risk (90.3% of the sample), Falling high risk (6.5%) and Rising high risk (3.3%). MSM following the Falling high risk (20.5%) and Rising high risk (25.0%) trajectories were more likely to acquire HIV during follow-up. The Falling high risk trajectory was associated with younger age at sexual debut, fewer steady partnerships and high percentages of substance use. The Rising high-risk trajectory was associated with increasing percentages of substance use over time. CONCLUSION: MSM follow different trajectories of changing sexual risk behaviour over time. Early identification of MSM following a trajectory of falling or rising high-risk behaviour and adequate timing of individual-based preventive interventions may reduce HIV transmission.

Musoro JZ, Struijk GH, Geskus RB, ten Berge IJM, Zwinderman AH. 2017. Dynamic prediction of recurrent events data by landmarking with application to a follow-up study of patients after kidney transplant Statistical Methods in Medical Research, 27 (3), pp. 096228021664356-096228021664356. | Show Abstract | Read more

© 2016, © The Author(s) 2016. This paper extends dynamic prediction by landmarking to recurrent event data. The motivating data comprised post-kidney transplantation records of repeated infections and repeated measurements of multiple markers. At each landmark time point t s , a Cox proportional hazards model with a frailty term was fitted using data of individuals who were at risk at landmark s. This model included the time-updated marker values at t s as time-fixed covariates. Based on a stacked data set that merged all landmark data sets, we considered supermodels that allow parameters to depend on the landmarks in a smooth fashion. We described and evaluated four ways to parameterize the supermodels for recurrent event data. With both the study data and simulated data sets, we compared supermodels that were fitted on stacked data sets that consisted of either overlapping or non-overlapping landmark periods. We observed that for recurrent event data, the supermodels may yield biased estimates when overlapping landmark periods are used for stacking. Using the best supermodel amongst the ones considered, we dynamically estimated the probability to remain infection free between t s and a prediction horizon t hor , conditional on the information available at t s .

Grafféo N, Latouche A, Geskus RB, Chevret S. 2018. Modeling time-varying exposure using inverse probability of treatment weights Biometrical Journal, 60 (2), pp. 323-332. | Show Abstract | Read more

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim For estimating the causal effect of treatment exposure on the occurrence of adverse events, inverse pro bability weights (IPW) can be used in marginal structural models to correct for time-dependent confounding. The R package ipw allows IPW estimation by modeling the relationship between the exposure and confounders via several regression models, among which is the Cox model. For right-censored data and time-dependent exposures such as treatment switches, the ipw package allows a single switch, assuming that patients are treated once and for all. However, to accommodate multiple switches, we extend this package by implementing a function that allows for multiple and intermittent exposure status in the estimation of IPW using a survival model. This extension allows for the whole exposure treatment trajectory in the estimation of IPW. The impact of the estimated weights on the estimated causal effect, with both methods, is assessed in a simulation study. Then, the function is illustrated on a real dataset from a nationwide prospective observational cohort including patients with inflammatory bowel disease. In this study, patients received one or multiple medications (thiopurines, methotrexate, and anti-TNF) over time. We used a Cox marginal structural model to assess the effect of thiopurines exposure on the cause-specific hazard for cancer incidence considering other treatments as confounding factors. To this end, we used our extended function which is available online in the Supporting Information.

Matser A, Schim van der Loeff M, Geskus R. 2018. Determining the Most Likely Source of Infection: An Application to Neisseria Gonorrhoeae Among Men Who Have Sex with Men. Epidemiology, 29 (3), pp. 421-430. | Show Abstract | Read more

BACKGROUND: The source of an infection is often unknown. To inform directed prevention measures, it is useful to know the location and partner type with the highest transmission risk. We developed a method to estimate infection risk of Neisseria gonorrhoeae per meeting location among men who have sex with men (MSM). METHODS: In 2008-2009, we collected information from 2,438 MSM attending the sexually transmitted infections clinic of Amsterdam. For up to four partners per participant (8,028 in total), we asked for details on meeting location, partner, and partnership characteristics. We used logistic regression to relate these to the participant's infection risk, accounting for unobserved transmission information in the likelihood. Based on the model estimates, we predicted the probability of a partner having N. gonorrhoeae. The probability that a partner was the source was proportional to his predicted infection risk. Each source was linked to the meeting location. We used a Bayesian method. RESULTS: Rectal N. gonorrhoeae was diagnosed in 157 MSM who reported data on 422 possible source partners, urethral N. gonorrhoeae in 126 reporting 285 possible sources, and pharyngeal N. gonorrhoeae in 162 reporting 451 possible sources. We estimated that most infections were acquired from long-lasting steady partners (21%; 95% CI = 17, 24). Partners met in an Amsterdam street with gay venues posed the highest transmission risk (13%; 95% CI = 7.9, 18). CONCLUSIONS: The presented method estimates the source of infection when there are multiple possible sources and enables the summation over various kinds of epidemiologic characteristics (here, meeting locations) that are relevant for prevention.

Musoro JZ, Zwinderman AH, Abu-Hanna A, Bosman R, Geskus RB. 2018. Dynamic prediction of mortality among patients in intensive care using the sequential organ failure assessment (SOFA) score: a joint competing risk survival and longitudinal modeling approach Statistica Neerlandica, 72 (1), pp. 34-47. | Show Abstract | Read more

© 2017 The Authors. Statistica Neerlandica © 2017 VVS. In intensive care units (ICUs), besides routinely collected admission data, a daily monitoring of organ dysfunction using scoring systems such as the sequential organ failure assessment (SOFA) score has become practice. Such updated information is valuable in making accurate predictions of patients' survival. Few prediction models that incorporate this updated information have been reported. We used follow-up data of ICU patients who either died or were discharged at the end of hospital stay, without censored cases. We propose a joint model comprising a linear mixed effects submodel for the development of longitudinal SOFA scores and a proportional subdistribution hazards submodel for death as end point with discharge as competing risk. The two parts are linked by shared latent terms. Because there was no censoring, it was straightforward to fit our joint model using available software. We compared predictive values, based on the Brier score and the area under the receiver operating characteristic curve, from our model with those obtained from an earlier modeling approach by Toma et al. [Journal of Biomedical Informatics 40, 649, (2007)] that relied on patterns discovered in the SOFA scores over a given period of time.

Stirrup OT, Copas AJ, Phillips AN, Gill MJ, Geskus RB, Touloumi G, Young J, Bucher HC, Babiker AG, CASCADE Collaboration in EuroCoord. 2018. Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion. HIV Med, 19 (3), pp. 184-194. | Show Abstract | Read more

OBJECTIVES: To investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. We make use of all pre-treatment CD4 counts, because analyses using only a single observation at initiation may be subject to biases. METHODS: We used data from the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) multinational cohort collaboration of HIV-1 seroconverters. We analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003-March 2014 (n = 7600 for primary analysis) using a statistical model in which the characteristics of recovery in CD4 counts are determined by multiple predictive factors. Secondary analyses were performed incorporating uncertainty in the exact timing of seroconversion to allow more precise estimation of the benefit of very early treatment initiation. RESULTS: 'True' CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. Allowing for lack of complete certainty in the date of seroconversion, CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post-treatment CD4 recovery. For other patient and drug characteristics, associations with recovery were statistically significant but small in magnitude. CONCLUSIONS: CD4 count at cART initiation is the most important factor in predicting post-treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid.

Zhang Z, Geskus RB, Kattan MW, Zhang H, Liu T. 2017. Nomogram for survival analysis in the presence of competing risks. Ann Transl Med, 5 (20), pp. 403. | Show Abstract | Read more

Clinical research usually involves time-to-event survival analysis, in which the presence of a competing event is prevalent. It is acceptable to use the conventional Cox proportional hazard regression to model cause-specific hazard. However, this cause-specific hazard cannot directly translate to the cumulative incidence function, and the latter is usually clinically relevant. The subdistribution hazard regression directly quantifies the impact of covariates on the cumulative incidence. When estimating the subdistribution hazard, subjects experiencing competing event continue to contribute to the risk set, and censoring weights are assigned to them after the competing event time. The weights are the conditional probability that a subject remains uncensored, and can be modelled to depend on the covariates of a subject. The first option to perform regression on the subdistribution hazard was the crr() function in the cmprsk package. However, it is not straightforward to draw a nomogram, which is a user-friendly tool for risk prediction, with the crr() function. To overcome this problem, we show an alternative method to use a nomogram function based on result of subdistribution hazard modeling.

Thao LTP, Heemskerk AD, Geskus RB, Mai NTH, Ha DTM, Chau TTH, Phu NH, Chau NVV, Caws M, Lan NH et al. 2018. Prognostic Models for 9-Month Mortality in Tuberculous Meningitis. Clin Infect Dis, 66 (4), pp. 523-532. | Show Abstract | Read more

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection. Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/). Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone. Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care.

Peters-Sengers H, Heemskerk MBA, Geskus RB, Kers J, Homan van der Heide JJ, Berger SP, Bemelman FJ. 2017. Validation of the Prognostic Kidney Donor Risk Index (KDRI) Scoring System of Deceased Donors for Renal Transplantation in the Netherlands Transplantation, 102 (1), pp. 1-1. | Show Abstract | Read more

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Background The prognostic Kidney Donor Risk Index (KDRI) - developed and internally validated in the United States - is a widely used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the United States. Methods We aimed to externally validate the KDRI donor-only and KDRI full as proposed by Rao et al (2009). KDRI donor-only consist of 10 donor factors, and KDRI full with an additional 4 transplant factors. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. Results The median Dutch KDRI was 1.21 and comparable with the year 2012 in the United States (median of 1.24). The calibration-slope was 0.98 and 0.96 for the KDRI full and KDRI donor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell C) of the KDRI full and the KDRI donor-only at 5 years was 0.63 (95% confidence interval [CI], 0.62-0.64), and 0.62 (95% CI, 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (P = 0.002), weight (P = 0.017), and cold ischemia time (P < 0.001). Adding the use of inotropic drugs before donation (P = 0.040) and the interact ion between circulatory-death donor kidneys and prolonged cold ischemic time ( > 24 hours vs 12 hours; P = 0.059) could improve predictive ability. Conclusions The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRI may contribute to a standardized policy meeting the growing demand of donor kidneys in the Eurotransplant region.

Hoogland J, Boel JA, de Bie RMA, Geskus RB, Schmand BA, Dalrymple-Alford JC, Marras C, Adler CH, Goldman JG, Tröster AI et al. 2017. Mild cognitive impairment as a risk factor for Parkinson's disease dementia Movement Disorders, 32 (7), pp. 1056-1065. | Show Abstract | Read more

© 2017 International Parkinson and Movement Disorder Society Background: The International Parkinson and Movement Disorder Society criteria for mild cognitive impairment in PD were recently formulated. Objectives: The aim of this international study was to evaluate the predictive validity of the comprehensive (level II) version of these criteria by assessment of their contribution to the hazard of PD dementia. Methods: Individual patient data were selected from four separate studies on cognition in PD that provided information on demographics, motor examination, depression, neuropsychological examination suitable for application of level II criteria, and longitudinal follow-up for conversion to dementia. Survival analysis evaluated the predictive value of level II criteria for cognitive decline toward dementia as expressed by the relative hazard of dementia. Results: A total of 467 patients were included. The analyses showed a clear contribution of impairment according to level II mild cognitive impairment criteria, age, and severity of PD motor symptoms to the hazard of dementia. There was a trend of increasing hazard of dementia with declining neuropsychological performance. Conclusions: This is the first large international study evaluating the predictive validity of level II mild cognitive impairment criteria for PD. The results showed a clear and unique contribution of classification according to level II criteria to the hazard of PD dementia. This finding supports their predictive validity and shows that they contribute important new information on the hazard of dementia, beyond known demographic and PD-specific factors of influence. © 2017 International Parkinson and Movement Disorder Society.

Ruizendaal E, Tahita MC, Geskus RB, Versteeg I, Scott S, d'Alessandro U, Lompo P, Derra K, Traore-Coulibaly M, de Jong MD et al. 2017. Increase in the prevalence of mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates collected from early to late pregnancy in Nanoro, Burkina Faso. Malar J, 16 (1), pp. 179. | Show Abstract | Read more

BACKGROUND: Pregnant women are a high-risk group for Plasmodium falciparum infections, which may result in maternal anaemia and low birth weight newborns, among other adverse birth outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy (IPTp-SP) is widely implemented to prevent these negative effects of malaria. However, resistance against SP by P. falciparum may decrease efficacy of IPTp-SP. Combinations of point mutations in the dhps (codons A437, K540) and dhfr genes (codons N51, C59, S108) of P. falciparum are associated with SP resistance. In this study the prevalence of SP resistance mutations was determined among P. falciparum found in pregnant women and the general population (GP) from Nanoro, Burkina Faso and the association of IPTp-SP dosing and other variables with mutations was studied. METHODS: Blood spots on filter papers were collected from pregnant women at their first antenatal care visit (ANC booking) and at delivery, from an ongoing trial and from the GP in a cross-sectional survey. The dhps and dhfr genes were amplified by nested PCR and products were sequenced to identify mutations conferring resistance (ANC booking, n = 400; delivery, n = 223; GP, n = 400). Prevalence was estimated with generalized estimating equations and for multivariate analyses mixed effects logistic regression was used. RESULTS: The prevalence of the triple dhfr mutation was high, and significantly higher in the GP and at delivery than at ANC booking, but it did not affect birth weight. Furthermore, quintuple mutations (triple dhfr and double dhps mutations) were found for the first time in Burkina Faso. IPTp-SP did not significantly affect the occurrence of any of the mutations, but high transmission season was associated with increased mutation prevalence in delivery samples. It is unclear why the prevalence of mutations was higher in the GP than in pregnant women at ANC booking. CONCLUSION: The high number of mutants and the presence of quintuple mutants in Burkina Faso confirm concerns about the efficacy of IPTp-SP in the near future. Other drug combinations to tackle malaria in pregnancy should, therefore, be explored. An increase in mutation prevalence due to IPTp-SP dosing could not be confirmed.

van Santen DK, van der Helm JJ, Del Amo J, Meyer L, D'Arminio Monforte A, Price M, Béguelin CA, Zangerle R, Sannes M, Porter K et al. 2017. Lack of decline in hepatitis C virus incidence among HIV-positive men who have sex with men during 1990–2014 Journal of Hepatology, 67 (2), pp. 255-262. | Show Abstract | Read more

© 2017 European Association for the Study of the Liver Background & Aims Hepatitis C virus (HCV) incidence among HIV-positive men who have sex with men (MSM) has increased since 2000, although there are regional differences. We aimed to 1) estimate trends in HCV incidence among HIV-positive MSM, 2) assess the association between incidence and geographical region, age and HIV-related measurements and, 3) assess temporal changes from HIV seroconversion to HCV infection. Methods Data was used from MSM with well-estimated dates of HIV seroconversion from the CASCADE Collaboration (1990–2014). Smoothly varying trends in HCV incidence over time were allowed, using restricted cubic splines. The association of calendar year, age, CD4 count (lagged), HIV RNA (lagged), geographical region and HIV infection stage (recent vs. chronic) with HCV incidence were assessed using Poisson regression. Results Of 5,941 MSM, 337 acquired HCV during follow-up. HCV incidence significantly increased from 0.7/1,000 person-years in 1990 to 18/1,000 person-years in 2014. Recent calendar years, younger age, recent HIV infection and higher HIV RNA levels were significantly associated with HCV incidence, while CD4 count was not. Trends differed by geographical region; while incidence appeared to have stabilized in Western Europe and remained stable in Southern Europe, it continued to increase in Northern Europe in recent years. Time from HIV to HCV infection significantly decreased over time (p < 0.001). Conclusions HCV has continued to spread among HIV-positive MSM in recent years, but trends differ by geographical region. Interventions to decrease the risk of HCV acquisition and increase early diagnosis are warranted. Lay summary Hepatitis C virus infection continues to spread among HIV-positive men who have sex with men, especially among younger individuals. However, trends seem to differ by European region in recent years. Furthermore, men who have sex with men with a higher HIV RNA load were more likely to get infected with the hepatitis C virus. During recent HIV infection, MSM appear to be at higher risk of acquiring hepatitis C.

Font-Gonzalez A, Feijen ELAM, Geskus RB, Dijkgraaf MGW, van der Pal HJH, Heinen RC, Jaspers MW, van Leeuwen FE, Reitsma JBJ, Caron HN et al. 2017. Risk and associated risk factors of hospitalization for specific health problems over time in childhood cancer survivors: a medical record linkage study Cancer Medicine, 6 (5), pp. 1123-1134. | Show Abstract | Read more

© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Childhood cancer survivors (CCS) experience higher hospitalization rates compared to the general population for neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. We studied trends in hospitalization rates and associated patient and treatment-specific risk factors for diagnosis subgroups among these four diseases. We performed medical record linkage of a ≥5-year CCS cohort with national registers, and obtained a random reference sample matched on age, gender and calendar year per CCS. For each diagnosis subgroup we compared hospitalization rates and trends over time in CCS and the reference population. Further, we analyzed risk factors for hospitalizations within the four CCS diagnosis groups. We used multivariate Poisson regression for all models. We retrieved hospitalization data from 1382 CCS and 26,583 reference persons. CCS had increased hospitalization rates for almost all diagnosis subgroups examined. Hospitalization rates for endocrine/nutritional/metabolic diseases appeared to increase with longer time since primary cancer diagnosis up to 30 years after primary cancer diagnosis. Survivors initially treated with radiotherapy had increased hospitalization rates for neoplasms (P  <  0.001), those initially treated with anthracyclines (2.5 [1.1–5.5]) and radiotherapy to thorax and/or abdomen (9.3 [2.4–36.6] ) had increased hospitalization rates for diseases of the circulatory system, and those initially treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases (6.7 [3.5–12.7]) and diseases of the eye (3.6 [1.5–8.9] ). Our study highlights that long-term health problems resulting in hospitalizations are still clinically relevant later in life of CCS. The identified treatment-related risk factors associated with hospitalizations support targeted follow-up care for these risk groups of CCS.

Vink AS, Clur S-AB, Geskus RB, Blank AC, De Kezel CCA, Yoshinaga M, Hofman N, Wilde AAM, Blom NA. 2017. Effect of Age and Sex on the QTc Interval in Children and Adolescents With Type 1 and 2 Long-QT Syndrome. Circ Arrhythm Electrophysiol, 10 (4), pp. e004645-e004645. | Show Abstract | Read more

BACKGROUND: In congenital long-QT syndrome, age, sex, and genotype have been associated with cardiac events, but their effect on the trend in QTc interval has never been established. We, therefore, aimed to assess the effect of age and sex on the QTc interval in children and adolescents with type 1 (LQT1) and type 2 (LQT2) long-QT syndrome. METHODS AND RESULTS: QTc intervals of 12-lead resting electrocardiograms were determined, and trends over time were analyzed using a linear mixed-effects model. The study included 278 patients with a median follow-up of 4 years (interquartile range, 1-9) and a median number of 6 (interquartile range, 2-10) electrocardiograms per patient. Both LQT1 and LQT2 male patients showed QTc interval shortening after the onset of puberty. In LQT2 male patients, this was preceded by a progressive QTc interval prolongation. In LQT1, after the age of 12 years, male patients had a significantly shorter QTc interval than female patients. In LQT2, during the first years of life and from 14 to 26 years, male patients had a significantly shorter QTc interval than female patients. On the contrary, between 5 and 14 years, LQT2 male patients had significantly longer QTc interval than LQT2 female patients. CONCLUSIONS: There is a significant effect of age and sex on the QTc interval in long-QT syndrome, with a unique pattern per genotype. The age of 12 to 14 years is an important transitional period. In the risk stratification and management of long-QT syndrome patients, clinicians should be aware of these age-, sex-, and genotype-related trends in QTc interval and especially the important role of the onset of puberty.

Hof MH, Musoro JZ, Geskus RB, Struijk GH, ten Berge IJM, Zwinderman AH. 2017. Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types, in the presence of a terminal event Journal of Applied Statistics, 44 (15), pp. 2756-2777. | Show Abstract | Read more

© 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.

de Vries EMG, Wang J, Leeflang MMG, Boonstra K, Weersma RK, Beuers UH, Geskus RB, Ponsioen CY. 2016. Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value. Liver Int, 36 (12), pp. 1867-1875. | Show Abstract | Read more

BACKGROUND: Primary sclerosing cholangitis (PSC) is a slowly progressive liver disease. Reliable biomarkers to predict outcome are urgently needed to serve as surrogate endpoints and/or stratifiers in clinical trials. Reduction in serum alkaline phosphatase (ALP) has been proposed as prognostic surrogate marker in PSC. The aim of this study was to asses if ALP at diagnosis (T0), 1 year later (T1), and percentage change between both time points hold prognostic value, and to determine the optimal threshold. METHODS: We retrospectively collected ALP levels at T0 and T1 for patients included in a large PSC cohort. The association of ALP at T0, T1, and percentage change with the combined endpoint (PSC-related death, liver transplantation) was analysed. Predictive value was determined using C-statistics. RESULTS: A total of 366 patients were included, of whom 66 (18%) reached an endpoint: 26 (7%) PSC-related death, 40 (11%) liver transplantation. At T0 and T1, 84% used ursodeoxycholic acid. A positive association was observed between level of ALP at T0 and T1 and the hazard of reaching an endpoint, up to values around 2.5 times upper limit of normal (xULN). A larger decrease in ALP between T0 and T1 decreased the event rate. A range of thresholds (0.5-3×ULN) with about similar C-statistics was found. In this cohort, the optimal threshold was 1.3×ULN at T1. CONCLUSION: ALP can be used to discriminate between PSC patients with a good and a poor prognosis. These findings indicate that ALP can serve as stratifier, and potentially as surrogate endpoint for clinical trials in PSC.

Font-Gonzalez A, Feijen EL, Sieswerda E, van Dulmen-den Broeder E, Grootenhuis M, Maurice-Stam H, Caron H, Essink-Bot M-L, van der Pal H, Geskus R, Kremer L. 2016. Social outcomes in adult survivors of childhood cancer compared to the general population: linkage of a cohort with population registers. Psychooncology, 25 (8), pp. 933-941. | Show Abstract | Read more

OBJECTIVE: Self-reported data show differences in social outcomes (not being married/having a registered partnership; not living independently; using social benefits) for childhood cancer survivors compared with their peers. We aimed to determine differences in these social outcomes between survivors and the general population using national register data and explored associated risk factors. METHODS: We performed medical record linkage between a single-centre cohort of 1768 ≥ 5-year survivors of childhood cancer (diagnosed 1966-2001) and two national registers (1999-2011) and obtained a random reference sample matched on gender and year of birth per survivor. We used multivariable logistic regression to calculate in adult survivors of childhood cancer (born before 1990) the odds of the specified social outcomes at the end of follow-up in both groups. Within the survivors, we analysed risk factors for the social outcomes. RESULTS: We retrieved data from 1283 adult childhood cancer survivors and 25 082 reference persons. Survivors had higher odds (odds ratio; 95% confidence interval) of not being married (1.2; 1.07-1.42), not living independently (1.7; 1.41-2.00) and using social benefits (2.3; 1.98-2.69) compared with reference persons. Radiotherapy to head and/or neck, and an original central nervous system tumour diagnosis negatively influenced all social outcomes examined in childhood cancer survivors. CONCLUSIONS: National register data show differences between social outcomes in childhood cancer survivors and the general population, especially for survivors treated with radiotherapy to head and/or neck and those originally diagnosed with central nervous system tumours. Development and implementation of effective targeted support strategies to improve social outcomes of childhood cancer survivors needs consideration. Copyright © 2015 John Wiley & Sons, Ltd.

Sieswerda E, Font-Gonzalez A, Reitsma JB, Dijkgraaf MGW, Heinen RC, Jaspers MW, van der Pal HJ, van Leeuwen FE, Caron HN, Geskus RB, Kremer LC. 2016. High Hospitalization Rates in Survivors of Childhood Cancer: A Longitudinal Follow-Up Study Using Medical Record Linkage. PLoS One, 11 (7), pp. e0159518. | Show Abstract | Read more

Hospitalization rates over time of childhood cancer survivors (CCS) provide insight into the burden of unfavorable health conditions on CCS and health care resources. The objective of our study was to examine trends in hospitalizations of CCS and risk factors in comparison with the general population. We performed a medical record linkage study of a cohort of 1564 ≥five-year CCS with national registers. We obtained a random sample of the general population matched on year of birth, gender and calendar year per CCS retrieved. We quantified and compared hospitalization rates of CCS and reference persons from 1995 until 2005, and we analyzed risk factors for hospitalization within the CCS cohort with multivariable Poisson models. We retrieved hospitalization information from 1382 CCS and 25583 reference persons. The overall relative hospitalization rate (RHR) was 2.2 (95%CI:1.9-2.5) for CCS compared to reference persons. CCS with central nervous system and solid tumors had highest RHRs. Hospitalization rates in CCS were increased compared to reference persons up to at least 30 years after primary diagnosis, with highest rates 5-10 and 20-30 years after primary cancer. RHRs were highest for hospitalizations due to neoplasms (10.7; 95%CI:7.1-16.3) and endocrine/nutritional/metabolic disorders (7.3; 95%CI:4.6-11.7). Female gender (P<0.001), radiotherapy to head and/or neck (P<0.001) or thorax and/or abdomen (P = 0.03) and surgery (P = 0.01) were associated with higher hospitalization rates in CCS. In conclusion, CCS have increased hospitalization rates compared to the general population, up to at least 30 years after primary cancer treatment. These findings imply a high and long-term burden of unfavorable health conditions after childhood cancer on survivors and health care resources.

Heijman T, Stolte I, Geskus R, Matser A, Davidovich U, Xiridou M, Schim van der Loeff M. 2016. Does online dating lead to higher sexual risk behaviour? A cross-sectional study among MSM in Amsterdam, the Netherlands. BMC Infect Dis, 16 (1), pp. 288. | Show Abstract | Read more

BACKGROUND: Men having sex with men (MSM) frequently use the Internet to find sex partners. We examined the association between unprotected anal intercourse (UAI) with partners dated online and with partners dated offline (met elsewhere), and examined whether differences can be explained by self-perceived HIV status of the index and knowledge of partnership characteristics. METHODS: MSM were recruited at the Sexually Transmitted Infections Clinic in Amsterdam, in 2008-2009. Participants completed a questionnaire concerning sexual behaviour. Only men reporting both online and offline casual sex partners were included. We assessed the association between online/offline partner dating and UAI, using random-effects logistic regression analysis. RESULTS: Five hundred seventy-seven men (351 HIV-negative, 153 HIV-positive, and 73 HIV-unaware) reported UAI in 26 % of 878 online, and 23 % of 903 offline casual partnerships. The crude OR of online dating for UAI was 1.36 (95 % CI 1.03-1.81). HIV-positive men were more likely to report UAI than HIV-negative men (49 % vs. 28 % of partnerships). Adjusted for demographic characteristics, online dating had no significant effect on UAI among HIV-negative and HIV status-unaware men, but HIV-positive men were more likely to have UAI with online partners (aOR = 1.65 [95 % CI 1.05-2.57]). After correction for partner and partnership characteristics the effect of online/offline dating on UAI among HIV-positive MSM was reduced and no longer significant. CONCLUSIONS: Online dating was not significantly associated with UAI among HIV-negative MSM. HIV-positive MSM were more likely to practise UAI with partners dated online; however, after correction for partner and partnership characteristics, online partnership acquisition was not associated with a significantly increased risk of UAI.

van Wonderen KE, Geskus RB, van Aalderen WMC, Mohrs J, Bindels PJE, van der Mark LB, Ter Riet G. 2016. Stability and predictiveness of multiple trigger and episodic viral wheeze in preschoolers. Clin Exp Allergy, 46 (6), pp. 837-847. | Show Abstract | Read more

BACKGROUND: In 2008, the European Respiratory Society Task Force proposed the terms multiple-trigger wheeze (MTW) and episodic (viral) wheeze (EVW) for children with wheezing episodes. We determined MTW and EVW prevalence, their 24-month stability and predictiveness for asthma. METHODS: In total, 565 preschoolers (1-, 2- and 3-year-olds) in primary care with respiratory symptoms were followed until the age of 6 years when asthma was diagnosed. MTW status and EVW status were determined using questionnaire data collected at baseline and after one and 2 years. We distinguished 3 phenotypes and determined their 24-month stability, also accounting for treatment with inhaled corticosteroids (ICS). Logistic regression was used to analyse the phenotypes' associations with asthma. RESULTS: Two hundred and eighty-one children had complete information. MTW and EVW were stable in 10 of 281 (3.6%) and 24 of 281 (8.5%), respectively. The odds of developing asthma for children with stable MTW and stable EVW were 14.4 (1.7-119) and 3.6 (1.2-11.3) times greater than those for children free of wheeze (for at least 1 year). ICS was associated with increased stability of MTW and EVW. CONCLUSIONS: Stable multiple-trigger and stable episodic viral wheeze are relatively uncommon. However, 1- to 3-year-olds with stable MTW are at much increased risk of asthma.

Geskus RB, González C, Torres M, Del Romero J, Viciana P, Masiá M, Blanco JR, Iribarren M, De Sanjosé S, Hernández-Novoa B et al. 2016. Incidence and clearance of anal high-risk human papillomavirus in HIV-positive men who have sex with men: estimates and risk factors. AIDS, 30 (1), pp. 37-44. | Show Abstract | Read more

BACKGROUND: To estimate incidence and clearance of high-risk human papillomavirus (HR-HPV), and their risk factors, in men who have sex with men (MSM) recently infected by HIV in Spain; 2007-2013. METHODS: Multicenter cohort. HR-HPV infection was determined and genotyped with linear array. Two-state Markov models and Poisson regression were used. RESULTS: We analysed 1570 HR-HPV measurements of 612 MSM over 13 608 person-months (p-m) of follow-up. Median (mean) number of measurements was 2 (2.6), median time interval between measurements was 1.1 years (interquartile range: 0.89-1.4). Incidence ranged from 9.0 [95% confidence interval (CI) 6.8-11.8] per 1000 p-m for HPV59 to 15.9 (11.7-21.8) per 1000 p-m for HPV51. HPV16 and HPV18 had slightly above average incidence: 11.9/1000 p-m and 12.8/1000 p-m. HPV16 showed the lowest clearance for both 'prevalent positive' (15.7/1000 p-m; 95% CI 12.0-20.5) and 'incident positive' infections (22.1/1000 p-m; 95% CI 11.8-41.1). More sexual partners increased HR-HPV incidence, although it was not statistically significant. Age had a strong effect on clearance (P-value < 0.001) due to the elevated rate in MSM under age 25; the effect of HIV-RNA viral load was more gradual, with clearance rate decreasing at higher HIV-RNA viral load (P-value 0.008). CONCLUSION: No large variation in incidence by HR-HPV type was seen. The most common incident types were HPV51, HPV52, HPV31, HPV18 and HPV16. No major variation in clearance by type was observed, with the exception of HPV16 which had the highest persistence and potentially, the strongest oncogenic capacity. Those aged below 25 or with low HIV-RNA- viral load had the highest clearance.

Mooij SH, van Santen DK, Geskus RB, van der Sande MAB, Coutinho RA, Stolte IG, Snijders PJF, Meijer CJLM, Speksnijder AGCL, de Vries HJC et al. 2016. The effect of HIV infection on anal and penile human papillomavirus incidence and clearance: a cohort study among MSM. AIDS, 30 (1), pp. 121-132. | Show Abstract | Read more

OBJECTIVES: A large portion of anogenital cancers is caused by high-risk human papillomavirus (hrHPV) infections, which are especially common in HIV-infected men. We aimed to compare the incidence and clearance of anal and penile hrHPV infection between HIV-infected and HIV-negative MSM. DESIGN: Analyses of longitudinal data from a prospective cohort study. METHODS: MSM aged 18 years or older were recruited in Amsterdam, the Netherlands, and followed-up semi-annually for 24 months. At each visit, participants completed risk-factor questionnaires. Anal and penile self-samples were tested for HPV DNA using the SPF10-PCR DEIA/LiPA25 system. Effects on incidence and clearance rates were quantified via Poisson regression, using generalized estimating equations to correct for multiple hrHPV types. RESULTS: Seven hundred and fifty MSM with a median age of 40 years (interquartile 35-48) were included in the analyses, of whom 302 (40%) were HIV-infected. The incidence rates of hrHPV were significantly higher in HIV-infected compared with HIV-negative MSM [adjusted incidence rate ratio (aIRR) 1.6; 95% confidence interval (CI) 1.3-2.1 for anal and aIRR 1.4; 95%CI 1.0-2.1 for penile infection]. The clearance rate of hrHPV was significantly lower for anal [adjusted clearance rate ratio (aCRR) 0.7; 95%CI 0.6-0.9], but not for penile infection (aCRR 1.3; 95%CI 1.0-1.7). HrHPV incidence or clearance did not differ significantly by nadir CD4 cell count. CONCLUSION: Increased anal and penile hrHPV incidence rates and decreased anal hrHPV clearance rates were found in HIV-infected compared with HIV-negative MSM, after adjusting for sexual behavior. Our findings suggest an independent effect of HIV infection on anal hrHPV infections.

Spoorenberg V, Hulscher MEJL, Geskus RB, de Reijke TM, Opmeer BC, Prins JM, Geerlings SE. 2016. [Better antibiotic use in complicated urinary tract infections; multicentre cluster randomised trial of 2 improvement strategies]. Ned Tijdschr Geneeskd, 160 pp. D460. | Show Abstract

OBJECTIVE: To compare the effectiveness of two strategies to improve antibiotic use in patients with a complicated urinary tract infection. DESIGN: Multicentre cluster randomised unblinded trial. METHOD: The departments of Internal Medicine and Urology from 19 hospitals in the Netherlands took part in this trial. Based on retrospective patient record investigations we performed baseline measurements on the scores of a validated set of quality indicators for antibiotic use in a minimum of 50 patients with a complicated urinary tract infection per department in 2009. A similar post-trial measurement took place in 2012. In 2010 we randomised the hospitals between 2 improvement strategies: a multifaceted strategy that included results of the baseline measurements, education, reminders and assistance with optional improvement interventions, and a competitive feedback strategy, in which the departments only received results of the baseline measurements and non-anonymous results from the other departments in this study arm. The primary outcome measure was improvement of the quality indicator scores. Secondary outcome measures were determinants of improvement of the indicators. (Netherlands Trial Register: NTR1742) RESULTS: The baseline and post-trial measurements were performed on 1,964 patients and 2,027 patients, respectively. Post-trial measurements revealed a significant, but limited, improvement of several indicators compared with baseline measurements. We found no significant difference in improvement between the two strategies for any indicator. The intensity with which the departments implemented improvement strategies was mostly suboptimal, but intensive implementation of a strategy was associated with greater improvement. CONCLUSION: The effectiveness of both improvement strategies was comparable, but limited. For real improvement in antibiotic use in patients with complicated urinary tract infections, improvement interventions should be developed and applied by local professionals themselves.

van Santen HM, Geskus RB, Raemaekers S, van Trotsenburg ASP, Vulsma T, van der Pal HJH, Caron HN, Kremer LCM. 2015. Changes in body mass index in long-term childhood cancer survivors. Cancer, 121 (23), pp. 4197-4204. | Show Abstract | Read more

BACKGROUND: Previous studies have reported changes in the body mass index (BMI) with time in childhood cancer survivors (CCSs) during follow-up. The limitations of these studies include that they described only a subgroup of survivors or used questionnaires with self-reported heights and weights. The goal of this study was to examine BMI in a large cohort of long-term CCSs and relate this to the BMI at diagnosis, age, sex, tumor type, treatment, and endocrine defects. METHODS: All patients treated for childhood cancer at the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 who had survived for at least 5 years were eligible for inclusion. For 893 CCSs with a mean follow-up of 14.9 years, the BMI at the late effects outpatient clinic was compared with the BMI for the general Dutch population. RESULTS: For girls, an increased prevalence of obesity was found. Risk factors for developing a high BMI at follow-up were a younger age and a high BMI at diagnosis and treatment with cranial radiotherapy. A significantly increased prevalence of severe underweight was found in all adult subgroups except for females aged 26 to 45 years. An association was found between a low BMI at diagnosis and a low BMI at follow-up. No treatment-related variables could be related to changes in BMI. CONCLUSIONS: The BMI at diagnosis is one of the most important predictors for the BMI at follow-up, and this suggests an important genetic or environmental cause. Adult CCSs are at high risk for developing severe underweight at follow-up. Future studies should focus on the causes and clinical consequences of underweight.

Spoorenberg V, Hulscher MEJL, Geskus RB, de Reijke TM, Opmeer BC, Prins JM, Geerlings SE. 2015. A Cluster-Randomized Trial of Two Strategies to Improve Antibiotic Use for Patients with a Complicated Urinary Tract Infection. PLoS One, 10 (12), pp. e0142672. | Show Abstract | Read more

BACKGROUND: Up to 50% of hospital antibiotic use is inappropriate and therefore improvement strategies are urgently needed. We compared the effectiveness of two strategies to improve the quality of antibiotic use in patients with a complicated urinary tract infection (UTI). METHODS: In a multicentre, cluster-randomized trial 19 Dutch hospitals (departments Internal Medicine and Urology) were allocated to either a multi-faceted strategy including feedback, educational sessions, reminders and additional/optional improvement actions, or a competitive feedback strategy, i.e. providing professionals with non-anonymous comparative feedback on the department's appropriateness of antibiotic use. Retrospective baseline- and post-intervention measurements were performed in 2009 and 2012 in 50 patients per department, resulting in 1,964 and 2,027 patients respectively. Principal outcome measures were nine validated guideline-based quality indicators (QIs) that define appropriate antibiotic use in patients with a complicated UTI, and a QI sumscore that summarizes for each patient the appropriateness of antibiotic use. RESULTS: Performance scores on several individual QIs showed improvement from baseline to post-intervention measurements, but no significant differences were found between both strategies. The mean patient's QI sum score improved significantly in both strategy groups (multi-faceted: 61.7% to 65.0%, P = 0.04 and competitive feedback: 62.8% to 66.7%, P = 0.01). Compliance with the strategies was suboptimal, but better compliance was associated with more improvement. CONCLUSION: The effectiveness of both strategies was comparable and better compliance with the strategies was associated with more improvement. To increase effectiveness, improvement activities should be rigorously applied, preferably by a locally initiated multidisciplinary team. TRIAL REGISTRATION: Nederlands Trial Register 1742.

Spoorenberg V, Geerlings SE, Geskus RB, de Reijke TM, Prins JM, Hulscher MEJL. 2015. Appropriate antibiotic use for patients with complicated urinary tract infections in 38 Dutch Hospital Departments: a retrospective study of variation and determinants. BMC Infect Dis, 15 (1), pp. 505. | Show Abstract | Read more

BACKGROUND: Appropriate antibiotic use in patients with complicated urinary tract infections can be measured by a valid set of nine quality indicators (QIs). We evaluated the performance of these QIs in a national setting and investigated which determinants influenced appropriate antibiotic use. For the latter, we distinguished patient, department and hospital characteristics, including organizational interventions aimed at improving the quality of antibiotic use (antibiotic stewardship elements). METHODS: A retrospective, observational multicentre study included 1964 patients (58% male sex) with a complicated urinary tract infection treated at Internal Medicine and Urology departments of 19 Dutch university and non-university hospitals. Data of 50 patients per department were extracted from medical charts. QI performance scores were calculated using previously constructed algorithms. Department and hospital characteristics were collected using questionnaires filled in by an internal medicine physician and an urologist. Regression analysis was performed to identify determinants of QI performance. Clustering at department and hospital level was taken into account through inclusion of random effects in a multi-level model. RESULTS: Median QI performance of departments varied between 31% ('Treat urinary tract infection in men according to local guideline') and 77% ('Perform urine culture'). The patient characteristics non-febrile urinary tract infection, female sex and presence of a urinary catheter were negatively associated with performance on many QIs. The presence of an infectious diseases physician and an antibiotic formulary were positively associated with 'Prescribe empirical therapy according to guideline'. No other department or hospital characteristics, including stewardship elements, were consistently associated with better QI performance. CONCLUSIONS: A large inter-department variation was demonstrated in the appropriateness of antibiotic use. In particular certain patient characteristics (more than department or hospital characteristics) influenced the quality of antibiotic use. Some, but not all antibiotic stewardship elements did translate into better QI performance.

Vanhommerig JW, Lambers FAE, Schinkel J, Geskus RB, Arends JE, van de Laar TJW, Lauw FN, Brinkman K, Gras L, Rijnders BJA et al. 2015. Risk Factors for Sexual Transmission of Hepatitis C Virus Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: A Case-Control Study. Open Forum Infect Dis, 2 (3), pp. ofv115. | Show Abstract | Read more

Background.  Since 2000, incidence of sexually acquired hepatitis C virus (HCV)-infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods.  From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands. Written questionnaires were administered, covering sociodemographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results.  Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0-52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63-15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04-12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02-6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27-192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39-8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19-2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60-14.53) had significant effects on HCV acquisition. Conclusions.  In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM.

Sieswerda E, Font-Gonzalez A, Dijkgraaf MGW, Geskus RB, Heinen RC, van der Pal HJ, van Leeuwen FE, Caron HN, Kremer LC, Reitsma JB. 2015. Studying Hospitalizations and Mortality in the Netherlands: Feasible and Valid Using Two-Step Medical Record Linkage with Nationwide Registers. PLoS One, 10 (7), pp. e0132444. | Show Abstract | Read more

In the Netherlands, the postal code is needed to study hospitalizations of individuals in the nationwide hospitalization register. Studying hospitalizations longitudinally becomes troublesome if individuals change address. We aimed to report on the feasibility and validity of a two-step medical record linkage approach to examine longitudinal trends in hospitalizations and mortality in a study cohort. First, we linked a study cohort of 1564 survivors of childhood cancer with the Municipal Personal Records Database (GBA) which has postal code history and mortality data available. Within GBA, we sampled a reference population matched on year of birth, gender and calendar year. Second, we extracted hospitalizations from the Hospital Discharge Register (LMR) with a date of discharge during unique follow-up (based on date of birth, gender and postal code in GBA). We calculated the agreement of death and being hospitalized in survivors according to the registers and to available cohort data. We retrieved 1477 (94%) survivors from GBA. Median percentages of unique/potential follow-up were 87% (survivors) and 83% (reference persons). Characteristics of survivors and reference persons contributing to unique follow-up were comparable. Agreement of hospitalization during unique follow-up was 94% and agreement of death was 98%. In absence of unique identifiers in the Dutch hospitalization register, it is feasible and valid to study hospitalizations and mortality of individuals longitudinally using a two-step medical record linkage approach. Cohort studies in the Netherlands have the opportunity to study mortality and hospitalization rates over time. These outcomes provide insight into the burden of clinical events and healthcare use in studies on patients at risk of long-term morbidities.

Grady BPX, Prins M, Rebers S, Molenkamp R, Geskus RB, Schinkel J. 2015. BMI, male sex and IL28B genotype associated with persistently high hepatitis C virus RNA levels among chronically infected drug users up to 23 years following seroconversion. J Viral Hepat, 22 (3), pp. 263-271. | Show Abstract | Read more

The natural course of serum HCV RNA levels during chronic infection remains unclear. We investigated HCV RNA levels and factors associated with HCV RNA levels for the entire course from HCV seroconversion. We measured HCV RNA levels of 54 HCV seroconverters from the Amsterdam Cohort Studies among drug users at yearly intervals up to 23 years using bDNA (VERSANT 3.0, lower limit of detection 615 IU/mL). Samples below the cut-off of the assay were tested by TMA (Siemens VERSANT, detection limit 5 IU/mL). We used a latent class linear mixed model to examine the HCV RNA patterns and factors associated with HCV RNA levels. The median follow-up time was 10.8 years (IQR 6.5-14.9). We found two distinct HCV RNA patterns characterized by 45/54 cases and 9/54 cases. In multivariable analyses, HCV RNA levels were 0.41 log(10) IU/mL (95% confidence interval (CI) 0.06-0.75) higher for males as compared to females. Individuals with the IL28B CC genotype had 0.40 log(10) IU/mL (95% 0.08-0.73) higher HCV RNA levels than individuals with IL28B CT/TT genotypes. Body mass index (BMI) was associated with higher HCV RNA levels, 0.055 log(10) IU/mL per BMI point (95% CI 0.027-0.083). In this unique study, which examines the HCV RNA patterns over an extended period and following seroconversion, male sex, IL28B CC genotype and BMI were independently associated with higher average HCV RNA levels. These results contribute to defining the natural history of HCV infection and could play an important part in clinical decision-making.

Gras L, de Wolf F, Smit C, Prins M, van der Meer JTM, Vanhommerig JW, Zwinderman AH, Schinkel J, Geskus RB, ATHENA national observational cohort and the MOSAIC study. 2015. Changes in HIV RNA and CD4 cell count after acute HCV infection in chronically HIV-infected individuals. J Acquir Immune Defic Syndr, 68 (5), pp. 536-542. | Show Abstract | Read more

OBJECTIVE: Little is known about the impact of acute hepatitis C virus (HCV) co-infection on HIV-1 disease progression. We investigated CD4 cell count and HIV RNA concentration changes after HCV infection in individuals chronically infected with HIV-1. METHODS: We selected individuals that had the last negative and first positive HCV RNA test less than 1 year apart. Bivariate linear mixed-effects regression was used to model trends in HIV RNA level and CD4 cell count from 2 years before the last negative HCV RNA test until the first of the following dates: start of anti-HCV medication, change in combination antiretroviral therapy (cART) status, and end of follow-up. RESULTS: At the estimated time of HCV co-infection, of 89 individuals, 63 (71%) were cART-treated and 26 (29%) were not on cART. In persons on cART, median CD4 cell count declined from 587 to 508 cells per cubic millimeter (P < 0.0001) during the first 5 months after HCV infection and returned to 587 cells per cubic millimeter after 2.2 years. Also, the probability of an HIV RNA >50 copies per milliliter peaked to 18.6% at HCV co-infection, with lower probabilities 6 months before (3.5%, P = 0.006 compared with peak probability) and after (2.9%, P = 0.009). In persons not on cART, no significant impact of HCV co-infection on trends in the HIV RNA level or CD4 cell count was observed. CONCLUSIONS: Acute HCV infection in cART-treated, chronically HIV-infected patients was associated with a temporary decrease in CD4 cell counts and increased risk of HIV viremia >50 copies per milliliter. This may increase the risk of further HIV transmission.

Langereis EJ, van Vlies N, Church HJ, Geskus RB, Hollak CEM, Jones SA, Kulik W, van Lenthe H, Mercer J, Schreider L et al. 2015. Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy. Mol Genet Metab, 114 (2), pp. 129-137. | Show Abstract | Read more

BACKGROUND: Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS I patients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition. METHODS: A total of 428 blood and urine samples were collected during long-term ERT in 24 MPS I patients and an extensive set of biomarkers was analyzed, including heparan sulfate (HS) and dermatan sulfate (DS) derived disaccharides; total urinary GAGs (DMBu); urinary DS:CS ratio and serum heparin co-factor II thrombin levels (HCII-T). IgG antibody titers and the effect of antibodies on cellular uptake of the enzyme were determined for 23 patients. RESULTS: Median follow-up was 2.3 years. In blood, HS reached normal levels more frequently than DS (50% vs 12.5%, p=0.001), though normalization could take several years. DMBu normalized more rapidly than disaccharide levels in urine (p=0.02). Nineteen patients (83%) developed high antibody titers. Significant antibody-mediated inhibition of enzyme uptake was observed in 8 patients (35%), and this correlated strongly with a poorer biomarker response for HS and DS in blood and urine as well as for DMBu, DS:CS-ratio and HCII-T (all p<0.006). CONCLUSIONS: This study shows that, despite a response of all studied biomarkers to initiation of ERT, some biomarkers were less responsive than others, suggesting residual disease activity. In addition, the correlation of cellular uptake inhibitory antibodies with a decreased biomarker response demonstrates a functional role of these antibodies which may have important clinical consequences.

Musoro JZ, Geskus RB, Zwinderman AH. 2015. A joint model for repeated events of different types and multiple longitudinal outcomes with application to a follow-up study of patients after kidney transplant. Biom J, 57 (2), pp. 185-200. | Show Abstract | Read more

This paper presents an extension of the joint modeling strategy for the case of multiple longitudinal outcomes and repeated infections of different types over time, motivated by postkidney transplantation data. Our model comprises two parts linked by shared latent terms. On the one hand is a multivariate mixed linear model with random effects, where a low-rank thin-plate spline function is incorporated to collect the nonlinear behavior of the different profiles over time. On the other hand is an infection-specific Cox model, where the dependence between different types of infections and the related times of infection is through a random effect associated with each infection type to catch the within dependence and a shared frailty parameter to capture the dependence between infection types. We implemented the parameterization used in joint models which uses the fitted longitudinal measurements as time-dependent covariates in a relative risk model. Our proposed model was implemented in OpenBUGS using the MCMC approach.

Möller LM, Stolte IG, Geskus RB, Okuku HS, Wahome E, Price MA, Prins M, Graham SM, Sanders EJ. 2015. Changes in sexual risk behavior among MSM participating in a research cohort in coastal Kenya. AIDS, 29 Suppl 3 pp. S211-S219. | Show Abstract | Read more

OBJECTIVE: To describe changes in sexual risk behavior among Kenyan MSM who received regular risk reduction counseling (RRC). DESIGN: Data were derived from two cohorts of HIV-1-negative and HIV-1-positive MSM in Kenya. Behavioral data were collected at enrollment and at monthly or quarterly scheduled follow-up visits. At each visit, RRC was provided to all men and HIV-1 testing to seronegative men. METHODS: Random effects logistic and Poisson regression models with time since study entry as main variable of interest were used to evaluate changes in number of sex partners and unprotected sex in the past week, and insertive, receptive, and unprotected anal intercourse in the past 3 months. Analyses were adjusted for HIV-1-status, calendar year of follow-up, and several baseline characteristics. Trends over follow-up time were allowed to differ by HIV-1-status. Men were censored when they seroconverted for HIV. RESULTS: Number of regular and casual sex partners and unprotected anal intercourse decreased in both HIV-1-negative and HIV-1-positive men. Unprotected sex with both regular and casual sex partners decreased more strongly early in follow-up in HIV-1-positive men than in HIV-1-negative men. Decreases in insertive anal intercourse were found for HIV-1-positive men only, whereas decreases in receptive anal intercourse were found for HIV-1-negative men only. CONCLUSION: MSM who were regularly exposed to RRC showed some reductions in sexual risk behavior, but it is uncertain if these reductions are sustained over time. As HIV-1 incidences in Kenyan MSM are very high, RRC should be supported by comprehensive biomedical interventions.

Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M et al. 2015. Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study. J Viral Hepat, 22 (9), pp. 708-717. | Show Abstract | Read more

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.

Vriend HJ, Stolte IG, Heijne JCM, Heijman T, De Vries HJC, Geskus RB, Van der Sande MAB, Prins M. 2015. Repeated STI and HIV testing among HIV-negative men who have sex with men attending a large STI clinic in Amsterdam: a longitudinal study. Sex Transm Infect, 91 (4), pp. 294-299. | Show Abstract | Read more

OBJECTIVE: In the Netherlands, men who have sex with men (MSM) are advised via informal guidelines to test for STI at least annually. We estimated the proportion of HIV-negative MSM testing repeatedly at 12-month or smaller intervals at a large STI clinic in the Netherlands. In addition, we explored whether repeated testing is related to risk behaviour. DESIGN AND METHODS: Longitudinal data of HIV-negative MSM visiting the Amsterdam STI clinic between 2009 and 2012 were analysed. To estimate the timing of repeated testing, Kaplan-Meier methods were used. Determinants for repeated testing (distinguishing testing at 12-month or smaller intervals and less than 12-monthly testing, with single testers as reference group) were identified using multivariate multinomial logistic regression analyses. RESULTS: In total, 19,479 consultations of 9174 HIV-negative MSM were identified. Of these MSM, 35% (95% CI 33% to 36%) were estimated to return to the STI clinic within 1 year following baseline consultation. Among 1767 men with at least two consultations and at least 2 years between baseline and last consultation, 43% tested repeatedly at 12-month or smaller intervals in those first 2 years. Repeated testers reported higher sexual risk behaviour (ie, only casual or both casual and steady sex partners, higher numbers of sex partners) at baseline compared with single testers. This effect tended to be slightly stronger for men testing repeatedly at 12-month or smaller intervals. CONCLUSIONS: The proportion of MSM testing for STI annually is low. MSM testing repeatedly had higher baseline levels of risk behaviour. Strategies to motivate MSM to test annually should be explored.

Wang J, Bossuyt P, Geskus R, Zwinderman A, Dolleman M, Broer S, Broekmans F, Mol BW, Leeflang M, IMPORT Study Group. 2015. Using individual patient data to adjust for indirectness did not successfully remove the bias in this case of comparative test accuracy. J Clin Epidemiol, 68 (3), pp. 290-298. | Show Abstract | Read more

OBJECTIVES: In comparative systematic reviews of diagnostic accuracy, inconsistencies between direct and indirect comparisons may lead to bias. We investigated whether using individual patient data (IPD) can adjust for this form of bias. STUDY DESIGN AND SETTING: We included IPD of 3 ovarian reserve tests from 32 studies. Inconsistency was defined as a statistically significant difference in relative accuracy or different comparative results between the direct and indirect evidence. We adjusted for the effect of threshold and reference standard, as well as for patient-specific variables. RESULTS: Anti-Müllerian hormone (AMH) and follicle stimulation hormone (FSH) differed significantly in sensitivity (-0.1563, P = 0.04). AMH and antral follicle count (AFC) differed significantly in sensitivity (0.1465, P < 0.01). AMH and AFC differed significantly in specificity (-0.0607, P = 0.02). The area under the curve (AUC) differed significantly between AFC and FSH (0.0948, P < 0.01) in the direct comparison but not (0.0678, P = 0.09) in the indirect comparison. The AUCs of AFC and AMH differed significantly (-0.0830, P < 0.01) in the indirect comparison but not (-0.0176, P = 0.29) in the direct comparison. These differences remained after adjusting for indirectness. CONCLUSION: Estimates of comparative accuracy obtained through indirect comparisons are not always consistent with those obtained through direct comparisons. Using IPD to adjust for indirectness did not successfully remove the bias in this case study.

van der Pal HJ, van Dijk IW, Geskus RB, Kok WE, Koolen M, Sieswerda E, Oldenburger F, Koning CC, van Leeuwen FE, Caron HN et al. 2015. Valvular abnormalities detected by echocardiography in 5-year survivors of childhood cancer: a long-term follow-up study. Int J Radiat Oncol Biol Phys, 91 (1), pp. 213-222. | Show Abstract | Read more

PURPOSE: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). METHODS AND MATERIALS: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD2). Using multivariable logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. RESULTS: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD2) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. CONCLUSIONS: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD2 to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities in CCS.

Matser A, Heijman T, Geskus R, de Vries H, Kretzschmar M, Speksnijder A, Xiridou M, Fennema H, Schim van der Loeff M. 2014. Perceived HIV status is a key determinant of unprotected anal intercourse within partnerships of men who have sex with men in Amsterdam. AIDS Behav, 18 (12), pp. 2442-2456. | Show Abstract | Read more

The practice of unprotected anal intercourse (UAI) involves at least two partners. We examined the associations between insertive or receptive UAI and perceived HIV seroconcordance and partnership type in self-perceived HIV-negative and self-perceived HIV-positive men who have sex with men (MSM). MSM (age ≥ 18 years) were recruited for a cross-sectional survey at the sexually transmitted infections clinic in Amsterdam, the Netherlands, in 2008-2009. Participants completed a questionnaire concerning partnerships in the preceding 6 months. Associations were quantified via multinomial logistic regression models using generalized estimating equations. The outcomes were 'no, or safe anal intercourse', 'insertive UAI', and 'receptive UAI'. We included 5,456 partnerships from 1,890 self-perceived HIV-negative men and 1,861 partnerships from 558 self-perceived HIV-positive men. Within the partnerships, perceived HIV status of the partner was an important determinant of UAI (p < 0.001). Among HIV-negative men, perceived HIV discordance was negatively associated with receptive UAI compared with no or safe UAI (OR 0.57; 95 % CI 0.36-0.92); when the partners were more familiar with each other, the risk of receptive UAI was increased relative to no or safe anal intercourse. Among HIV-positive men, perceived HIV discordance was negatively associated with insertive UAI (OR 0.05; 95 % CI 0.03-0.08). Within partnerships, perceived HIV status of the partner was one of the strongest determinants of UAI among self-perceived HIV-negative and HIV-positive MSM, and discordant serostatus was negatively associated with UAI. The findings suggest that serosorting is one of the main strategies when engaging in UAI.

Siebeling L, Musoro JZ, Geskus RB, Zoller M, Muggensturm P, Frei A, Puhan MA, ter Riet G. 2014. Prediction of COPD-specific health-related quality of life in primary care COPD patients: a prospective cohort study. NPJ Prim Care Respir Med, 24 (1), pp. 14060. | Show Abstract | Read more

BACKGROUND: Health-related quality of life (HRQL) is an important patient-reported outcome for chronic obstructive pulmonary disease (COPD). AIM: We developed models predicting chronic respiratory questionnaire (CRQ) dyspnoea, fatigue, emotional function, mastery and overall HRQL at 6 and 24 months using predictors easily available in primary care. METHODS: We used the "least absolute shrinkage and selection operator" (lasso) method to build the models and assessed their predictive performance. RESULTS: were displayed using nomograms. RESULTS: For each domain-specific CRQ outcome, the corresponding score at baseline was the best predictor. Depending on the domain, these predictions could be improved by adding one to six other predictors, such as the other domain-specific CRQ scores, health status and depression score. To predict overall HRQL, fatigue and dyspnoea scores were the best predictors. Predicted and observed values were on average the same, indicating good calibration. Explained variance ranged from 0.23 to 0.58, indicating good discrimination. CONCLUSIONS: To predict COPD-specific HRQL in primary care COPD patients, previous HRQL was the best predictor in our models. Asking patients explicitly about dyspnoea, fatigue, depression and how they cope with COPD provides additional important information about future HRQL whereas FEV1 or other commonly used predictors add little to the prediction of HRQL.

Vanhommerig JW, Stolte IG, Lambers FAE, Geskus RB, van de Laar TJW, Bruisten SM, Schinkel J, Prins M. 2014. Stabilizing incidence of hepatitis C virus infection among men who have sex with men in Amsterdam. J Acquir Immune Defic Syndr, 66 (5), pp. e111-e115. | Read more

Urbanus AT, Van De Laar TJW, Geskus R, Vanhommerig JW, Van Rooijen MS, Schinkel J, Heijman T, Coutinho RA, Prins M. 2014. Trends in hepatitis C virus infections among MSM attending a sexually transmitted infection clinic; 1995-2010. AIDS, 28 (5), pp. 781-790. | Show Abstract | Read more

BACKGROUND: Since 2000, there is growing evidence that hepatitis C virus (HCV) infection has emerged as a sexually transmitted infection (STI) among HIV-positive MSM. Here, we present a 15-year overview of the HCV epidemic among MSM visiting a large STI-clinic in the Netherlands. METHODS: During biannual cross-sectional anonymous surveys (1995-2010), participants were interviewed and tested for HIV and HCV-antibodies. Additional HCV RNA tests were performed in all HIV-positives. Determinants of HCV infection were analysed using logistic regression. Phylogenetic analysis provided evidence for sexual transmission. RESULTS: HCV prevalence among HIV-positive MSM increased from 1995 onwards (5.6%) and peaked in 2008 (20.9%). Prevalent HCV infection was more strongly associated with fisting in 2007-2008 [adjusted odds ratio (aOR) 2.85, 95% confidence interval (CI) 1.19-6.82] than in 2009-2010 (aOR 0.92, 95% CI0.42-2.02). In addition, HCV infection was independently associated with Chlamydia, injecting drug use, unprotected anal intercourse and older age. Phylogenetic analysis revealed a high degree of MSM-specific clustering from 2000 onwards. Identification of a new MSM-specific HCV lineage and the finding of recent HCV infections (0-4%) in established HCV clusters during recent years argue for ongoing transmission of HCV among HIV-positive MSM. HCV prevalence among HIV-negative MSM remained low (2007-2010: 0.5%). CONCLUSION: HCV prevalence among HIV-positive MSM significantly increased over calendar time but appears to level off in recent years, possibly due to increased awareness, saturation in the population, decreased risk behaviour and earlier HCV screening and treatment. The association with fisting became less strong over time, but our analyses continue to support sexual transmission. Monitoring HIV-positive and HIV-negative MSM for HCV infection remains needed to guide prevention efforts.

Geskus RB. 2014. Which individuals make dropout informative? Stat Methods Med Res, 23 (1), pp. 91-106. | Show Abstract | Read more

Markers are internal host factors that measure the current disease or recovery status of an individual. Individuals with more advanced disease progression are more likely to drop out, e.g. because they die. Marker data after dropout are missing. Such missingness is certainly not completely at random. A mixed effects model can be used if missingness of the marker data depends on measured marker values only (missing at random). If missingness is not at random, such models yield biased results. We describe various approaches that jointly model the marker development and dropout risk and may eliminate bias. One example of such a model is a random effects selection model. Based on a real data set with frequent follow-up, we compare results from a random effects model and a random effects selection model. Results are remarkably similar. In a simulation study, we investigate how the bias in the parameter estimates from a random effects model depends on the frequency of measurements and the time between the last measurement and the dropout or censoring time. Results from the simulation study confirm that the bias is small if follow-up is frequent.

van der Helm JJ, Geskus R, Lodi S, Meyer L, Schuitemaker H, Gunsenheimer-Bartmeyer B, Monforte AD, Olson A, Touloumi G, Sabin C et al. 2014. Characterisation of long-term non-progression of HIV-1 infection after seroconversion: a cohort study. Lancet HIV, 1 (1), pp. e41-e48. | Show Abstract | Read more

BACKGROUND: Some individuals remain AIDS-free with a high and stable CD4 cell count without antiretroviral therapy (ART) for many years. We estimated long-term progression-free survival after HIV seroconversion and aimed to identify factors associated with loss of long-term non-progression (LTNP) status. METHODS: For this cohort study, we used data for individuals with well-estimated dates of HIV-1 seroconversion from the CASCADE Collaboration a network of 28 HIV seroconverter cohort studies in Europe, Australia, Canada, and sub-Saharan Africa. The first cohort began enrolling patients in 1979, and for this analysis we used data pooled in May 1, 2011. We defined non-progression as being HIV-positive without AIDS, ART-naive, and with CD4 counts of 500 cells per μL or higher. We defined LTNP as non-progression during the first 10 years after seroconversion. We used longitudinal methods to characterise LTNP. FINDINGS: Of the 4979 HIV seroconverters in our dataset, 3708 (75%) were men. Median time to progression was 2·07 years (95% CI 1·96-2·17), giving estimated progression-free survivals of 18·4% (17·2-19·6) 5 years, 4·0% (3·6-4·5) 10 years, and 1·4% (0·9-1·5) 15 years after seroconversion. The rate of progression did not change beyond 10 years after seroconversion (0·28 [95%CI 0·26-0·31] per person-year at 10 years after seroconversion, 0·24 [0·19-0·29] per person-year at 15 years, and 0·18 [0·10-0·33] per person-year at 20 years). At 10 years since HIV seroconversion, 283 individuals had LTNP, of whom 202 subsequently lost this status (median time to loss of status 2·49 years [2·05-2·92]). In univariable analyses, loss of LTNP status was associated with CD4 cell count at 10 years after seroconversion (p < 0·0001) and HIV RNA load at 10 years after seroconversion (p = 0·005), but not age (p = 0·544), mode of infection (p = 0·621), sex (p = 0·676), or calendar year of seroconversion (p = 0·397). In the multivariable analyses, loss of LTNP status was associated with lower CD4 counts at 10 years after seroconversion (p < 0·0001). After exclusion of CD4 cell counts from the model, higher HIV RNA load at 10 years after seroconversion was independently associated with loss of LTNP status (p = 0·009). INTERPRETATION: Progression-free survival is rare. Most individuals with LTNP eventually lose immunological and clinical control of HIV infection eventually. FUNDING: European Union Seventh Framework Programme.

van Geloven N, Geskus RB, Mol BW, Zwinderman AH. 2014. Correcting for the dependent competing risk of treatment using inverse probability of censoring weighting and copulas in the estimation of natural conception chances. Stat Med, 33 (26), pp. 4671-4680. | Show Abstract | Read more

When estimating the probability of natural conception from observational data on couples with an unfulfilled child wish, the start of assisted reproductive therapy (ART) is a competing event that cannot be assumed to be independent of natural conception. In clinical practice, interest lies in the probability of natural conception in the absence of ART, as this probability determines the need for therapy. We thus want to estimate the marginal cumulative pregnancy distribution. Without assumptions on the dependence structure between the two competing events, this marginal distribution is not identifiable. We first use inverse probability of censoring weighting assuming that the factors influencing the choice to start ART are known. Then, we parameterize the event distributions for conception and for start of ART and use copulas to account for the dependency between both events. By using these two ways of correcting for the dependent risk of treatment, we obtain a plausible estimation region for the cumulative pregnancy curve and for the prognostic effect of tubal tests.

Vanhommerig JW, Thomas XV, van der Meer JTM, Geskus RB, Bruisten SM, Molenkamp R, Prins M, Schinkel J, MOSAIC (MSM Observational Study for Acute Infection with hepatitis C) Study Group. 2014. Hepatitis C virus (HCV) antibody dynamics following acute HCV infection and reinfection among HIV-infected men who have sex with men. Clin Infect Dis, 59 (12), pp. 1678-1685. | Show Abstract | Read more

BACKGROUND: A decline of hepatitis C virus (HCV) antibody titers (anti-HCV), ultimately resulting in seroreversion, has been reported following clearance of viremia in both acute and chronic HCV infection. However, frequency of seroreversion remains unknown in human immunodeficiency virus (HIV)/HCV-coinfected patients. We describe anti-HCV dynamics among HIV-infected men who have sex with men (MSM) following acute HCV infection and reinfection. METHODS: Primary acute HCV infection was assumed when a subject was anti-HCV negative prior to the first positive HCV RNA test. Anti-HCV was measured at least annually in 63 HIV-infected MSM, with a median follow-up of 4.0 years (interquartile range [IQR], 2.5-5.7 years). Time from HCV infection to seroconversion, and from seroconversion to seroreversion, was estimated using the Kaplan-Meier method. Longitudinal anti-HCV patterns were studied using a random-effects model to adjust for repeated measures. RESULTS: Median time from HCV infection to seroconversion was 74 days (IQR, 47-125 days). Subjects who cleared HCV RNA (n = 36) showed a significant decrease in anti-HCV levels (P < .001). Among 31 subjects with sustained virologic response (SVR), anti-HCV became undetectable during follow-up in 8; cumulative incidence of seroreversion within 3 years after seroconversion was 37% (95% confidence interval, 18%-66%). Eighteen subjects became reinfected during follow-up; this coincided with a subsequent increase in anti-HCV reactivity. CONCLUSIONS: A decline of anti-HCV reactivity was associated with HCV RNA clearance. Seroreversion was very common following SVR. Upon reinfection, anti-HCV levels increased again. Monitoring anti-HCV levels might therefore be an effective alternative for diagnosis of HCV reinfection.

Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M et al. 2014. Interferon lambda 3 genotype predicts hepatitis C virus RNA levels in early acute infection among people who inject drugs: the InC(3) study. J Clin Virol, 61 (3), pp. 430-434. | Show Abstract | Read more

BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) RNA level in acute HCV infection is predictive of spontaneous clearance. This study assessed factors associated with HCV RNA levels during early acute infection among people who inject drugs with well-defined acute HCV infection. STUDY DESIGN: Data were from International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study, an international collaboration of nine prospective cohorts studying acute HCV infection. Individuals with available HCV RNA levels during early acute infection (first two months following infection) were included. The distribution of HCV RNA levels during early acute infection were compared by selected host and virological factors. RESULTS: A total of 195 individuals were included. Median HCV RNA levels were significantly higher among individuals with interferon lambda 3 (IFNL3, formerly called IL28B) CC genotype compared to those with TT/CT genotype (6.28 vs. 5.39logIU/mL, respectively; P=0.01). IFNL3 CC genotype was also associated with top tertile HCV RNA levels (≥6.3log IU/mL; vs. TT/CT genotype; adjusted Odds Ratio: 4.28; 95%CI: 2.01, 9.10; P<0.01). CONCLUSIONS: This study indicates that IFNL3 CC genotype predicts higher HCV RNA levels in early acute HCV infection.

Matser A, Heiligenberg M, Geskus R, Heijman T, Low N, Kretzschmar M, van der Loeff MS. 2014. The importance of partnership factors and individual factors associated with absent or inconsistent condom use in heterosexuals: a cross-sectional study. Sex Transm Infect, 90 (4), pp. 325-331. | Show Abstract | Read more

OBJECTIVES: Decisions to use condoms are made within partnerships. We examined the associations between inconsistent or no condom use and individual and partnership characteristics. We also examined the relative importance of individual versus partnership factors. METHODS: Cross-sectional study of heterosexual individuals enrolled from the sexually transmitted infections (STI) outpatient clinic in Amsterdam, the Netherlands, from May to August 2010. Participants completed a questionnaire about sexual behaviour with the last four partners in the preceding year. Participant and partnership factors associated with inconsistent or no condom use in steady and casual partnerships were identified. RESULTS: 2144 individuals were included, reporting 6401 partnerships; 54.7% were female, the median age was 25 (IQR 22-30) years and 79.9% were Dutch. Inconsistent or no condom use occurred in 86.1% of 2387 steady partnerships and in 66.5% of 4014 casual partnerships. There was statistical evidence of associations between inconsistent condom use in steady partnerships and ethnic concordance, longer duration, higher number of sex acts, practising anal sex, and sex-related drug use. In casual partnerships, associations were found with having an older partner, ethnic concordance, longer duration, higher number of sex acts, anal sex, sex-related drug use, ongoing partnerships and concurrency. In multivariable models, partnership factors explained 50.9% of the variance in steady partnerships and 70.1% in casual partnerships compared with 10.5% and 15.4% respectively for individual factors. CONCLUSIONS: Among heterosexual STI clinic attendees in Amsterdam, partnership factors are more important factors related with inconsistent condom use than characteristics of the individual.

Musoro JZ, Zwinderman AH, Puhan MA, ter Riet G, Geskus RB. 2014. Validation of prediction models based on lasso regression with multiply imputed data. BMC Med Res Methodol, 14 (1), pp. 116. | Show Abstract | Read more

BACKGROUND: In prognostic studies, the lasso technique is attractive since it improves the quality of predictions by shrinking regression coefficients, compared to predictions based on a model fitted via unpenalized maximum likelihood. Since some coefficients are set to zero, parsimony is achieved as well. It is unclear whether the performance of a model fitted using the lasso still shows some optimism. Bootstrap methods have been advocated to quantify optimism and generalize model performance to new subjects. It is unclear how resampling should be performed in the presence of multiply imputed data. METHOD: The data were based on a cohort of Chronic Obstructive Pulmonary Disease patients. We constructed models to predict Chronic Respiratory Questionnaire dyspnea 6 months ahead. Optimism of the lasso model was investigated by comparing 4 approaches of handling multiply imputed data in the bootstrap procedure, using the study data and simulated data sets. In the first 3 approaches, data sets that had been completed via multiple imputation (MI) were resampled, while the fourth approach resampled the incomplete data set and then performed MI. RESULTS: The discriminative model performance of the lasso was optimistic. There was suboptimal calibration due to over-shrinkage. The estimate of optimism was sensitive to the choice of handling imputed data in the bootstrap resampling procedure. Resampling the completed data sets underestimates optimism, especially if, within a bootstrap step, selected individuals differ over the imputed data sets. Incorporating the MI procedure in the validation yields estimates of optimism that are closer to the true value, albeit slightly too larger. CONCLUSION: Performance of prognostic models constructed using the lasso technique can be optimistic as well. Results of the internal validation are sensitive to how bootstrap resampling is performed.

van Rijckevorsel G, Whelan J, Kretzschmar M, Siedenburg E, Sonder G, Geskus R, Coutinho R, van den Hoek A. 2013. Targeted vaccination programme successful in reducing acute hepatitis B in men having sex with men in Amsterdam, the Netherlands. J Hepatol, 59 (6), pp. 1177-1183. | Show Abstract | Read more

BACKGROUND & AIMS: In the Netherlands, transmission of hepatitis B virus occurs mainly within behavioural high-risk groups, such as in men who have sex with men. Therefore, a vaccination programme has targeted these high-risk groups. This study evaluates the impact of the vaccination programme targeting Amsterdam's large population of men who have sex with men from 1998 through 2011. METHODS: We used Amsterdam data from the national database of the vaccination programme for high-risk groups (January 1, 1998 to December 31, 2011). Programme and vaccination coverage were estimated with population statistics. Incidence of acute hepatitis B was analyzed with notification data from the Amsterdam Public Health Service (1992-2011). Mathematical modelling accounting for vaccination data and trends in sexual risk behaviour was used to explore the impact of the programme. RESULTS: At the end of 2011, programme coverage was estimated at 41% and vaccination coverage from 30% to 38%. Most participants (67%) were recruited from the outpatient department for sexually transmitted infections and outreach locations such as saunas and gay bars. Incidence of acute hepatitis B dropped sharply after 2005. The mathematical model in which those who engage most in high-risk sex are vaccinated, best explained the decline in incidence. CONCLUSIONS: Transmission of hepatitis B virus among Amsterdam's men who have sex with men has decreased, despite ongoing high-risk sexual behaviour. Vaccination programmes targeting men who have sex with men do not require full coverage; they may be effective when those who engage most in high-risk sex are reached.

Mulder RL, Knijnenburg SL, Geskus RB, van Dalen EC, van der Pal HJH, Koning CCE, Bouts AH, Caron HN, Kremer LCM. 2013. Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study. Cancer Epidemiol Biomarkers Prev, 22 (10), pp. 1736-1746. | Show Abstract | Read more

BACKGROUND: Impaired glomerular function is one of the health problems affecting childhood cancer survivors (CCS). It is unclear whether glomerular function deteriorates or recovers. We investigated time trends and predictors of glomerular function in CCS. METHODS: We evaluated repeated observations of estimated glomerular filtration rate (GFR) and glomerular dysfunction (GFR <90 mL/min/1.73 m(2)) among adult five-year CCS treated in the EKZ/AMC between 1966 and 2003. Ifosfamide, cisplatin, carboplatin, high-dose (HD) methotrexate, HD-cyclophosphamide, radiotherapy to the kidney region, and nephrectomy (i.e., potentially nephrotoxic therapy) were investigated as predictors of glomerular function patterns over time in multivariable longitudinal analyses. RESULTS: At a median follow-up of 21 years after diagnosis, glomerular function was assessed in 1,122 CCS aged ≥18 years. CCS treated with potentially nephrotoxic therapy had a significantly lower GFR and higher glomerular dysfunction probability up to 35 years after cancer diagnosis compared with CCS treated without nephrotoxic therapy (P < 0.001). Especially ifosfamide, cisplatin, and nephrectomy were associated with worse glomerular function that persisted during the entire follow-up period (P < 0.001). Glomerular function deteriorated over time in all CCS (P < 0.001). CCS treated with higher doses of cisplatin seem to have a higher deterioration rate as compared with other CCS (P < 0.005). CONCLUSIONS: The loss in glomerular function starts early, especially for CCS treated with ifosfamide, higher doses of cisplatin, and nephrectomy, and seems to be persistent. We have an indication that CCS treated with higher doses of cisplatin experience faster decline than other CCS. IMPACT: As glomerular function continues to deteriorate, CCS are at risk for premature chronic renal failure.

Matser A, Luu N, Geskus R, Heijman T, Heiligenberg M, van Veen M, Schim van der Loeff M. 2013. Higher Chlamydia trachomatis prevalence in ethnic minorities does not always reflect higher sexual risk behaviour. PLoS One, 8 (6), pp. e67287. | Show Abstract | Read more

BACKGROUND: In affluent countries, the prevalence of Chlamydia trachomatis (CT) is often higher in certain ethnic minorities than in the majority population. In The Netherlands, we examined why CT prevalence is higher in Surinamese/Antilleans, the largest minority in the country. METHODS: Heterosexuals were recruited for a cross-sectional survey from May through August 2010 at the sexually transmitted infections (STI) clinic in Amsterdam. Participants completed a questionnaire and were tested for STI. A causal directed acyclic graph was assumed to investigate whether the association between ethnicity and CT could be explained by differences in sexual risk behaviour and socio-economic status. RESULTS: Subjects included 1044 with Dutch background and 335 with Surinamese/Antillean background. Median age for the combined population was 25 (IQR 22-30) years, and 55.4% was female. Sexual risk behaviour did not differ significantly between the two groups. CT was diagnosed in 17.9% of Surinamese/Antilleans and in 11.4% of Dutch. Surinamese/Antilleans were significantly more likely to have CT (OR 1.70; 95% CI 1.21-2.38). The association between ethnicity and CT remained statistically significant after adjusting for sexual risk behaviour, age, sex, and ethnic mixing (aOR 1.48; 95% CI 1.00-2.18), but not after adjusting for education and neighbourhood, markers of socio-economic status (aOR 1.08; 95% CI 0.71-1.64). CONCLUSION: The difference in CT prevalence between the minority and majority groups was not explained by differences in sexual risk behaviour. The higher CT prevalence found among Surinamese/Antilleans appeared to reflect their lower educational level and neighbourhood, two markers of lower socio-economic status. We hypothesise that the effect results from lower health-seeking behaviour.

Gras L, Geskus RB, Jurriaans S, Bakker M, van Sighem A, Bezemer D, Fraser C, Prins JM, Berkhout B, de Wolf F, ATHENA National Observational Cohort. 2013. Has the rate of CD4 cell count decline before initiation of antiretroviral therapy changed over the course of the Dutch HIV epidemic among MSM? PLoS One, 8 (5), pp. e64437. | Show Abstract | Read more

INTRODUCTION: Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline. METHODS: Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART, <100 CD4 cells/mm³, or AIDS) among therapy-naïve MSM HIV-1 seroconverters in the Netherlands. These models make different assumptions about the censoring process. RESULTS: All 3 models estimated lower median CD4 cell counts 9 months after seroconversion in later calendar years (623, 582, and 541 cells/mm³ for 1984-1995 [n = 111], 1996-2002 [n = 139], and 2003-2007 seroconverters [n = 356], respectively, shared-parameter model). Only the 2 joint-models found a trend for a steeper decline of CD4 cell counts with seroconversion in later calendar years (overall p-values 0.002 and 0.06 for the pattern-mixture and the shared-parameter model, respectively). In the shared-parameter model the median decline from 9 to 48 months was 276 cellsmm³ for 1984-1995 seroconverters and 308 cells/mm³ for 2003-2007 seroconverters (difference in slope, p = 0.045). CONCLUSION: Mixed-effects models underestimate the CD4 cell decline prior to starting ART. Joint-models suggest that CD4 cell count declines more rapidly in patients infected between 2003 and 2007 compared to patients infected before 1996.

del Amo J, González C, Geskus RB, Torres M, Del Romero J, Viciana P, Masiá M, Blanco JR, Hernández-Novoa B, Ortiz M, CoRIS-HPV Study Group. 2013. What drives the number of high-risk human papillomavirus types in the anal canal in HIV-positive men who have sex with men? J Infect Dis, 207 (8), pp. 1235-1241. | Show Abstract | Read more

We estimated the effect of sexual behavior, age, and immunodeficiency on the number of high-risk human papillomavirus (HR-HPV) types in the anal canal among human immunodeficiency virus-positive men who have sex with men (MSM). Anal samples were genotyped with the Linear Array HPV Genotyping Test, and risk factors were investigated with Poisson regression. Of 586 MSM, 69% were Spanish, and 25.6% were Latin American; the median age was 34.9 years (interquartile range [IQR], 30.1-40.8). The median number of recent sex partners was 6 (IQR, 2-24 sex partners), and the median CD4(+) T-cell count was 531.5 cells/mm(3) (IQR, 403-701 cells/mm(3)). The prevalence of any and multiple HR-HPV infections was 83.4% and 60.5%, respectively. The most common types were HPV-16 (42%), HPV-51 (24%), HPV-39 (23.7%), and HPV-59 (23.5%). Age had a statistically significant, nonlinear association with the number of types, with the highest number detected around 35 years of age (P < .001). The number of recent sex partners had a statistically significant, fairly linear association on the log scale (P = .033). The high prevalence of HR-HPV types is associated with recent sexual behavior and age.

Matser A, Vanhommerig J, Schim van der Loeff MF, Geskus RB, de Vries HJC, Prins JM, Prins M, Bruisten SM. 2013. Correction: HIV-Infected Men Who Have Sex with Men Who Identify Themselves as Belonging to Subcultures Are at Increased Risk for Hepatitis C Infection PLoS ONE, 8 (4), | Read more

van der Helm J, Geskus R, Sabin C, Meyer L, Del Amo J, Chêne G, Dorrucci M, Muga R, Porter K, Prins M, CASCADE Collaboration in EuroCoord. 2013. Effect of HCV infection on cause-specific mortality after HIV seroconversion, before and after 1997. Gastroenterology, 144 (4), pp. 751-760.e2. | Show Abstract | Read more

BACKGROUND & AIMS: Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the duration of HIV infection. METHODS: We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural. RESULTS: Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease. CONCLUSIONS: Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression.

Kroon MW, Vrijman C, Chandeck C, Wind BS, Wolkerstorfer A, Luiten RM, Bos JD, Geskus RB, van Trotsenburg P, van der Veen JPW. 2013. High prevalence of autoimmune thyroiditis in children and adolescents with vitiligo. Horm Res Paediatr, 79 (3), pp. 137-144. | Show Abstract | Read more

BACKGROUND/AIMS: Vitiligo is considered to be an autoimmune disease and is known to be associated with other autoimmune diseases, particularly affecting the thyroid. In children and adolescents this association has been reported in only a few studies, with varying results. The aim of this study was to examine thyroid function and prevalence of thyroid autoimmunity in children and adolescents with vitiligo and to investigate the utility of screening. METHODS: Two hundred and sixty patients with vitiligo were enrolled. Plasma TSH, FT4 and anti-thyroid peroxidase (TPO) antibody concentrations were measured. The prevalence of thyroid dysfunction and autoimmunity were compared to the general healthy paediatric population. RESULTS: Autoimmune thyroiditis (AIT) with thyroid hormone disturbances was diagnosed in 16 patients (6.2%). This is significantly higher than the prevalence reported in the general healthy paediatric population. Increased levels of anti-TPO antibodies (= 30 kU/l), without thyroid hormone disturbances, were found in 27 patients (10.5%). CONCLUSION: The prevalence of AIT in children and adolescents with vitiligo is significantly higher than in the general population. It may be advantageous to screen thyroid function and antibody levels in all paediatric patients with non-segmental vitiligo. To strengthen recommendations on screening, research on the burden for patients and cost-effectiveness is needed.

van der Knaap N, Grady BPX, Schim van der Loeff MF, Heijman T, Speksnijder A, Geskus R, Prins M. 2013. Drug users in Amsterdam: are they still at risk for HIV? PLoS One, 8 (3), pp. e59125. | Show Abstract | Read more

BACKGROUND AND AIMS: To examine whether drug users (DU) in the Amsterdam Cohort Study (ACS) are still at risk for HIV, we studied trends in HIV incidence and injecting and sexual risk behaviour from 1986 to 2011. METHODS: The ACS is an open, prospective cohort study on HIV. Calendar time trends in HIV incidence were modelled using Poisson regression. Trends in risk behaviour were modelled via generalized estimating equations. In 2010, a screening for STI (chlamydia, gonorrhoea and syphilis) was performed. Determinants of unprotected sex were studied using logistic regression analysis. RESULTS: The HIV incidence among 1298 participants of the ACS with a total follow-up of 12,921 person-years (PY) declined from 6.0/100 PY (95% confidence interval [CI] 3.2-11.1) in 1986 to less than 1/100 PY from 1997 onwards. Both injection and sexual risk behaviour declined significantly over time. Out of 197 participants screened for STI in 2010-2011, median age 49 years (IQR 43-59), only 5 (2.5%) were diagnosed with an STI. In multivariable analysis, having a steady partner (aOR 4.1, 95% CI 1.6-10.5) was associated with unprotected sex. HIV-infected participants were less likely to report unprotected sex (aOR 0.07, 95% CI 0.02-0.37). CONCLUSIONS: HIV incidence and injection risk behaviour declined from 1986 onwards. STI prevalence is low; unprotected sex is associated with steady partners and is less common among HIV-infected participants. These findings indicate a low transmission risk of HIV and STI, which suggests that DU do not play a significant role in the current spread of HIV in Amsterdam.

Noordik E, van der Klink JJ, Geskus RB, de Boer MR, van Dijk FJH, Nieuwenhuijsen K. 2013. Effectiveness of an exposure-based return-to-work program for workers on sick leave due to common mental disorders: a cluster-randomized controlled trial. Scand J Work Environ Health, 39 (2), pp. 144-154. | Show Abstract | Read more

OBJECTIVES: In case of long-term sick leave, gradually increasing workload appears to be an effective component of work-directed interventions to reduce sick leave due to common mental disorders (CMD). CMD are defined as stress-related, adjustment, anxiety, or depressive disorders. We developed an exposure-based return-to-work (RTW-E) intervention and evaluated the effect on time-to-full return to work (RTW) among workers who were on sick leave due to CMD in comparison to those treated with care-as-usual (CAU). CAU is guideline-directed and consists of problem-solving strategies and graded activities. METHODS: Using a two-armed cluster-randomized trial, we randomized 56 occupational physicians (OP). Of these, 35 OP treated 160 workers at the start of their sick leave; 75 workers received RTW-E and 85 workers received CAU. These workers were followed over a 12-month follow-up period. The time-to-full RTW lasting ≥28 days without recurrence was the primary outcome measure. To evaluate differences between groups, we used intention-to-treat and multilevel Cox's regression analysis. RESULTS: The median time-to-full RTW differed significantly between groups [hazard ratio (HR) 0.55; 95% confidence interval (95% CI) 0.33-0.89]. The workers receiving RTW-E (209 days; 95% CI 62-256) had a prolonged time-to-full RTW compared to workers receiving CAU (153 days; 95% CI 128-178). CONCLUSIONS: Workers on sick leave due to CMD treated with RTW-E showed a prolonged time-to-full RTW compared to those treated with CAU. We recommend that OP do not apply RTW-E but continue counseling workers on sick leave due to CMD according to CAU.

Matser A, Vanhommerig J, Schim van der Loeff MF, Geskus RB, de Vries HJC, Prins JM, Prins M, Bruisten SM. 2013. HIV-infected men who have sex with men who identify themselves as belonging to subcultures are at increased risk for hepatitis C infection. PLoS One, 8 (3), pp. e57740. | Show Abstract | Read more

BACKGROUND: Hepatitis C virus (HCV) emerged as sexually transmitted infection among HIV-infected men who have sex with men (MSM). We studied whether HCV circulated in identifiable high-risk MSM subcultures and performed phylogenetic analysis. METHODS: HIV-infected MSM were recruited at the sexually transmitted infections (STI) outpatient clinic and a university HIV clinic in Amsterdam, the Netherlands, 2008-2009. Participants completed a detailed questionnaire and were tested for HCV antibodies and RNA, with NS5B regions sequenced for analysis of clusters. RESULTS: Among 786 participants, the median age was 43 (IQR 37-48) years, and 93 (11.8%) were HCV-positive. Seropositivity was associated with belonging to subcultures identified as leather (aOR 2.60; 95% CI 1.56-4.33), rubber/lycra (aOR 2.15; 95% CI 1.10-4.21), or jeans (aOR 2.23; 95% CI 1.41-3.54). The two largest HCV-RNA monophyletic clusters were compared; MSM in cluster I (genotype 1a, n = 13) reported more partners (P = 0.037) than MSM in cluster II (genotype 4d, n = 14), but demographics, subculture characteristics and other risk behaviors did not differ significantly between the two clusters. DISCUSSION: HCV infection is associated with identifiable groups of leather/rubber/lycra/jeans subcultures among HIV-infected MSM. Separate epidemiological HCV transmission networks were not revealed. Active HCV screening and treatment within specific subcultures may reduce HCV spread among all MSM.

Sobrino-Vegas P, Pérez-Hoyos S, Geskus R, Padilla B, Segura F, Rubio R, Del Romero J, Santos J, Moreno S, Del Amo J. 2012. Imputation of the Date of HIV Seroconversion in a Cohort of Seroprevalent Subjects: Implications for Analysis of Late HIV Diagnosis. AIDS Res Treat, 2012 pp. 725412. | Show Abstract | Read more

Objectives. Since subjects may have been diagnosed before cohort entry, analysis of late HIV diagnosis (LD) is usually restricted to the newly diagnosed. We estimate the magnitude and risk factors of LD in a cohort of seroprevalent individuals by imputing seroconversion dates. Methods. Multicenter cohort of HIV-positive subjects who were treatment naive at entry, in Spain, 2004-2008. Multiple-imputation techniques were used. Subjects with times to HIV diagnosis longer than 4.19 years were considered LD. Results. Median time to HIV diagnosis was 2.8 years in the whole cohort of 3,667 subjects. Factors significantly associated with LD were: male sex; Sub-Saharan African, Latin-American origin compared to Spaniards; and older age. In 2,928 newly diagnosed subjects, median time to diagnosis was 3.3 years, and LD was more common in injecting drug users. Conclusions. Estimates of the magnitude and risk factors of LD for the whole cohort differ from those obtained for new HIV diagnoses.

van der Mark LB, Lyklema PHE, Geskus RB, Mohrs J, Bindels PJE, van Aalderen WMC, Ter Riet G. 2012. A systematic review with attempted network meta-analysis of asthma therapy recommended for five to eighteen year olds in GINA steps three and four. BMC Pulm Med, 12 (1), pp. 63. | Show Abstract | Read more

BACKGROUND: The recommendations for the treatment of moderate persistent asthma in the Global Initiative for Asthma (GINA) guidelines for paediatric asthma are mainly based on scientific evidence extrapolated from studies in adults or on consensus. Furthermore, clinical decision-making would benefit from formal ranking of treatments in terms of effectiveness.Our objective is to assess all randomized trial-based evidence specifically pertaining to 5-18 year olds with moderate persistent asthma. Rank the different drug treatments of GINA guideline steps 3&4 in terms of effectiveness. METHODS: Systematic review with network meta-analysis. After a comprehensive search in Central, Medline, Embase, CINAHL and the WHO search portal two reviewers selected RCTs performed in 4,129 children from 5-18 year old, with moderate persistent asthma comparing any GINA step 3&4 medication options. Further quality was assessed according the Cochrane Collaboration's tool and data-extracted included papers and built a network of the trials. Attempt at ranking treatments with formal statistical methods employing direct and indirect (e.g. through placebo) connections between all treatments. RESULTS: 8,175 references were screened; 23 randomized trials (RCT), comparing head-to-head (n=17) or against placebo (n=10), met the inclusion criteria. Except for theophylline as add-on therapy in step 4, a closed network allowed all comparisons to be made, either directly or indirectly. Huge variation in, and incomplete reporting of, outcome measurements across RCTs precluded assessment of relative efficacies. CONCLUSION: Evidence-based ranking of effectiveness of drug treatments in GINA steps 3&4 is not possible yet. Existing initiatives for harmonization of outcome measurements in asthma trials need urgent implementation.

van der Gaag NA, Kloek JJ, de Bakker JK, Musters B, Geskus RB, Busch ORC, Bosma A, Gouma DJ, van Gulik TM. 2012. Survival analysis and prognostic nomogram for patients undergoing resection of extrahepatic cholangiocarcinoma. Ann Oncol, 23 (10), pp. 2642-2649. | Show Abstract | Read more

BACKGROUND: Tumor location of extrahepatic cholangiocarcinoma (CCA) might influence survival after resection. METHODS: A consecutive series of 175 patients who had undergone a potentially curative resection of extrahepatic CCA was analyzed. We calculated concordance indices of different constructed prognostic models for survival including TNM (tumour-node-metastasis) staging and developed a nomogram of the most sensitive model. RESULTS: Overall cancer-specific survival rates were 83%, 58%, and 26% at 1, 2, and 5 years, respectively. Cancer-specific survival according to location was 42% for proximal, 23% for mid, and 19% for distal CCA after 5 years. Tumor location was not an independent significant predictor (P = 0.06). A prognostic model using all potential prognostic variables predicted survival better compared with TNM staging (concordance index 0.65 versus 0.63). A reduced model containing only lymph node status, microscopically residual tumor status, and tumor differentiation grade, also outperformed TNM staging (concordance index 0.66). CONCLUSIONS: Tumor location of extrahepatic CCA does not independently predict cancer-specific survival after resection. We developed a nomogram, based on a prognostic model with lymph node status, microscopically residual tumor status of resection margins, and tumor differentiation grade, that predicted survival better than TNM staging.

Zugna D, Geskus RB, De Stavola B, Rosinska M, Bartmeyer B, Boufassa F, Chaix M-L, Babiker A, Porter K, CASCADE Collaboration in EuroCoord. 2012. Time to virological failure, treatment change and interruption for individuals treated within 12 months of HIV seroconversion and in chronic infection. Antivir Ther, 17 (6), pp. 1039-1048. | Show Abstract | Read more

BACKGROUND: Estimates of treatment failure, change and interruption are lacking for individuals treated in early HIV infection. METHODS: Using CASCADE data, we compared the effect of treatment in early infection (within 12 months of seroconversion) with that seen in chronic infection on risk of virological failure, change and interruption. Failure was defined as two subsequent measures of HIV RNA>1,000 copies/ml following suppression (<500 copies/ml), or >500 copies/ml 6 months following initiation. Treatment change and interruption were defined as modification or interruption lasting >1 week. In multivariable competing risks proportional subdistribution hazards models, we adjusted for combination antiretroviral therapy (cART) class, sex, risk group, age, CD4(+) T-cell count, HIV RNA and calendar period at treatment initiation. RESULTS: Of 1,627 individuals initiating cART early (median 1.8 months from seroconversion), 159, 395 and 692 failed, changed and interrupted therapy, respectively. For 2,710 individuals initiating cART in chronic infection (median 35.9 months from seroconversion), the corresponding values were 266, 569 and 597. Adjusted hazard ratios (HRs; 95% CIs) for treatment failure and change were similar between the two treatment groups (0.93 [0.72, 1.20] and 1.06 [0.91, 1.24], respectively). There was an increasing trend in rates of interruption over calendar time for those treated early, and a decreasing trend for those starting treatment in chronic infection. Consequently, compared with chronic infection, treatment interruption was similar for early starters in the early cART period, but the relative hazard increased over calendar time (1.54 [1.33, 1.79] in 2000). CONCLUSIONS: Individuals initiating treatment in early HIV infection are more likely to interrupt treatment than those initiating later. However, rates of failure and treatment change were similar between the two groups.

Jonker FAM, Calis JCJ, van Hensbroek MB, Phiri K, Geskus RB, Brabin BJ, Leenstra T. 2012. Iron status predicts malaria risk in Malawian preschool children. PLoS One, 7 (8), pp. e42670. | Show Abstract | Read more

INTRODUCTION: Iron deficiency is highly prevalent in pre-school children in developing countries and an important health problem in sub-Saharan Africa. A debate exists on the possible protective effect of iron deficiency against malaria and other infections; yet consensus is lacking due to limited data. Recent studies have focused on the risks of iron supplementation but the effect of an individual's iron status on malaria risk remains unclear. Studies of iron status in areas with a high burden of infections often are exposed to bias. The aim of this study was to assess the predictive value of baseline iron status for malaria risk explicitly taking potential biases into account. METHODS AND MATERIALS: We prospectively assessed the relationship between baseline iron deficiency (serum ferritin <30 µg/L) and malaria risk in a cohort of 727 Malawian preschool children during a year of follow-up. Data were analyzed using marginal structural Cox regression models and confounders were selected using causal graph theory. Sensitivity of results to bias resulting from misclassification of iron status by concurrent inflammation and to bias from unmeasured confounding were assessed using modern causal inference methods. RESULTS AND CONCLUSIONS: The overall incidence of malaria parasitemia and clinical malaria was 1.9 (95% CI 1.8-2.0) and 0.7 (95% CI 0.6-0.8) events per person-year, respectively. Children with iron deficiency at baseline had a lower incidence of malaria parasitemia and clinical malaria during a year of follow-up; adjusted hazard ratio's 0.55 (95%-CI:0.41-0.74) and 0.49 (95%-CI:0.33-0.73), respectively. Our results suggest that iron deficiency protects against malaria parasitemia and clinical malaria in young children. Therefore the clinical importance of treating iron deficiency in a pre-school child should be weighed carefully against potential harms. In malaria endemic areas treatment of iron deficiency in children requires sustained prevention of malaria.

Heymans R, A Matser A, Bruisten SM, Heijman T, Geskus RB, Speksnijder AGCL, Davidovich U, de Vries HJC, Coutinho RA, Schim van der Loeff MF. 2012. Distinct Neisseria gonorrhoeae transmission networks among men who have sex with men in Amsterdam, The Netherlands. J Infect Dis, 206 (4), pp. 596-605. | Show Abstract | Read more

BACKGROUND: Molecular typing was used to elucidate Neisseria gonorrhoeae transmission networks among men who have sex with men (MSM) in Amsterdam, the Netherlands. We determined whether clusters of patients infected with specific N. gonorrhoeae genotypes were related to various epidemiological characteristics. METHODS: MSM (age ≥18 years) visiting the sexually transmitted infections (STI) clinic between July 2008 and August 2009 were eligible. After STI screening, participants completed a behavioral questionnaire concerning the previous 6 months. N. gonorrhoeae cultures were genotyped using multiple-locus variable-number tandem repeat analysis typing. RESULTS: We obtained 278 N. gonorrhoeae-positive isolates from 240 MSM. Five large clusters (≥10 isolates), a unique sixth cluster (n = 9), and 8 smaller clusters (5-9 isolates) were identified. Prevalence of human immunodeficiency virus differed between clusters I and VI (P = .003), ranging from 27.8% to 100%. Receptive unprotected anal intercourse was frequently reported by MSM (51.8%) but did not differ significantly among clusters. Significant differences were identified concerning the participant's history of syphilis (P = .030), having met partners at a popular sex venue in Amsterdam (P = .048), and meeting partners outside Amsterdam (P = .036). CONCLUSIONS: Distinct N. gonorrhoeae transmission networks were present in a mixed high-risk MSM population; concordance between clusters and epidemiological characteristics was present but not marked.

Heuker J, Sonder G, Stolte I, Geskus R, van den Hoek A. 2012. HIV incidence among men who have sex with men prescribed postexposure prophylaxis AIDS, 26 (12), pp. 1583-1584. | Read more

Andersen PK, Geskus RB, de Witte T, Putter H. 2012. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol, 41 (3), pp. 861-870. | Show Abstract | Read more

BACKGROUND: In studies of all-cause mortality, the fundamental epidemiological concepts of rate and risk are connected through a well-defined one-to-one relation. An important consequence of this relation is that regression models such as the proportional hazards model that are defined through the hazard (the rate) immediately dictate how the covariates relate to the survival function (the risk). METHODS: This introductory paper reviews the concepts of rate and risk and their one-to-one relation in all-cause mortality studies and introduces the analogous concepts of rate and risk in the context of competing risks, the cause-specific hazard and the cause-specific cumulative incidence function. RESULTS: The key feature of competing risks is that the one-to-one correspondence between cause-specific hazard and cumulative incidence, between rate and risk, is lost. This fact has two important implications. First, the naïve Kaplan-Meier that takes the competing events as censored observations, is biased. Secondly, the way in which covariates are associated with the cause-specific hazards may not coincide with the way these covariates are associated with the cumulative incidence. An example with relapse and non-relapse mortality as competing risks in a stem cell transplantation study is used for illustration. CONCLUSION: The two implications of the loss of one-to-one correspondence between cause-specific hazard and cumulative incidence should be kept in mind when deciding on how to make inference in a competing risks situation.

Castro-Sánchez A, Shkedy Z, Hens N, Aerts M, Geskus R, Prins M, Wiessing L, Kretzschmar M. 2012. Estimating the force of infection for HCV in injecting drug users using interval-censored data. Epidemiol Infect, 140 (6), pp. 1064-1074. | Show Abstract | Read more

Injecting drug users (IDUs) account for most new HCV infections. The objectives of this study were: to estimate the force of infection for hepatitis C virus in IDUs within the interval-censoring framework and to determine the impact of risk factors such as frequency of injection, drug injected, sharing of syringes and time of first injection on the time to HCV infection. We used data from the Amsterdam Cohort Study collected in The Netherlands and focused on those individuals who were HCV negative upon entry into the study. Based on the results, the force of infection was found to vary with time of first injection. The risk of infection was higher in the first 3 years of an IDU's career, implying estimates based on single cross-sectional studies could be biased. Frequency of injection and type of drug injected were found to be highly significant predictors, whereas sharing syringes was not.

Sigaloff KCE, Hamers RL, Menke J, Labib M, Siwale M, Ive P, Botes ME, Kityo C, Mandaliya K, Wellington M et al. 2012. Early warning indicators for population-based monitoring of HIV drug resistance in 6 African countries. Clin Infect Dis, 54 Suppl 4 (suppl_4), pp. S294-S299. | Show Abstract | Read more

Human immunodeficiency virus (HIV) RNA testing and HIV drug resistance (HIVDR) testing are not routinely available for therapeutic monitoring of patients receiving antiretroviral therapy (ART) in resource-limited settings. World Health Organization HIVDR early warning indicators (EWIs) assess ART site factors known to favor the emergence of HIVDR. HIV drug resistance EWI monitoring was performed within the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) study, comprising 13 ART sites in 6 African countries. Early warning indicator assessment in the PASER network identified vulnerable aspects of ART programs and triggered interventions aimed at minimizing HIVDR emergence. Additionally, data suggest an advantage of medication possession ratio over on-time antiretroviral drug pickup in identifying patients at risk for HIVDR development.

van der Pal HJ, van Dalen EC, van Delden E, van Dijk IW, Kok WE, Geskus RB, Sieswerda E, Oldenburger F, Koning CC, van Leeuwen FE et al. 2012. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol, 30 (13), pp. 1429-1437. | Show Abstract | Read more

PURPOSE: To evaluate the long-term risk for validated symptomatic cardiac events (CEs) and associated risk factors in childhood cancer survivors (CCSs). PATIENTS AND METHODS: We determined CEs grade 3 or higher: congestive heart failure (CHF), cardiac ischemia, valvular disease, arrhythmia and/or pericarditis (according to Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) in a hospital-based cohort of 1,362 5-year CCSs diagnosed between 1966 and 1996. We calculated both marginal and cause-specific cumulative incidence of CEs and cause-specific cumulative incidence of separate events. We analyzed different risk factors in multivariable Cox regression models. RESULTS: Overall, 50 CEs, including 27 cases of CHF, were observed in 42 survivors (at a median attained age of 27.1 years). The 30-year cause-specific cumulative incidence of CEs was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3% to 20.3%), after anthracyclines (7.3%; 95% CI, 3.8% to 10.7%), and after cardiac irradiation (4.0%; 95% CI, 0.5% to 7.4%) compared with other treatments. In the proportional hazards analyses, anthracycline (dose), cardiac irradiation (dose), combination of these treatments, and congenital heart disease were significantly associated with developing a CE. We demonstrated an exponential relationship between the cumulative anthracycline dose, cardiac irradiation dose, and risk of CE. CONCLUSION: CCSs have a high risk of developing symptomatic CEs at an early age. The most common CE was CHF. Survivors treated with both anthracyclines and radiotherapy have the highest risk; after 30 years, one in eight will develop severe heart disease. The use of potentially cardiotoxic treatments should be reconsidered for high-risk groups, and frequent follow-up for high-risk survivors is needed.

Kramer A, Stel VS, Geskus RB, Tizard EJ, Verrina E, Schaefer F, Heaf JG, Kramar R, Krischock L, Leivestad T et al. 2012. The effect of timing of the first kidney transplantation on survival in children initiating renal replacement therapy. Nephrol Dial Transplant, 27 (3), pp. 1256-1264. | Show Abstract | Read more

BACKGROUND: Controversy exists concerning the timing of the first kidney transplantation for children who need to start renal replacement therapy (RRT). Our aim was to estimate the effect of timing of the first transplantation on patient survival in children, for the first time also taking into account the mortality on dialysis before transplantation. METHODS: We included 2091 patients who started RRT between the age of 3 and 18 years in the period 1988-2007, from 13 European renal registries. A multistate model was used to simulate patient survival assuming (i) pre-emptive transplantation, (ii) transplantation after 1 or 2 years on dialysis and (iii) remaining on dialysis. RESULTS: Over the 20-year period, the highest 8-year survival probabilities were achieved in children transplanted pre-emptively {living donor (LD): 95.9% [95% confidence interval (CI): 93.1-98.8], deceased donor (DD): 95.3% (95% CI: 90.9-99.9)} rather than after 2 years of dialysis [LD: 94.2% (95% CI: 91.6-96.8), DD: 93.4% (95% CI: 91.0-95.9)], although these differences were not statistically significant. CONCLUSIONS: Even after taking mortality on dialysis into account, the potentially negative effect of postponing transplantation for 1 or 2 years was relatively small and not statistically significant. Therefore, if pre-emptive transplantation is not possible, starting RRT with a short period of dialysis and receiving a transplant thereafter seems an acceptable alternative from the perspective of patient survival.

Bakker OJ, van Santvoort HC, van Brunschot S, Geskus RB, Besselink MG, Bollen TL, van Eijck CH, Fockens P, Hazebroek EJ, Nijmeijer RM et al. 2012. Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis: a randomized trial. JAMA, 307 (10), pp. 1053-1061. | Show Abstract | Read more

CONTEXT: Most patients with infected necrotizing pancreatitis require necrosectomy. Surgical necrosectomy induces a proinflammatory response and is associated with a high complication rate. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, may reduce the proinflammatory response and reduce complications. OBJECTIVE: To compare the proinflammatory response and clinical outcome of endoscopic transgastric and surgical necrosectomy. DESIGN, SETTING, AND PATIENTS: Randomized controlled assessor-blinded clinical trial in 3 academic hospitals and 1 regional teaching hospital in The Netherlands between August 20, 2008, and March 3, 2010. Patients had signs of infected necrotizing pancreatitis and an indication for intervention. INTERVENTIONS: Random allocation to endoscopic transgastric or surgical necrosectomy. Endoscopic necrosectomy consisted of transgastric puncture, balloon dilatation, retroperitoneal drainage, and necrosectomy. Surgical necrosectomy consisted of video-assisted retroperitoneal debridement or, if not feasible, laparotomy. MAIN OUTCOME MEASURES: The primary end point was the postprocedural proinflammatory response as measured by serum interleukin 6 (IL-6) levels. Secondary clinical end points included a predefined composite end point of major complications (new-onset multiple organ failure, intra-abdominal bleeding, enterocutaneous fistula, or pancreatic fistula) or death. RESULTS: We randomized 22 patients, 2 of whom did not undergo necrosectomy following percutaneous catheter drainage and could not be analyzed for the primary end point. Endoscopic transgastric necrosectomy reduced the postprocedural IL-6 levels compared with surgical necrosectomy (P = .004). The composite clinical end point occurred less often after endoscopic necrosectomy (20% vs 80%; risk difference [RD], 0.60; 95% CI, 0.16-0.80; P = .03). Endoscopic necrosectomy did not cause new-onset multiple organ failure (0% vs 50%, RD, 0.50; 95% CI, 0.12-0.76; P = .03) and reduced the number of pancreatic fistulas (10% vs 70%; RD, 0.60; 95% CI, 0.17-0.81; P = .02). CONCLUSION: In patients with infected necrotizing pancreatitis, endoscopic necrosectomy reduced the proinflammatory response as well as the composite clinical end point compared with surgical necrosectomy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN07091918.

Kroon MW, Joore ICKW, Wind BS, Leloup MAC, Wolkerstorfer A, Luiten RM, Bos JD, Geskus RB, van der Veen JPW. 2012. Low yield of routine screening for thyroid dysfunction in asymptomatic patients with vitiligo. Br J Dermatol, 166 (3), pp. 532-538. | Show Abstract | Read more

BACKGROUND: Nonsegmental vitiligo is considered to be an autoimmune disease and is known to be associated with other autoimmune diseases, particularly affecting the thyroid. Screening patients with nonsegmental vitiligo for thyroid function and for the presence of thyroid autoantibodies has been recommended. OBJECTIVE: To investigate the prevalence of thyroid dysfunction and thyroid peroxidase-specific (TPO) antibodies in a large cohort of patients with nonsegmental vitiligo in order to help decide whether routine screening is justified. METHODS: A total of 434 adults with nonsegmental vitiligo who were referred to our institute were enrolled. Thyroid function and anti-TPO antibody titres were assessed in those patients who had no history of thyroid disease or recent thyroid screening. RESULTS: Forty-three patients had already been diagnosed with thyroid dysfunction, and in 27 patients the general practitioner had performed a thyroid function test with negative results <3months previously. In these patients, thyroid function assessment was not repeated. The remaining 364 patients were screened for thyroid dysfunction. Overt hypothyroidism was newly diagnosed in three (0·8%) patients; subclinical disease was found in 10 (2·7%) patients and increased levels of TPO antibodies, without thyroid disease, were found in 49 (13·5%) patients. An elevated risk for thyroid disease was found among older women and in women with a positive family history of thyroid disease. CONCLUSION: The overall prevalence of thyroid dysfunction in adult patients with nonsegmental vitiligo was higher than reported in the general population. However, the number of newly diagnosed cases with overt and subclinical thyroid dysfunction in our population was low. Most patients had already been diagnosed by their general practitioner and had symptoms indicative for thyroid disease. Thyroid disease was found predominantly among older women and in subjects with a positive family history of thyroid disease. Thyroid screening including anti-TPO antibodies is advisable in these high-risk subpopulations.

Matser A, Urbanus A, Geskus R, Kretzschmar M, Xiridou M, Buster M, Coutinho R, Prins M. 2012. The effect of hepatitis C treatment and human immunodeficiency virus (HIV) co-infection on the disease burden of hepatitis C among injecting drug users in Amsterdam. Addiction, 107 (3), pp. 614-623. | Show Abstract | Read more

AIMS: The hepatitis C virus (HCV) disease burden among injecting drug users (IDUs) is determined by HCV incidence, the long latency period of HCV, competing mortality causes, presence of co-infection and HCV treatment uptake. We examined the effect of these factors and estimated the HCV disease burden in Amsterdam. DESIGN: A Markov model was developed, incorporating HCV and human immunodeficiency virus (HIV), and parameterized with data from the Amsterdam Cohort Studies, surveillance studies and literature. SETTING: IDU population of Amsterdam. MEASUREMENTS: HCV infection simulated from its acute phase to HCV-related liver disease (i.e. decompensated cirrhosis and hepatocellular carcinoma). FINDINGS: The HCV prevalence among IDUs in Amsterdam increased to approximately 80% in the 1980s. From 2011 to 2025, the HCV-related disease prevalence will accordingly rise by 36%, from 57 cases (95% range 33-94) to 78 (95% range 43-138), respectively. In total, 945 (95% range 617-1309) individuals will develop HCV-related liver disease. This burden would have been 33% higher in the absence of HIV, resulting in 1219 cases (95% range 796-1663). In Amsterdam, 25% of HIV-negative IDUs receive successful HCV treatment, reducing the cumulative disease burden by 14% to 810 (95% range 520-1120). Further reduction of 36% can be achieved by improving treatment, resulting in 603 cases (95% range 384-851). CONCLUSIONS: The hepatitis C virus burden among injecting drug users in Amsterdam has been reduced by a high competing mortality rate, particularly caused by HIV infection, and to a smaller extent by hepatitis C virus treatment. Improved hepatitis C virus treatment is expected to contribute to reduce the future hepatitis C virus disease burden.

Heuker J, Sonder GJB, Stolte I, Geskus R, van den Hoek A. 2012. High HIV incidence among MSM prescribed postexposure prophylaxis, 2000-2009: indications for ongoing sexual risk behaviour. AIDS, 26 (4), pp. 505-512. | Show Abstract | Read more

OBJECTIVE: To determine (trends in) HIV incidence among MSM\ who have recently had postexposure prophylaxis (PEP) prescribed in Amsterdam, compared with MSM participating in the Amsterdam Cohort Studies (ACS). DESIGN AND METHODS: We used data from MSM who were prescribed PEP in Amsterdam between 2000 and 2009, who were HIV-negative at the time of PEP prescription and had follow-up HIV testing 3 and/or 6 months after PEP prescription (n = 395). For comparison, cohort data from MSM participating in the ACS in the same period were used (n = 782). Poisson log-linear regression analyses were performed to model trends in HIV incidence and identify differences in HIV incidence between both cohorts at different time points. RESULTS: Between 2000 and 2009, among MSM who were prescribed PEP, an overall HIV incidence of 6.4 [95% confidence interval (CI) 3.4-11.2] per 100 person-years was found, compared with an HIV incidence of 1.6 (95% CI 1.3-2.1) per 100 person-years among MSM participating in the ACS (P < 0.01). In both cohorts, an increasing trend in HIV incidence over time was observed [incidence rate ratio (IRR(per calendar year)) 1.3 (95% CI 0.9-1.7) and 1.1 (95% CI 1.0-1.2) among MSM prescribed PEP and MSM of the ACS, respectively]. The difference in HIV incidence between both cohorts was most evident in more recent years [IRR(PEP versus ACS in 2009) 4.8 (95% CI 2.0-11.5)]. CONCLUSION: Particularly in more recent years, MSM recently prescribed PEP had a higher HIV incidence compared with MSM participating in the ACS, indicating ongoing sexual risk behaviour.

Heijman T, Geskus RB, Davidovich U, Coutinho RA, Prins M, Stolte IG. 2012. Less decrease in risk behaviour from pre-HIV to post-HIV seroconversion among MSM in the combination antiretroviral therapy era compared with the pre-combination antiretroviral therapy era. AIDS, 26 (4), pp. 489-495. | Show Abstract | Read more

OBJECTIVE: To gain insight in the ongoing HIV transmission, we compared sexual risk behaviour pre-HIV and post-HIV seroconversion in 206 MSM participating in the Amsterdam Cohort Studies (1984-2008) before and after the introduction of combination antiretroviral therapy (cART). DESIGN AND METHODS: MSM completed behavioural questionnaires and were tested for HIV antibodies every 6 months. Trends in anal intercourse and number of sex partners from 4 years before HIV seroconversion until 4 years after diagnosis were analysed with latent class random effects logistic regression models. RESULTS: The risk of having unprotected anal intercourse (UAI) 1 year after HIV diagnosis decreased significantly when compared with 1 year before diagnosis in both the pre-cART era [difference, 30%; 95% confidence interval (CI), 22-36%] and cART era (difference, 19%; 95% CI, 9-30%). In contrast to a continuing decrease of UAI in the pre-cART era, the probability of UAI in the cART era increased again to preseroconversion levels (61%; 95% CI, 48-74%)) 4 years after diagnosis. CONCLUSION: This study provides evidence that recently seroconverted MSM reduce their sexual risk behaviour following HIV diagnosis both in the pre-cART as well as the cART period. However, in the cART period this reduction in sexual risk behaviour is less and returns to pre-cART levels within 4 years. These findings not only confirm the need for early HIV testing but also make it clear that much more effort should go into identifying, counselling, and possibly treating recently seroconverted MSM who have been found to be one of the most important drivers of HIV transmission among MSM.

Eskes SA, Endert E, Fliers E, Geskus RB, Dullaart RPF, Links TP, Wiersinga WM. 2012. Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial. J Clin Endocrinol Metab, 97 (2), pp. 499-506. | Show Abstract | Read more

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) type 2 is self-limiting in nature, but most physicians are reluctant to continue amiodarone. When prednisone fails to restore euthyroidism, possibly due to mixed cases of AIT type 1 and 2, perchlorate (ClO(4)) might be useful because ClO(4) reduces the cytotoxic effect of amiodarone on thyrocytes. OBJECTIVES: Our objectives were to demonstrate the feasibility of continuation of amiodarone in AIT type 2 and to evaluate the usefulness of ClO(4) (given alone or in combination with prednisone) in AIT type 2. DESIGN AND SETTING: A randomized multicenter study was conducted in 10 Dutch hospitals. METHODS: Patients with AIT type 2 were randomized to receive prednisone 30 mg/d (group A, n = 12), sodium perchlorate 500 mg twice daily (group B, n = 14), or prednisone plus perchlorate (group C, n = 10); all patients continued amiodarone and were also treated with methimazole 30 mg/d. Follow-up was 2 yr. MAIN OUTCOME MEASURES: Treatment efficacy (defined as TSH values ≥ 0.4 mU/liter under continuation of amiodarone) and recurrent thyrotoxicosis were evaluated. RESULTS: Initial therapy was efficacious in 100, 71, and 100% of groups A, B, and C, respectively (P = 0.03). The 29% failures in group B became euthyroid after addition of prednisone. Neither the time to reach TSH of 0.4 mU/liter or higher [8 wk (4-20), 14 wk (4-32), and 12 wk (4-28) in groups A, B, and C respectively] nor the time to reach free T(4) of 25 pmol/liter or below [4 wk (4-20), 12 wk (4-20), and 8 wk (4-20) in groups A, B, and C) were significantly different between groups (values as median with range). Recurrent thyrotoxicosis occurred in 8.3%. CONCLUSION: Euthyroidism was reached despite continuation of amiodarone in all patients. Prednisone remains the preferred treatment modality of AIT type 2, because perchlorate given alone or in combination with prednisone had no better outcomes.

Jarrin I, Pantazis N, Gill MJ, Geskus R, Perez-Hoyos S, Meyer L, Prins M, Touloumi G, Johnson A, Hamouda O et al. 2012. Uptake of combination antiretroviral therapy and HIV disease progression according to geographical origin in seroconverters in Europe, Canada, and Australia. Clin Infect Dis, 54 (1), pp. 111-118. | Show Abstract | Read more

BACKGROUND: We examined differences by geographical origin (GO) in time from HIV seroconversion (SC) to AIDS, death, and initiation of antiretroviral therapy (cART). METHODS: Data from HIV seroconverter cohorts in Europe, Australia and Canada (CASCADE) was used; GO was classified as: western countries (WE), North Africa and Middle East (NAME), sub-Saharan Africa (SSA), Latin America (LA), and Asia (ASIA). Differences by GO were assessed using Cox models. Administrative censoring date was 30 June 2008. RESULTS: Of 16 941 seroconverters, 15 548 were from WE, 158 NAME, 762 SSA, 349 LA, and 124 ASIA. We found no differences by GO in risks of AIDS (P = .99) and death (P = .12), although seroconverters from NAME (adjusted hazard ratio [aHR]: 0.57; 95% CI: 0.33-.94) and SSA (aHR: 0.74; 95% CI: 0.50-1.10) appeared to have lower mortality than WE. Chances of initiating cART differed by GO (P < .001): seroconverters from SSA were more likely to initiate cART than WE (aHR: 1.48; 95% CI: 1.26-1.74), but not after adjustment for CD4 at SC (aHR: 1.11; 95% CI: 0.88-1.40). CONCLUSIONS: In settings with universal access to healthcare, GO does not play a major role in HIV disease progression.

Lodi S, Phillips A, Touloumi G, Geskus R, Meyer L, Thiébaut R, Pantazis N, Amo JD, Johnson AM, Babiker A et al. 2011. Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds <200, <350, and <500 Cells/mm³: assessment of need following changes in treatment guidelines. Clin Infect Dis, 53 (8), pp. 817-825. | Show Abstract | Read more

BACKGROUND: Recent updates of human immunodeficiency virus (HIV) treatment guidelines have raised the CD4+ cell count thresholds for antiretroviral therapy initiation from 350 to 500 cells/mm(3) in the United States and from 200 to 350 cells/mm³ in mid- and low-income countries. Robust data of time from HIV seroconversion to CD4+ cell counts of 200, 350, and 500 cells/mm³ are lacking but are needed to inform health care planners of the likely impact and cost effectiveness of these and possible future changes in CD4+ cell count initiation threshold. METHODS: Using Concerted Action on Seroconversion to AIDS and Death in Europe data from individuals with well-estimated dates of HIV seroconversion, we fitted mixed models on the square root of CD4+ cell counts measured before combined antiretroviral therapy (cART) initiation. Restricting analyses to adults (age >16 years), we predicted time between seroconversion and CD4+ cell count <200, <350, and <500 cells/mm³ as well as CD4+ cell count distribution and proportions reaching these thresholds at 1, 2, and 5 years after seroconversion. RESULTS: Median (interquartile range [IQR]) follow-up for the 18495 eligible individuals from seroconversion while cART-free was 3.7 years (1.5, 7). Most of the subjects were male (78%), had a median age at seroconversion of 30 years (IQR, 25-37 years), and were infected through sex between men (55%). Estimated median times (95% confidence interval [CI]) from seroconversion to CD4+ cell count <500, <350, and <200 cells/mm(3) were 1.19 (95% CI, 1.12-1.26), 4.19 (95% CI, 4.09-4.28), and 7.93 (95% CI, 7.76-8.09) years, respectively. Almost half of infected individuals would require treatment within 1 year of seroconversion for guidelines recommending its initiation at 500 cells/mm³, compared with 26% and 9% for guidelines recommending initiation at 350 and 200 cells/mm³, respectively. CONCLUSIONS: These data suggest substantial increases in the number of individuals who require treatment and call for early HIV testing.

van der Plas EM, van den Tweel XW, Geskus RB, Heijboer H, Biemond BJ, Peters M, Fijnvandraat K. 2011. Mortality and causes of death in children with sickle cell disease in the Netherlands, before the introduction of neonatal screening. Br J Haematol, 155 (1), pp. 106-110. | Show Abstract | Read more

This study analyzed the mortality and causes of death in sickle cell disease patients in the Netherlands, to provide a baseline for monitoring the effect of the recently introduced neonatal screening programme and to indicate areas of improvement in the care for these patients. All children (<18 years) diagnosed with sickle cell disease in a tertiary hospital from 1985 to 2007 were included. Vital status was determined up to March 2008. A total of 298 children were included: 189 (63%) patients had HbSS, 17 (6%) HbSβ(0) thalassaemia, 72 (24%) HbSC and 20 (7%) HbSβ(+) thalassaemia. Twelve patients (4%) died during a total follow-up of 3896 patient years. All known deaths were sickle cell disease-related. Meningitis/sepsis (n=4; 33%), stroke (n=3; 25%) and death during a visit to the country of origin (n=3; 25%) were the most common causes of death. The overall mortality rate was 0·27 deaths/100 patient years [95% confidence interval (CI): 0·15-0·43]. The estimated survival at the age of 18 years was 97·3% (95% CI: 95-99%). This report confirms that the burden of mortality in sickle cell disease is increasingly shifting to adults. It is recommended that compliance to antibiotic prophylaxis, thorough counselling and support for patients travelling abroad and specialized peri-operative care should receive continuous attention.

Baaten GG, Geskus RB, Kint JA, Roukens AHE, Sonder GJ, van den Hoek A. 2011. Symptoms of infectious diseases in immunocompromised travelers: a prospective study with matched controls. J Travel Med, 18 (5), pp. 318-326. | Show Abstract | Read more

BACKGROUND: Immunocompromised travelers to developing countries are thought to have symptomatic infectious diseases more often and longer than non-immunocompromised travelers. Evidence for this is lacking. This study evaluates whether immunocompromised short-term travelers are at increased risk of diseases. METHODS: A prospective study was performed between October 2003 and May 2010 among adult travelers using immunosuppressive agents (ISA) and travelers with inflammatory bowel disease (IBD), with their non-immunocompromised travel companions serving as matched controls with comparable exposure to infection. Data on symptoms of infectious diseases were recorded by using a structured diary. RESULTS: Among 75 ISA, the incidence of travel-related diarrhea was 0.76 per person-month, and the number of symptomatic days 1.32 per month. For their 75 controls, figures were 0.66 and 1.50, respectively (p > 0.05). Among 71 IBD, the incidence was 1.19, and the number of symptomatic days was 2.48. For their 71 controls, figures were 0.73 and 1.31, respectively (p > 0.05). These differences also existed before travel. ISA had significantly more and longer travel-related signs of skin infection and IBD suffered more and longer from vomiting. As for other symptoms, no significant travel-related differences were found. Only 21% of immunocompromised travelers suffering from diarrhea used their stand-by antibiotics. CONCLUSIONS: ISA and IBD did not have symptomatic infectious diseases more often or longer than non-immunocompromised travelers, except for signs of travel-related skin infection among ISA. Routine prescription of stand-by antibiotics for these immunocompromised travelers to areas with good health facilities is probably not more useful than for healthy travelers.

van der Wal WM, Noordzij M, Dekker FW, Boeschoten EW, Krediet RT, Korevaar JC, Geskus RB, Netherlands Cooperative Study on the Adequacy of Dialysis Study Group (NECOSAD). 2011. Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model. Nephrol Dial Transplant, 26 (9), pp. 2978-2983. | Show Abstract | Read more

BACKGROUND: Declining residual renal function, as indicated by the glomerular filtration rate (GFR), is associated with an increased mortality risk in patients with end-stage renal disease (ESRD) on dialysis. METHODS: We monitored GFR and mortality in 1800 haemodialysis (HD) and peritoneal dialysis (PD) patients in 1996-2006. We used a marginal structural model to estimate the causal effects both of GFR when it was not completely lost and of the subsequent full loss of GFR on mortality, avoiding the drawbacks of standard regression models that include covariates to adjust for confounding. Instead, effect estimates were adjusted for possible baseline and time-varying confounders using inverse probability weighting. RESULTS: We estimated a hazard ratio (HR) corresponding to the effect of the full loss of GFR on mortality, as compared to not having fully lost GFR, of 1.50 [95% confidence interval (CI) 1.09-2.07]. The HR corresponding to the effect of GFR when GFR is not (yet) fully lost on mortality was 0.97 (95% CI 0.92-1.02) (per mL/min/1.73 m(2)). We found no significant difference in the effect of GFR on mortality between patients starting on PD and HD. CONCLUSIONS: Preventing or delaying the full loss of GFR can improve survival in dialysis patients. This supports the importance that is given to the effect of treatment options for patients with ESRD on the rate of decline of the residual renal function.

Borgdorff MW, Sebek M, Geskus RB, Kremer K, Kalisvaart N, van Soolingen D. 2011. The incubation period distribution of tuberculosis estimated with a molecular epidemiological approach. Int J Epidemiol, 40 (4), pp. 964-970. | Show Abstract | Read more

BACKGROUND: There is limited information on the distribution of incubation periods of tuberculosis (TB). METHODS: In The Netherlands, patients whose Mycobacterium tuberculosis isolates have identical DNA fingerprints in the period 1993-2007 were interviewed to identify epidemiological links between cases. We determined the incubation period distribution in secondary cases. Survival analysis techniques were used to include secondary cases not yet symptomatic at diagnosis with weighting to adjust for lower capture probabilities of couples with longer time intervals between their diagnoses. In order to deal with missing data, we used multiple imputations. RESULTS: We identified 1095 epidemiologically linked secondary cases, attributed to 688 source cases with pulmonary TB. Of those developing disease within 15 years, the Kaplan-Meier probability to fall ill within 1 year was 45%, within 2 years 62% and within 5 years 83%. The incubation time was shorter in secondary cases who were men, young, those with extra-pulmonary TB and those not reporting previous TB or previous preventive therapy. CONCLUSIONS: Molecular epidemiological analysis has allowed a more precise description of the incubation period of TB than was possible in previous studies, including the identification of risk factors for shorter incubation periods.

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Scopus

van der Wal WM, Geskus RB. 2011. Ipw: An R package for inverse probability weighting Journal of Statistical Software, 43 (13), pp. 2-23. | Show Abstract

We describe the R package ipw for estimating inverse probability weights. We show how to use the package to fit marginal structural models through inverse probability weighting, to estimate causal effects. Our package can be used with data from a point treatment situation as well as with a time-varying exposure and time-varying confounders. It can be used with binomial, categorical, ordinal and continuous exposure variables.

van der Helm JJ, Prins M, del Amo J, Bucher HC, Chêne G, Dorrucci M, Gill J, Hamouda O, Sannes M, Porter K et al. 2011. The hepatitis C epidemic among HIV-positive MSM: incidence estimates from 1990 to 2007. AIDS, 25 (8), pp. 1083-1091. | Show Abstract | Read more

BACKGROUND: Outbreaks of acute hepatitis C virus (HCV) infection among HIV-infected MSM have been described since 2000. However, phylogenetic analysis suggests that the spread of HCV started around 1996. We estimated the incidence of HCV in HIV-infected MSM with well estimated dates of HIV seroconversion from 1990 to 2007. METHODS: Data from 12 cohorts within the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) Collaboration were used. HCV incidence was estimated using standard incidence methods and methods for interval-censored data. We accounted for the fact that routine HCV data collection in each cohort started in different calendar years. RESULTS: Of 4724 MSM, 3014 had an HCV test result and were included. Of these, 124 (4%) had only positive HCV test results, 2798 (93%) had only negative results and 92 (3%) had both. In 1990, HCV incidence ranged from 0.9 to 2.2 per 1000 person-years, depending on the analysis strategy used. HCV incidence increased up to 1995 when it was estimated to range between 5.5 and 8.1 per 1000 person-years. From 2002 onwards, it increased substantially to values between 16.8 and 30.0 per 1000 person-years in 2005 and between 23.4 and 51.1 per 1000 person-years in 2007. CONCLUSION: Our data support phylodynamic findings that HCV incidence had already increased among HIV-infected MSM from the mid-1990s. However, the main expansion of the HCV epidemic started after 2002. Incidence estimates obtained from cohort studies may help identify changes in the spread of important infections earlier and should guide routine testing policies to minimize further disease burden.

Geskus RB. 2011. Cause-specific cumulative incidence estimation and the fine and gray model under both left truncation and right censoring. Biometrics, 67 (1), pp. 39-49. | Show Abstract | Read more

Summary The standard estimator for the cause-specific cumulative incidence function in a competing risks setting with left truncated and/or right censored data can be written in two alternative forms. One is a weighted empirical cumulative distribution function and the other a product-limit estimator. This equivalence suggests an alternative view of the analysis of time-to-event data with left truncation and right censoring: individuals who are still at risk or experienced an earlier competing event receive weights from the censoring and truncation mechanisms. As a consequence, inference on the cumulative scale can be performed using weighted versions of standard procedures. This holds for estimation of the cause-specific cumulative incidence function as well as for estimation of the regression parameters in the Fine and Gray proportional subdistribution hazards model. We show that, with the appropriate filtration, a martingale property holds that allows deriving asymptotic results for the proportional subdistribution hazards model in the same way as for the standard Cox proportional hazards model. Estimation of the cause-specific cumulative incidence function and regression on the subdistribution hazard can be performed using standard software for survival analysis if the software allows for inclusion of time-dependent weights. We show the implementation in the R statistical package. The proportional subdistribution hazards model is used to investigate the effect of calendar period as a deterministic external time varying covariate, which can be seen as a special case of left truncation, on AIDS related and non-AIDS related cumulative mortality.

de Vries HJC, Smelov V, Ouburg S, Pleijster J, Geskus RB, Speksnijder AGCL, Fennema JSA, Morré SA. 2010. Anal lymphogranuloma venereum infection screening with IgA anti-Chlamydia trachomatis-specific major outer membrane protein serology. Sex Transm Dis, 37 (12), pp. 789-795. | Show Abstract | Read more

BACKGROUND: Anal lymphogranuloma venereum (LGV) infections, caused by Chlamydia trachomatis biovar L (Ct+/LGV+), are endemic among men who have sex with men (MSM). Anal non-LGV biovar Ct infections (Ct+/LGV-) can be eradicated with 1 week doxycycline, whereas Ct+/LGV+ infections require 3-week doxycycline. To differentiate Ct+/LGV+ from Ct+/LGV- infections, biovar-specific Nucleic Acid Amplification Test (NAAT) are standard, but also expensive and laborious. A chlamydia-specific serological assay could serve as an alternative test. METHODS: MSM were screened for anal Ct+/LGV+ and Ct+/LGV- infections with a commercial nonspecific NAAT and an in house biovar L-specific NAAT. Serum samples were evaluated with chlamydia-specific anti-Major Outer Membrane Protein (MOMP) and antilipopolysaccharide assays of IgA and IgG classes. Asymptomatic patients were identified as: (1) no anal complaints or (2) no microscopic inflammation (i.e., <10 leucocytes per high power field in anal smears). The best differentiating assay was subsequently evaluated in 100 Ct+/LGV+ and 100 Ct+/LGV- MSM using different cut-off points. RESULTS: The anti-MOMP IgA assay was the most accurate to differentiate Ct+/LGV+ (n = 42) from Ct+/LGV- (n = 19) with 85.7% sensitivity (95% confidence interval [CI], 72.2-93.3) and 84.2% specificity (95% CI, 62.4-94.5), even among asymptomatic patients. In a population comprising 98 Ct+/LGV+ and 105 Ct+/LGV- patients, the anti-MOMP IgA assay scored most accurate when the cut-off point was set to 2.0 with 75.5% (95% CI, 65.8-83.6) sensitivity and 74.3% (95% CI, 64.8-82.3) specificity. CONCLUSIONS: The IgA anti-MOMP assay can identify a considerable proportion of the (asymptomatic) anal LGV infections correctly. Yet, biovar L-specific NAAT are still the preferred diagnostic tests in clinical settings.

van Rijckevorsel GGC, Sonder GJB, Geskus RB, Wetsteyn JCFM, Ligthelm RJ, Visser LG, Keuter M, van Genderen PJJ, van den Hoek A. 2010. Declining incidence of imported malaria in the Netherlands, 2000-2007. Malar J, 9 (1), pp. 300. | Show Abstract | Read more

BACKGROUND: To describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007. METHODS: Based on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers. RESULTS: Importation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007. CONCLUSION: The annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome.

Baaten GG, Roukens AH, Geskus RB, Kint JA, Coutinho RA, Sonder GJ, van den Hoek A. 2010. Symptoms of infectious diseases in travelers with diabetes mellitus: a prospective study with matched controls. J Travel Med, 17 (4), pp. 256-263. | Show Abstract | Read more

BACKGROUND: Travelers with diabetes mellitus to developing countries are thought to have symptomatic infectious diseases more often and longer than travelers without diabetes. Evidence for this is needed. This study evaluates whether travelers with diabetes are at increased risk of symptomatic infectious diseases. METHODS: A prospective study was performed between October 2003 and February 2008 among adult medication-dependent travelers with diabetes, with their healthy travel companions without diabetes serving as matched controls. Thus, travelers with diabetes and controls were assumed to have comparable exposure to infection. Data on symptoms of infectious diseases were recorded by using a structured diary. RESULTS: Among 70 travelers with insulin-dependent diabetes, the incidence of travel-related diarrhea was 0.99 per person-month, and the median number of symptomatic days 1.54 per month. For their 70 controls, figures were 0.74 and 1.57, respectively (p > 0.05). Among 82 travelers with non-insulin-dependent diabetes, incidence was 0.75, and the median number of symptomatic days was 1.68. For their 82 controls, figures were 0.70 and 1.68, respectively (p > 0.05). As for other symptoms, no significant travel-related differences were found. Only 17% of travelers with diabetes suffering from diarrhea used their stand-by antibiotics. CONCLUSIONS: Medication-dependent travelers with diabetes traveling to developing countries do not have symptomatic infectious diseases more often or longer than travelers without diabetes. Routine prescription of stand-by antibiotics for travelers with diabetes to areas with good health facilities is probably not more useful than for healthy travelers.

Saeed P, Blank L, Selva D, Wolbers JG, Nowak PJCM, Geskus RB, Weis E, Mourits MP, Rootman J. 2010. Primary radiotherapy in progressive optic nerve sheath meningiomas: a long-term follow-up study. Br J Ophthalmol, 94 (5), pp. 564-568. | Show Abstract | Read more

BACKGROUND/AIMS To report the outcome of primary radiotherapy in patients with progressive optic nerve sheath meningioma (ONSM). METHODS The clinical records of all patients were reviewed in a retrospective, observational, multicentre study. RESULTS Thirty-four consecutive patients were included. Twenty-six women and eight men received conventional or stereotactic fractionated radiotherapy, and were followed for a median 58 (range 51-156) months. Fourteen eyes (41%) showed improved visual acuity of at least two lines on the Snellen chart. In 17 (50%) eyes, the vision stabilised, while deterioration was noted in three eyes (9%). The visual outcome was not associated with age at the time of radiotherapy (p=0.83), sex (p=0.43), visual acuity at the time of presentation (p=0.22) or type of radiotherapy (p=0.35). Optic disc swelling was associated with improved visual acuity (p<0.01) and 4/11 patients with optic atrophy also showed improvement. Long-term complications were dry eyes in five patients, cataracts in three, and mild radiation retinopathy in four. CONCLUSION Primary radiotherapy for patients with ONSM is associated with long-term improvement of visual acuity and few adverse effects.

Jarrín I, Geskus R, Pérez-Hoyos S, del Amo J. 2010. [Analytical methods in cohort studies of patients with HIV infection]. Enferm Infecc Microbiol Clin, 28 (5), pp. 298-303. | Show Abstract | Read more

This paper provides an overview of the main statistical methods used in the analysis of data from cohort studies and presents a detailed description of the way these methods are applied in HIV/AIDS research. First, we describe methods for analyzing events in person-time data. Second, we present survival methods for the analysis of time-to-event data. In this context, we illustrate the application of these methods to describe the AIDS incubation period and survival from HIV seroconversion, to determine the factors and biological markers associated with disease progression, and to evaluate effectiveness of therapy. The review ends by illustrating the statistical methods used for the analysis of markers measured repeatedly over time.

van den Heuvel MEN, van der Lee JH, Cornelissen EAM, Bemelman FJ, Hoitsma A, Geskus RB, Bouts AHM, Groothoff JW. 2010. Transition to the adult nephrologist does not induce acute renal transplant rejection. Nephrol Dial Transplant, 25 (5), pp. 1662-1667. | Show Abstract | Read more

BACKGROUND: In spite of the overall increased renal graft survival, long-term allograft survival has remained least successful in adolescent recipients. A major change in their care is the transition from the paediatric to the adult nephrology unit. METHODS: To analyse the effect of transition on the acute rejection frequency and graft survival, we performed a historical cohort study in all patients transplanted at the paediatric unit between 1980 and 2004. Data were obtained by reviewing medical charts in two of the four Dutch pediatric renal transplantation centers from time of transplantation until 3 years after transition. For analysis, we used a Cox proportional hazards model. RESULTS: The cohort consisted of 162 patients: 133 native Dutch and 29 immigrant patients. Transition occurred at a mean age of 18 years (range 14-22). At transition, 72% had a functioning allograft. Acute rejections occurred in 92/162 patients before (median follow-up 4.8 years, range 0.2-12.8) and in 15/116 patients after transition (median follow-up 3.0 years, range 1.6-3.0). Most rejections (62%) occurred within the first year after transplantation. The relative risk of acute rejections after transition in comparison to before transition was 0.10 [95% confidence interval (95% CI) 0.04-0.28] in Dutch patients and 0.69 (95% CI 0.33-1.40) in immigrant patients. In the 3 years before transition, 28/154 patients (18%) experienced graft failure compared to 19/116 patients (16%) in the 3 years after transition. CONCLUSIONS: The risk for acute rejection decreases after transition to the adult unit. There is less risk reduction in immigrant patients. Nephrologists should pay special attention to these patients.

van der Wal WM, Noordzij M, Dekker FW, Boeschoten EW, Krediet RT, Korevaar JC, Geskus RB. 2010. Comparing mortality in renal patients on hemodialysis versus peritoneal dialysis using a marginal structural model. Int J Biostat, 6 (1), pp. Article-2. | Show Abstract | Read more

When comparing the causal effect of peritoneal dialysis (PD) and hemodialysis (HD) treatment on lowering mortality in renal patients, using observational data, it is necessary to adjust for different forms of confounding and informative censoring. Both the type of dialysis treatment that is started with and mortality are affected by baseline covariates. Longitudinal and baseline variables can affect both the probability of switching from one type of dialysis to the other, and mortality. Longitudinal and baseline variables can also affect the probability of receiving a kidney transplant, possibly causing informative censoring. Adjusting for longitudinal variables by including them as covariates in a regression model potentially causes bias, for instance by losing a possible indirect effect of dialysis on mortality via these longitudinal variables. Instead, we fitted a marginal structural model (MSM) to estimate the causal effect of dialysis type, adjusted for confounding and informative censoring. We used the MSM to compare the hazard of death as well as cumulative survival between the potential treatment trajectories "always PD" and "always HD" over time, conditional on age and diabetes mellitus status. We used inverse probability weighting (IPW) to fit the MSM.

van Houdt R, Bruisten SM, Geskus RB, Bakker M, Wolthers KC, Prins M, Coutinho RA. 2010. Ongoing transmission of a single hepatitis B virus strain among men having sex with men in Amsterdam. J Viral Hepat, 17 (2), pp. 108-114. | Show Abstract | Read more

For the past decade, a specific hepatitis B virus (HBV) genotype A strain has been prevalent among men having sex with men (MSM) in Amsterdam, the Netherlands. At what point in time this strain was introduced in the MSM population, and why only this specific strain continues to be transmitted, remains unclear. Between 1984 and 2003, sera of 1862 MSM were retrospectively screened for anti-HBc in the context of the Amsterdam Cohort studies. After 2003, most MSM participating in this study were vaccinated, making further testing less useful. HBV DNA from anti-HBc seroconverters was amplified and sequenced. Poisson regression was used to test for temporal trends in HBV and HIV incidence. Of the 1042 MSM who were negative for anti-HBc at entry, 64 had seroconverted during follow-up at a median age of 32. At the point of seroconversion, 31 MSM were HIV positive. HBV incidence declined dramatically in the first years and then remained stable throughout the study period. The HBV and HIV incidence ran almost in parallel. With the exception of three MSM, all were infected with genotype A. Fifteen of these (41%) were infected with an identical genotype A strain. For the past two decades, an identical genotype A strain has been circulating among MSM in the Netherlands. Although HBV is generally considered more infectious than HIV, this study shows that the trend and magnitude in HBV and HIV incidence among MSM are similar.

van der Wal WM, Prins M, Lumbreras B, Geskus RB. 2009. A simple G-computation algorithm to quantify the causal effect of a secondary illness on the progression of a chronic disease. Stat Med, 28 (18), pp. 2325-2337. | Show Abstract | Read more

Progression of a chronic disease can lead to the development of secondary illnesses. An example is the development of active tuberculosis (TB) in HIV-infected individuals. HIV disease progression, as indicated by declining CD4 + T-cell count (CD4), increases both the risk of TB and the risk of AIDS-related mortality. This means that CD4 is a time-dependent confounder for the effect of TB on AIDS-related mortality. Part of the effect of TB on AIDS-related mortality may be indirect by causing a drop in CD4. Estimating the total causal effect of TB on AIDS-related mortality using standard statistical techniques, conditioning on CD4 to adjust for confounding, then gives an underestimate of the true effect. Marginal structural models (MSMs) can be used to obtain an unbiased estimate. We describe an easily implemented algorithm that uses G-computation to fit an MSM, as an alternative to inverse probability weighting (IPW). Our algorithm is simplified by utilizing individual baseline parameters that describe CD4 development. Simulation confirms that the algorithm can produce an unbiased estimate of the effect of a secondary illness, when a marker for primary disease progression is both a confounder and intermediary for the effect of the secondary illness. We used the algorithm to estimate the total causal effect of TB on AIDS-related mortality in HIV-infected individuals, and found a hazard ratio of 3.5 (95 per cent confidence interval 1.2-9.1).

Vergouwen MDI, Meijers JCM, Geskus RB, Coert BA, Horn J, Stroes ESG, van der Poll T, Vermeulen M, Roos YBWEM. 2009. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Cereb Blood Flow Metab, 29 (8), pp. 1444-1453. | Show Abstract | Read more

Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality. It was hypothesized that the beneficial effect resulted from pleiotropic effects of statins. The purpose of this study was to investigate the biologic effects of acute statin treatment in patients with SAH. We performed an exploratory single-center, prospective, randomized, double-blind, placebo-controlled trial. Patients were randomized to simvastatin 80 mg or placebo once daily. A total of 32 patients were included. There were no statistically significant differences in clinical baseline characteristics. With regard to primary outcomes, there were significant differences by treatment group for total cholesterol and low-density lipoprotein (LDL) cholesterol (P<0.0001), but not for parameters of coagulation, fibrinolysis, endothelium function, and inflammation. With regard to secondary outcomes, no differences were observed in the incidence of transcranial Doppler vasospasm, clinical signs of DCI, and poor outcome. We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH.

Eckhardt CL, Menke LA, van Ommen CH, van der Lee JH, Geskus RB, Kamphuisen PW, Peters M, Fijnvandraat K. 2009. Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost, 7 (6), pp. 930-937. | Show Abstract | Read more

BACKGROUND: A severe and challenging complication in the treatment of hemophilia A is the development of inhibiting antibodies (inhibitors) directed towards factor VIII (FVIII). Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. OBJECTIVES: In a large cohort study in patients with mild/moderate hemophilia A we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. PATIENTS/METHODS: Longitudinal clinical data from 138 mild/moderate hemophilia A patients were retrospectively collected from 1 January 1980 to 1 January 2008 and analyzed by multivariate analysis using Poisson regression. RESULTS: Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients; the remaining 86 patients had 26 other missense mutations. Sixty-three (46%) patients received intensive FVIII concentrate administration, 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. Compared with the other patients, those with the Arg593Cys mutation had a 10-fold increased risk of developing inhibitors (RR 10; 95% CI, 0.9-119).The other two inhibitor patients had the newly detected mutations Pro1761Gln and Glu2228Asp. In both these patients and in five patients with genotype Arg593Cys, inhibitors developed after intensive peri-operative use of FVIII concentrate (RR 186; 95% CI, 25-1403). In five of the 10 inhibitor patients FVIII was administered by continuous infusion during surgery (RR 13; 95% CI, 1.9-86). CONCLUSION: The Arg593Cys genotype and intensive peri-operative use of FVIII, especially when administered by continuous infusion, are associated with an increased risk for inhibitor development in mild/moderate hemophilia A.

Siebeling L, ter Riet G, van der Wal WM, Geskus RB, Zoller M, Muggensturm P, Joleska I, Puhan MA. 2009. ICE COLD ERIC--International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts--study protocol for an international COPD cohort study. BMC Pulm Med, 9 (1), pp. 15. | Show Abstract | Read more

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2-4. METHODS/DESIGN: We will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years. DISCUSSION: Despite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After completion of this study, we will have a practical COPD-disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2-4. In a second step we will incorporate evidence-based treatment effects into this model, such that the instrument may guide physicians in selecting treatment based on the individual patients' prognosis. TRIAL REGISTRATION: ClinicalTrials.gov Archive NCT00706602.

Roede I, Bresser P, Bindels P, Kok A, Prins M, Riet GT, Geskus R, Herings R, Prins J. 2009. Antibiotics for exacerbation of chronic obstructive pulmonary disease seems to reduce relapses Huisarts en Wetenschap, 52 (5), pp. 218-224.

When To Start Consortium, Sterne JAC, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, Funk MJ, Geskus RB, Gill J et al. 2009. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet, 373 (9672), pp. 1352-1363. | Show Abstract | Read more

BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

van Wonderen KE, van der Mark LB, Mohrs J, Geskus RB, van der Wal WM, van Aalderen WMC, Bindels PJE, ter Riet G. 2009. Prediction and treatment of asthma in preschool children at risk: study design and baseline data of a prospective cohort study in general practice (ARCADE). BMC Pulm Med, 9 (1), pp. 13. | Show Abstract | Read more

BACKGROUND: Asthma is a difficult diagnosis to establish in preschool children. A few years ago, our group presented a prediction rule for young children at risk for asthma in general practice. Before this prediction rule can safely be used in practice, cross-validation is required. In addition, general practitioners face many therapeutic management decisions in children at risk for asthma. The objectives of the study are: (1) identification of predictors for asthma in preschool children at risk for asthma with the aim of cross-validating an earlier derived prediction rule; (2) compare the effects of different treatment strategies in preschool children. DESIGN: In this prospective cohort study one to five year old children at risk of developing asthma were selected from general practices. At risk was defined as 'visited the general practitioner with recurrent coughing (>or= 2 visits), wheezing (>or=1) or shortness of breath (>or=1) in the previous 12 months'. All children in this prospective cohort study will be followed until the age of six. For our prediction rule, demographic data, data with respect to clinical history and additional tests (specific immunoglobulin E (IgE), fractional exhaled nitric oxide (FENO), peak expiratory flow (PEF)) are collected. History of airway specific medication use, symptom severity and health-related quality of life (QoL) are collected to estimate the effect of different treatment intensities (as expressed in GINA levels) using recently developed statistical techniques. In total, 1,938 children at risk of asthma were selected from general practice and 771 children (40%) were enrolled. At the time of writing, follow-up for all 5-year olds and the majority of the 4-year olds is complete. The total and specific IgE measurements at baseline were carried out by 87% of the children. Response rates to the repeated questionnaires varied from 93% at baseline to 73% after 18 months follow-up; 89% and 87% performed PEF and FENO measurements, respectively. DISCUSSION: In this study a prediction rule for asthma in young children, to be used in (general) practice, will be cross-validated. Our study will also provide more insight in the effect of treatment of asthma in preschool children.

Eskes SA, Tomasoa NB, Endert E, Geskus RB, Fliers E, Wiersinga WM. 2009. Establishment of reference values for endocrine tests. Part VII: growth hormone deficiency. Neth J Med, 67 (4), pp. 127-133. | Show Abstract

BACKGROUND: Plasma insulin-like growth factor (IGF-I) concentration can be used as a rough indicator of the growth-hormone status. However, for the diagnosis of growth hormone deficiency, dynamic tests are required. The growth hormone (GH) response in the insulin tolerance test (ITT) is considered to be the gold standard in this respect. An alternative for the ITT is the GHRH/ GHRP-6 test, which has fewer side effects. In this study we established reference values for IGF-I levels and for the GH response in both dynamic tests. METHODS: We studied 296 subjects recruited from the general population, equally distributed according to sex and aged between 20 and 70 years. Serum IGF-I level was measured in all subjects and an insulin tolerance test (0.15 U/kg Actrapid iv) and GHRH/GHRP-6 test (1 microg GHRH/kg and 1 microg GHRP-6/kg) were performed in 49 subjects. RESULTS: In multivariate analyses both IGF-I and the GH response in the ITT were significantly influenced by age, whereas the GH response in the GHRH/GHRP-6 test was significantly affected by BMI. There was no sex difference in IGF-I and in the GHRH/GHRP-6 test, but in the ITT males had a higher GH peak. There was a significant correlation between the GH responses in both tests, and the GH response was significantly higher in the GHRH/GHRP-6 test than in the ITT. Age-adjusted reference values were established for each test. CONCLUSION: We have established age-adjusted reference values for serum IGF-I and for the GH response in the ITT and GHRH/GHRP-6 test.

Kramer MA, van Veen MG, de Coul ELMO, Geskus RB, Coutinho RA, van de Laar MJW, Prins M. 2008. Migrants travelling to their country of origin: a bridge population for HIV transmission? Sex Transm Infect, 84 (7), pp. 554-555. | Show Abstract | Read more

BACKGROUND: By having unprotected heterosexual contact in both The Netherlands and their homeland, migrants who travel to their homeland might form a bridge population for HIV and sexually transmitted infection (STI) transmission. We studied the determinants for such a population in two large migrant communities in The Netherlands. METHODS: From 2003 to 2005, 1938 people of Surinamese and Antillean origin were recruited at social venues in two large cities, interviewed and their saliva samples tested for HIV antibodies. We used multivariate multinomial logistic regression to explore characteristics of groups with four risk levels (no, low, moderate and high) for cross-border transmission. RESULTS: 1159/1938 (60%) participants had travelled from The Netherlands to their homeland in the previous 5 years and 1092 (94%) of them reported partnerships and condom use in both countries. Of these 9.2% reported having unprotected sex with partners in both countries. People in this high-risk or bridge population group were more likely to be male, frequent travellers and older compared with people who had no sex or had sexual contact solely in one country in the past 5 years. CONCLUSIONS: Older male travellers of Surinamese and Antillean origin are at high risk for cross-border heterosexual transmission of HIV/STIs. They should be targeted by prevention programmes, which are focused on sexual health education and HIV/STI testing, to raise their risk awareness and prevent transmission.

Van Rijckevorsel GGC, Sonder GJB, Bovée LPMJ, Thiesbrummel HFJ, Geskus RB, Van Den Hoek A. 2008. Trends in hepatitis A, B, and shigellosis compared with gonorrhea and syphilis in men who have sex with men in Amsterdam, 1992-2006. Sex Transm Dis, 35 (11), pp. 930-934. | Show Abstract | Read more

BACKGROUND: Since the mid-1990s, sexually transmitted infections (STIs) among men who have sex with men (MSM) have increased and appear to be related to more risky sexual behavior. We compare trends in hepatitis A, acute hepatitis B, and shigellosis with the trends of gonorrhea and infectious syphilis in Amsterdam MSM more than a period of 15 years. METHODS: We used data of all reported hepatitis A, acute hepatitis B, and shigellosis, and from all patients newly diagnosed with gonorrhea and infectious syphilis who visited the Public Health Service STI outpatient department in Amsterdam between January 1, 1992 and December 31, 2006. RESULTS: Hepatitis A incidence remained unchanged in MSM (mean 0.97 per 1000 MSM, range 0.04-2.27), who had 21% of all 1697 infections. Hepatitis B likewise remained unchanged in MSM (mean 0.47 per 1000 MSM, range 0.19-0.77), who had 41% of all 448 infections. Most shigellosis is travel-related (657/974), and 16% of the infections occurred in MSM. Its incidence dropped in general, but not in MSM. Both gonorrhea and infectious syphilis in MSM show a steep increase, mainly after 1998. DISCUSSION: Hepatitis A, B, and shigellosis do not follow the rising trends of conventional STI in MSM, which are believed to result from increased risky sexual behavior. This disparity in trends implies differences in transmission dynamics. Recent molecular epidemiologic studies suggest that clustered transmission in social MSM networks plays a major role.

Roede BM, Bresser P, Bindels PJE, Kok A, Prins M, ter Riet G, Geskus RB, Herings RMC, Prins JM. 2008. Antibiotic treatment is associated with reduced risk of a subsequent exacerbation in obstructive lung disease: an historical population based cohort study. Thorax, 63 (11), pp. 968-973. | Show Abstract | Read more

OBJECTIVES: The risk of a subsequent exacerbation after treatment of an exacerbation with oral corticosteroids without (OS) or with (OSA) antibiotics was evaluated in a historical population based cohort study comprising patients using maintenance medication for obstructive lung disease. METHODS: The Pharmo database includes drug dispensing records of more than 2 million subjects in The Netherlands. Eligible were patients >or=50 years who in 2003 were dispensed >or=2 prescriptions of daily used inhaled beta(2) agonists, anticholinergics and/or corticosteroids, and experienced at least one exacerbation before 1 January 2006. Exacerbation was defined as a prescription of OS or OSA. The times to the second and third exacerbations were compared using Kaplan-Meier survival analysis. Independent determinants of new exacerbations were identified using multivariable Cox recurrent event survival analysis. RESULTS: Of 49,599 patients using maintenance medication, 18 928 had at least one exacerbation; in 52%, antibiotics had been added. The OS and OSA groups were comparable for potential confounding factors. Median time to the second exacerbation was 321 days in the OS group and 418 days in the OSA group (p<0.001); and between the second and third exacerbation 127 vs 240 days (p<0.001). The protective effect of OSA was most pronounced during the first 3 months following treatment (hazard ratio (HR) 0.62; 99% CI 0.60 to 0.65). In the OSA group, mortality during follow-up was lower (HR 0.82; 99% CI 0.66 to 0.98). CONCLUSION: Treatment with antibiotics in addition to oral corticosteroids was associated with a longer time to the next exacerbation, and a decreased risk of developing a new exacerbation.

Jarrin I, Geskus R, Bhaskaran K, Prins M, Perez-Hoyos S, Muga R, Hernández-Aguado I, Meyer L, Porter K, del Amo J, CASCADE Collaboration. 2008. Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women. Am J Epidemiol, 168 (5), pp. 532-540. | Show Abstract | Read more

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk framework, they used Cox proportional hazards models allowing for late entry to evaluate sex differences in time from HIV seroconversion to death, to acquired immunodeficiency syndrome (AIDS), and to each first AIDS-defining disease and death without AIDS. While no significant sex differences were found before 1997, from 1997 onward, women had a lower risk of AIDS (adjusted cumulative relative risk (aCRR) = 0.76, 95% confidence interval (CI): 0.63, 0.90) and death (adjusted hazard ratio = 0.68, 95% CI: 0.56, 0.82) than men did. Compared with men, women also had lower risks of AIDS dementia complex (aCRR = 0.23, 95% CI: 0.07, 0.74), tuberculosis (aCRR = 0.60, 95% CI: 0.39, 0.92), Kaposi's sarcoma (aCRR = 0.27, 95% CI: 0.07, 0.99), lymphomas (aCRR = 0.47, 95% CI: 0.23, 0.96), and death without AIDS (aCRR = 0.74, 95% CI: 0.56, 0.98). Sex differences in HIV disease progression have become larger and statistically significant in the era of highly active antiretroviral therapy, supporting a stronger impact of health interventions among women.

Schellens IMM, Borghans JAM, Jansen CA, De Cuyper IM, Geskus RB, van Baarle D, Miedema F. 2008. Abundance of early functional HIV-specific CD8+ T cells does not predict AIDS-free survival time. PLoS One, 3 (7), pp. e2745. | Show Abstract | Read more

BACKGROUND: T-cell immunity is thought to play an important role in controlling HIV infection, and is a main target for HIV vaccine development. HIV-specific central memory CD8(+) and CD4(+) T cells producing IFNgamma and IL-2 have been associated with control of viremia and are therefore hypothesized to be truly protective and determine subsequent clinical outcome. However, the cause-effect relationship between HIV-specific cellular immunity and disease progression is unknown. We investigated in a large prospective cohort study involving 96 individuals of the Amsterdam Cohort Studies with a known date of seroconversion whether the presence of cytokine-producing HIV-specific CD8(+) T cells early in infection was associated with AIDS-free survival time. METHODS AND FINDINGS: The number and percentage of IFNgamma and IL-2 producing CD8(+) T cells was measured after in vitro stimulation with an overlapping Gag-peptide pool in T cells sampled approximately one year after seroconversion. Kaplan-Meier survival analysis and Cox proportional hazard models showed that frequencies of cytokine-producing Gag-specific CD8(+) T cells (IFNgamma, IL-2 or both) shortly after seroconversion were neither associated with time to AIDS nor with the rate of CD4(+) T-cell decline. CONCLUSIONS: These data show that high numbers of functional HIV-specific CD8(+) T cells can be found early in HIV infection, irrespective of subsequent clinical outcome. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression.

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth TD, Prins M, Geskus RB, Gras L, Coutinho RA, Fraser C. 2008. A resurgent HIV-1 epidemic among men who have sex with men in the era of potent antiretroviral therapy. AIDS, 22 (9), pp. 1071-1077. | Show Abstract | Read more

OBJECTIVE: Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. DESIGN: We focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. METHODS: We used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. RESULTS: We show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, the risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. CONCLUSION: We provide the first detailed quantitative analysis of the HIV epidemic in a well defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Noordzij M, Korevaar JC, Dekker FW, Boeschoten EW, Bos WJ, Krediet RT, Bossuyt PM, Geskus RB, NECOSAD study group. 2008. Mineral metabolism and mortality in dialysis patients: a reassessment of the K/DOQI guideline. Blood Purif, 26 (3), pp. 231-237. | Show Abstract | Read more

BACKGROUND: Several studies found associations between higher plasma calcium and phosphorus and mortality in dialysis patients. However, different predefined categories and reference values were applied and the precise shape of these relationships remains unclear. METHODS: We evaluated 1,621 patients from NECOSAD, a prospective multicenter cohort study of incident dialysis patients (60 +/- 15 years, 61% male, 64% hemodialysis). We used multivariate Cox regression and restricted cubic spline regression to study the effects of time-updated plasma concentrations on mortality in a flexible manner. RESULTS: 486 patients (30%) died during follow-up. Elevated phosphorus concentration was associated with higher mortality (p = 0.0009). The association of high calcium with mortality was borderline significant (p = 0.07). Within the studied ranges, we could not identify a threshold where an appreciable change in mortality risk occurred. CONCLUSIONS: Mortality risk started to increase at a relatively low phosphorus concentration (4.5 mg/dl). Low-normal calcium combined with low-normal phosphorus concentration was associated with the lowest mortality.

Smit C, van den Berg C, Geskus R, Berkhout B, Coutinho R, Prins M. 2008. Risk of hepatitis-related mortality increased among hepatitis C virus/HIV-coinfected drug users compared with drug users infected only with hepatitis C virus: a 20-year prospective study. J Acquir Immune Defic Syndr, 47 (2), pp. 221-225. | Show Abstract | Read more

BACKGROUND: Progression of liver-related disease is accelerated in individuals coinfected with HIV and hepatitis C virus (HCV). Because the life expectancy of HIV-infected drug users (DUs) improved after the widespread use of highly active antiretroviral therapy (HAART), HCV-related death is likely to become more important. To disentangle the effects of HCV and HIV, we compared the overall and cause-specific mortality between HCV/HIV-infected DUs and HCV-infected DUs and DUs without HCV or HIV, followed up between 1985 and 2006. METHODS: A total of 1295 participants in the Amsterdam Cohort Study were included. Cause-specific hazard ratios (CHRs) were estimated for the eras before (<1997) and since HAART (> or =1997) within and among serologic groups. RESULTS: The risk of dying decreased for most causes of death > or =1997; this decrease was not the same for the different serologic groups. Among HCV/HIV-coinfected DUs, the risk of hepatitis/liver-related death did not substantially change over time (CHR = 0.87, 95% confidence interval [CI]: 0.21 to 3.58), whereas the risk of AIDS-related mortality decreased. Compared with DUs solely infected with HCV, HCV/HIV-coinfected DUs were at increased risk of dying from hepatitis/liver-related disease (CHR = 7.15, 95% CI: 1.98 to 25.8), other natural causes (CHR = 3.09, 95% CI: 1.41 to 6.79), and nonnatural causes (CHR = 2.30, 95% CI: 1.07 to 4.95) in the HAART era. CONCLUSIONS: HCV/HIV-coinfected DUs remain at increased risk of dying from hepatitis/liver-related death in the HAART era compared with HCV-monoinfected DUs. This risk did not change in HCV/HIV-coinfected DUs after HAART was introduced, suggesting that in the HAART era, HIV continues to accelerate HCV disease progression. Efforts should be made to establish effective treatment for HCV infection in HCV/HIV-coinfected individuals.

Garre FG, Zwinderman AH, Geskus RB, Sijpkens YWJ. 2007. A joint latent class changepoint model to improve the prediction of time to graft failure Journal of the Royal Statistical Society: Series A (Statistics in Society), pp. 071029094155005-???. | Show Abstract | Read more

The reciprocal of serum creatinine concentration, RC, is often used as a biomarker to monitor renal function. It has been observed that RC trajectories remain relatively stable after transplantation until a certain moment, when an irreversible decrease in the RC levels occurs. This decreasing trend commonly precedes failure of a graft. Two subsets of individuals can be distinguished according to their RC trajectories: a subset of individuals having stable RC levels and a subset of individuals who present an irrevocable decrease in their RC levels. To describe such data, the paper proposes a joint latent class model for longitudinal and survival data with two latent classes. RC trajectories within latent class one are modelled by an intercept-only random-effects model and RC trajectories within latent class two are modelled by a segmented random changepoint model. A Bayesian approach is used to fit this joint model to data from patients who had their first kidney transplantation in the Leiden University Medical Center between 1983 and 2002. The resulting model describes the kidney transplantation data very well and provides better predictions of the time to failure than other joint and survival models. © 2008 Royal Statistical Society.

Geskus R. 2007. Censoring strategies when using competing risks with time-dependent covariates. J Acquir Immune Defic Syndr, 46 (4), pp. 512. | Read more

Bakker B, Oostdijk W, Geskus RB, Stokvis-Brantsma WH, Vossen JM, Wit JM. 2007. Growth hormone (GH) secretion and response to GH therapy after total body irradiation and haematopoietic stem cell transplantation during childhood. Clin Endocrinol (Oxf), 67 (4), pp. 589-597. | Show Abstract | Read more

OBJECTIVE: In January 1997 we introduced a protocol for the treatment with GH of children with impaired growth after unfractionated total body irradiation (TBI). This study is an evaluation of that protocol. PATIENTS AND METHODS: Between January 1997 and July 2005, 66 patients (48 male) treated for haematological malignancies had at least two years of disease-free survival after TBI-based conditioning for stem cell transplantation (SCT). Stimulated and/or spontaneous GH secretion was decreased in 8 of the 29 patients tested because of impaired growth. Treatment with GH (daily dose 1.3 mg/m2 body surface area) was offered to all 29 patients and initiated in 23 of them (17 male). The main outcome measure was the effect of GH therapy on height standard deviation scores (SDS) after onset of GH therapy, estimated by random-effect modelling with corrections for sex, age at time of SCT and puberty (data analysed on intention-to-treat basis). RESULTS: At time of analysis, median duration of therapy was 3.2 years; median follow-up after start of GH therapy was 4.2 years. The estimated effect of GH therapy, modelled as nonlinear (logit) curve, was +1.1 SD after 5 years. Response to GH therapy did not correlate to GH secretion status. CONCLUSION: GH therapy has a positive effect on height SDS after TBI, irrespective of GH secretion status.

Geskus RB, Prins M, Hubert J-B, Miedema F, Berkhout B, Rouzioux C, Delfraissy J-F, Meyer L. 2007. The HIV RNA setpoint theory revisited. Retrovirology, 4 (1), pp. 65. | Show Abstract | Read more

BACKGROUND: The evolution of plasma viral load after HIV infection has been described as reaching a setpoint, only to start rising again shortly before AIDS diagnosis. In contrast, CD4 T-cell count is considered to show a stable decrease. However, characteristics of marker evolution over time depend on the scale that is used to visualize trends. In reconsidering the setpoint theory for HIV RNA, we analyzed the evolution of CD4 T-cell count and HIV-1 RNA level from HIV seroconversion to AIDS diagnosis. Follow-up data were used from two cohort studies among homosexual men (N = 400), restricting to the period before highly active antiretroviral therapy became widely available (1984 until 1996). Individual trajectories of both markers were fitted and averaged, both from seroconversion onwards and in the four years preceding AIDS diagnosis, using a bivariate random effects model. Both markers were evaluated on a scale that is directly related to AIDS risk. RESULTS: Individuals with faster AIDS progression had higher HIV RNA level six months after seroconversion. For CD4 T-cell count, this ordering was less clearly present. However, HIV RNA level and CD4 T-cell count showed qualitatively similar evolution over time after seroconversion, also when stratified by rate of progression to AIDS. In the four years preceding AIDS diagnosis, a non-significant change in HIV RNA increase was seen, whereas a significant biphasic pattern was present for CD4 T-cell decline. CONCLUSION: HIV RNA level has more setpoint behaviour than CD4 T-cell count as far as the level shortly after seroconversion is concerned. However, with respect to the, clinically more relevant, marker evolution over time after seroconversion, a setpoint theory holds as much for CD4 T-cell count as for HIV RNA level.

Willemze AJ, Geskus RB, Noordijk EM, Kal HB, Egeler RM, Vossen JM. 2007. HLA-identical haematopoietic stem cell transplantation for acute leukaemia in children: less relapse with higher biologically effective dose of TBI. Bone Marrow Transplant, 40 (4), pp. 319-327. | Show Abstract | Read more

To examine relapse, survival and transplant-related complications in relationship to disease- and pre-treatment-related characteristics, we evaluated 132 children, who consecutively received an allogeneic HLA-identical SCT for acute leukaemia in our centre: ALL in first remission (n=24), ALL in second remission (n=53) and AML in first remission (n=55). The source of the stem cells was bone marrow in all but three cases. Most patients (89%) were pre-treated with cyclophosphamide and an age-related dose of TBI. Initially, GVHD prophylaxis consisted of long-course MTX only (n=24), later short-course MTX and CsA (n=102) was given. All patients were nursed in strictly protective isolation and received total gut decontamination to suppress their potentially pathogenic enteric microflora. The 5-year probability of overall survival was 63, 53 and 74% for ALL1, ALL2 and AML1, respectively (median follow-up: 10.6 years). The overall transplant-related mortality was 6%. The incidence of acute GVHD was 17%; 6% was grades II-IV. A higher total biologically effective TBI dose (BED) resulted in a decreased relapse frequency (P=0.034) and increased overall survival. AML patients with acute GVHD got no relapse (P=0.02); this was not the case in ALL patients. Fractionated TBI regimens with higher BED should be evaluated in prospective studies.

Van der Bij AK, Geskus RB, Fennema HSA, Adams K, Coutinho RA, Dukers NHTM. 2007. No evidence for a sustained increase in sexually transmitted diseases among heterosexuals in Amsterdam, the Netherlands: a 12-year trend analysis at the sexually transmitted disease outpatient clinic, Amsterdam. Sex Transm Dis, 34 (7), pp. 461-467. | Show Abstract | Read more

OBJECTIVES: Sexually transmitted diseases (STDs) are on the rise, mainly among men having sex with men (MSM). GOAL: The goal of this study was to evaluate whether STD increases as seen in MSM are also visible among heterosexuals. STUDY DESIGN: Attendees of the STD clinic in Amsterdam, The Netherlands, are routinely tested for chlamydia, gonorrhea, and syphilis. Additionally, all women are tested for trichomoniasis. STD time trends of heterosexual attendees between 1994 and 2005 were analyzed by logistic regression and generalized linear models with a negative binomial distribution. RESULTS: The number of consultations doubled since 1994. However, no long-term increase was seen in the number of syphilis and gonorrhea infections. Additionally, the trichomonas prevalence declined. However, the number of chlamydia infections increased over time. CONCLUSIONS: Although the number of attendees increased, no evidence for increasing STD incidence was found among heterosexuals. The increase in chlamydia infections can probably be explained by increased screening resulting from increased numbers of attendees.

Putter H, Fiocco M, Geskus RB. 2007. Tutorial in biostatistics: competing risks and multi-state models. Stat Med, 26 (11), pp. 2389-2430. | Show Abstract | Read more

Standard survival data measure the time span from some time origin until the occurrence of one type of event. If several types of events occur, a model describing progression to each of these competing risks is needed. Multi-state models generalize competing risks models by also describing transitions to intermediate events. Methods to analyze such models have been developed over the last two decades. Fortunately, most of the analyzes can be performed within the standard statistical packages, but may require some extra effort with respect to data preparation and programming. This tutorial aims to review statistical methods for the analysis of competing risks and multi-state models. Although some conceptual issues are covered, the emphasis is on practical issues like data preparation, estimation of the effect of covariates, and estimation of cumulative incidence functions and state and transition probabilities. Examples of analysis with standard software are shown.

van den Berg CHSB, Smit C, Bakker M, Geskus RB, Berkhout B, Jurriaans S, Coutinho RA, Wolthers KC, Prins M. 2007. Major decline of hepatitis C virus incidence rate over two decades in a cohort of drug users. Eur J Epidemiol, 22 (3), pp. 183-193. | Show Abstract | Read more

Injecting drug users (DU) are at high risk for hepatitis C virus (HCV) and HIV infections. To examine the prevalence and incidence of these infections over a 20-year period (1985-2005), the authors evaluated 1276 DU from the Amsterdam Cohort Studies who had been tested prospectively for HIV infection and retrospectively for HCV infection. To compare HCV and HIV incidences, a smooth trend was assumed for both curves over calendar time. Risk factors for HCV seroconversion were determined using Poisson regression. Among ever-injecting DU, the prevalence of HCV antibodies was 84.5% at study entry, and 30.9% were co-infected with HIV. Their yearly HCV incidence dropped from 27.5/100 person years (PY) in the 1980s to 2/100 PY in recent years. In multivariate analyses, ever-injecting DU who currently injected and borrowed needles were at increased risk of HCV seroconversion (incidence rate ratio 29.9, 95% CI 12.6, 70.9) compared to ever-injecting DU who did not currently inject. The risk of HCV seroconversion decreased over calendar time. The HCV incidence in ever-injecting DU was on average 4.4 times the HIV incidence, a pattern seen over the entire study period. The simultaneous decline of both HCV and HIV incidence probably results from reduced risk behavior at the population level.

Dukers NHTM, Fennema HSA, van der Snoek EM, Krol A, Geskus RB, Pospiech M, Jurriaans S, van der Meijden WI, Coutinho RA, Prins M. 2007. HIV incidence and HIV testing behavior in men who have sex with men: using three incidence sources, The Netherlands, 1984-2005. AIDS, 21 (4), pp. 491-499. | Show Abstract | Read more

BACKGROUND: In The Netherlands, the western part, including Rotterdam and Amsterdam harbors the majority of the known HIV-infected population, of whom men who have sex with men (MSM) comprise the largest transmission category. Given a general rise in sexually transmitted infections (STI) and risky sexual behavior, we examine the HIV incidence among MSM in the Netherlands with data from three different sources. METHODS: To describe the HIV epidemic among MSM we use: a prospective cohort study in Rotterdam (ROHOCO: 1998-2003, n = 265) and another in Amsterdam (ACS: 1984-2005, n = 1498]) plus an anonymous HIV surveillance study (Amsterdam STI clinic: 1991-2004, n = 3733) in which HIV-positive MSM were tested with a less-sensitive HIV assay. We evaluated calendar trends in HIV incidence, also focusing on age effects. RESULTS: Since the start of the HIV epidemic in the early 1980s, incidence has declined strongly in the ACS. In recent years, an increase was noted among older MSM attending the Amsterdam STI clinic (P = 0.0334). In both cohort studies, HIV incidence was lower and recent time-trends were not statistically significant. Among recently infected men at the STI clinic, only 40% accepted named HIV testing at their STI consultation. CONCLUSIONS: Data suggest that among MSM in the Netherlands, the HIV incidence is between one and four infections per 100 person-years. The epidemic expands among older STI clinic attendees. Prevention should be developed specifically for older men, along with a more efficient HIV testing approach such as routine HIV testing of MSM when they are screened for STI.

Tjon GMS, Coutinho RA, van den Hoek A, Esman S, Wijkmans CJ, Hoebe CJPA, Wolters B, Swaan C, Geskus RB, Dukers N, Bruisten SM. 2006. High and persistent excretion of hepatitis A virus in immunocompetent patients. J Med Virol, 78 (11), pp. 1398-1405. | Show Abstract | Read more

The duration and level of virus excretion in blood and faeces of patients with hepatitis A virus (HAV) infection were studied in relation to levels of alanine aminotransferase (ALT), disease severity and HAV genotype. Clinical data, blood and faeces were collected from 27 patients with acute hepatitis A (median age: 33 years) for a maximum of 26 weeks. Single blood donations from 55 other patients with acute HAV (median age: 32 years) were also used. Virus loads were quantified by competitive nested RT-PCR. HAV was excreted in faeces for a median period of 81 days after disease onset, with 50% of patients still excreting high levels at Day 36 (2 x 10(6) - 2 x 10(8) copies/ml faeces suspension). Viraemia was detected, but not quantifiable, for a median period of 42 days. In the first 10 days of illness, higher ALT levels were correlated with higher viraemia levels. Comparison of patients infected with genotype 1a with those infected with type 1b did not differ significantly in terms of the duration of HAV excretion or jaundice. In conclusion, faecal excretion of HAV is at a high titre in the first month, perhaps making patients infectious for a longer period than assumed currently. Blood banks should be aware that viraemia may be present for more than 1 month, and genotype did not affect the duration of virus excretion or jaundice.

Ziem JB, Olsen A, Magnussen P, Horton J, Agongo E, Geskus RB, Polderman AM. 2006. Distribution and clustering of Oesophagostomum bifurcum and hookworm infections in northern Ghana. Parasitology, 132 (Pt 4), pp. 525-534. | Show Abstract | Read more

Human Oesophagostomum infections are locally common in northern Ghana. The present study describes the results of a cross-sectional survey involving 1011 subjects, selected by a compound-based random sampling method from 1227 compounds in 24 villages. Selected persons were examined by both Kato and coproculture methods. Hookworm-like eggs, representing ova of Oesophagostomum bifurcum and hookworm were detected in 87.5% of the Kato smears. The geometric mean egg count of the infected subjects was 1018. Upon coproculture, third-stage larvae of O. bifurcum and hookworm were detected in 53.0% and 86.9% of subjects respectively. Oesophagostomum infections were clustered but no clear explanation for aggregation of infections could be found as yet. Subjects infected with hookworm had a 5-fold higher risk of being infected with O. bifurcum. Infection rates in adult women were higher than in adult men. No association was found with family size, level of hygiene or with the presence of animals in the compounds. Representatives of the Bimoba-tribe were significantly more infected than those of the other tribes. It appears, however, that this tribal association is a geographical phenomenon: Bimoba are mostly living in villages with the highest infection rates.

Smit C, Geskus R, Walker S, Sabin C, Coutinho R, Porter K, Prins M, CASCADE Collaboration. 2006. Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion. AIDS, 20 (5), pp. 741-749. | Show Abstract | Read more

INTRODUCTION: Although HAART has led to a reduction in overall mortality among HIV-infected individuals, its impact on death from specific causes is unknown. METHODS: Twenty-two cohorts of HIV-infected individuals with known dates of seroconversion are pooled in the CASCADE collaboration. Causes of death (COD) were categorized into three AIDS-related and seven non-AIDS-related causes. The unknown causes were assigned a separate category. The cumulative incidence for each COD was calculated in the presence of the other competing COD, for the pre-HAART and HAART eras. A multivariate regression analyses for the cumulative rate of progression to the different COD was performed. RESULTS: A total of 1938 of 7680 HIV-seroconverters died. Pre-HAART, AIDS opportunistic infections (OI) was the most common COD, followed by unknown and HIV/AIDS-unspecified. In the HAART era, the cumulative incidence for all AIDS-related COD decreased, OI remaining the most important. Large reductions in death due to other infections and organ failure were seen. Cumulative death risk decreased in the HAART era for most causes. The effect of HAART was not the same for all risk groups. The cumulative risk of death from AIDS-related malignancies, OI and non-AIDS-related malignancies decreased significantly among homosexual men (MSM), whereas the risk of dying from (un)-intentional death increased significantly among injecting drug users (IDU). A non-significant increase in hepatitis/liver-related death was seen in MSM, IDU and haemophiliacs. CONCLUSION: Overall and cause specific mortality decreased following the introduction of HAART. OI remain the most common COD in the HAART era, suggesting that AIDS-related events will continue to be important in the future. Future trends in COD should be monitored using standardized guidelines.

Smit C, Lindenburg K, Geskus RB, Brinkman K, Coutinho RA, Prins M. 2006. Highly active antiretroviral therapy (HAART) among HIV-infected drug users: a prospective cohort study of sexual risk and injecting behaviour. Addiction, 101 (3), pp. 433-440. | Show Abstract | Read more

AIMS: To study sexual risk and injecting behaviour among HIV-infected drug users (DU) receiving highly active antiretroviral therapy (HAART). DESIGN AND SETTING: As part of an ongoing prospective cohort study, HIV-infected DU who commenced HAART (n=67) were matched with those not starting HAART (n=130) on CD4 cell counts, duration of cohort participation, age and calendar year of visit. Immunological and virological responses of the HAART-treated DU were compared with the HAART-treated homosexual men from the same cohort (n=212). MEASUREMENTS: Trends in behaviour and therapeutic response were tested with a logistic regression model adjusted for repeated measurements and a piecewise random effects model, respectively. FINDINGS: Non-HAART users reported more episodes of injecting than HAART users. In both groups injecting declined over time with no effect of HAART initiation. Before HAART initiation an increase in sexual risk behaviour was observed among those who had been assigned to receive HAART; their sexual risk behaviour declined thereafter. No change in sexual risk behaviour was found among non-HAART users. Relative to homosexual men, DU had a similar initial therapeutic response, but DU started HAART at lower CD4 cell counts and higher viral load levels. Conclusion DU who are treated with HAART are not increasing their risk behaviour, and their early response to HAART is similar to homosexual men. However, before the treated DU received HAART they were seen to inject less often than those not treated with HAART. This suggests that selection of potential HAART starters is based on limited drug use. Although the DU who commence HAART are a selected group, our results show that HIV-infected DU can be treated effectively.

Bakker B, Oostdijk W, Geskus RB, Stokvis-Brantsma WH, Vossen JM, Wit JM. 2006. Patterns of growth and body proportions after total-body irradiation and hematopoietic stem cell transplantation during childhood. Pediatr Res, 59 (2), pp. 259-264. | Show Abstract | Read more

Patterns of growth and body proportions were studied in 75 children receiving total-body irradiation (TBI) and hematopoietic stem cell transplantation (SCT) before onset of puberty. Of the 19 patients receiving GH, only data obtained before onset of GH were included. Thirty-two patients reached final height (FH). Median change in height SD score (SDS) between SCT and FH was -1.7 in boys and -1.1 in girls. Peak height velocity (PHV) was decreased in the majority of the patients (median PHV 5.7 cm/y in boys and 5.3 cm/y in girls), even though it occurred at appropriate ages. Changes in body proportions were analyzed by linear mixed-effects models. Decrease in sitting height SDS did not differ between boys and girls. In boys, decrease in leg length SDS was of comparable magnitude, whereas, in girls, decrease in leg length was less pronounced, leading to a significant decrease in SDS for sitting height/height ratio in girls only. The sex-specific effects of several variables on height SDS were analyzed by linear mixed-effects modeling, showing a slightly faster decrease in younger children and a more pronounced decrease during puberty in boys compared with girls. We conclude that 1) younger children are more susceptible to growth retardation after TBI and SCT, 2) pubertal growth is more compromised in boys, and 3) leg growth is relatively less affected in girls, possibly due to a high incidence of gonadal failure in girls.

Schade RP, Schinkel J, Roelandse FWC, Geskus RB, Visser LG, van Dijk JMC, Voormolen JHC, Van Pelt H, Kuijper EJ. 2006. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. J Neurosurg, 104 (1), pp. 101-108. | Show Abstract | Read more

OBJECT: Routine microbiological and chemical analysis of cerebrospinal fluid (CSF) is often performed to diagnose external drainage-related bacterial meningitis (ED-BM) at an early stage. A cohort study was performed to investigate the value of several commonly used CSF parameters for the prediction and diagnosis of ED-BM. METHODS: In a cohort of 230 consecutive patients in whom external drains had been placed, CSF samples were collected daily, prospectively evaluated for the presence of bacteria using Gram stain and microbiological culture, and analyzed for leukocyte count, protein concentration, glucose concentration, and ratio of CSF glucose to blood glucose. In addition, the CSF concentration of interleukin-6 (IL-6) was determined. The definition of ED-BM was based on positive culture results in combination with clinical symptoms. A matched case-control study was performed to evaluate the cohort longitudinally and to control for biasing factors such as duration of external drainage. External drainage-related bacterial meningitis developed in 22 patients (9.6%). Results from analyses of 1516 CSF samples showed no significant differences between the patients in whom ED-BM developed and a control group without ED-BM during the first 3 days of infection or during the 3 days preceding the infection with regard to leukocyte count, protein concentration, glucose concentration, and CSF/blood glucose ratio. No significant difference between groups was found for the CSF IL-6 concentration during the 3 days preceding the infection. In the matched case-control study, none of the parameters had significant predictive or diagnostic value for ED-BM in analyses using absolute values, ratios, and differences between the current and previous day's values. A comparison of the results from Gram stains and CSF cultures showed that the Gram staining had a very high specificity (99.9%) but a low sensitivity (18% [four of 22 patients] on the 1st day of infection and 60% [nine of 15 patients] on the 2nd day). CONCLUSIONS: Severe disturbances in the CSF of patients with external drains limit the value of routine CSF analysis for prediction or diagnosis of ED-BM. Routine Gram stain of CSF has also limited predictive or diagnostic value due to its low sensitivity in screening for ED-BM.

Kramer GWPM, Wanders SL, Noordijk EM, Vonk EJA, van Houwelingen HC, van den Hout WB, Geskus RB, Scholten M, Leer J-WH. 2005. Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol, 23 (13), pp. 2962-2970. | Show Abstract | Read more

PURPOSE: A national multicenter randomized study compared the efficacy of 2 x 8 Gy versus our standard 10 x 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non-small-cell lung cancer. PATIENTS AND METHODS: Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival. RESULTS: Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 x 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 x 8-Gy. Survival in the 10 x 3-Gy arm was significantly (P = .03) better than in the 2 x 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%). CONCLUSION: The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.

Xiridou M, Kretzschmar M, Geskus R. 2005. Competition of pathogen strains leading to infection with variable infectivity and the effect of treatment. Math Biosci, 197 (2), pp. 153-172. | Show Abstract | Read more

A model for the spread of two strains of a pathogen leading to an infection with variable infectivity is considered. The course of infection is described by two stages with different infectivity levels. The model is extended to account for treatment by including a third stage with different infectivity and survival for those treated. The contribution of each stage to incidence and prevalence is investigated and the effect of infectivity and survival on the basic reproduction ratio is examined. Standard equilibrium analysis is performed for both models, revealing that the successful strain is the one with highest reproduction ratio. If therapy, however, is more effective against the strain that wins in the absence of treatment and its reproduction ratio is sufficiently reduced, it might be outcompeted by the other strain after treatment becomes widely available. In this case, early introduction of treatment can prevent a major outbreak.

van der Lugt JCT, Geskus RB, Rozing PM. 2005. Limited influence of prosthetic position on aseptic loosening of elbow replacements: 125 elbows followed for an average period of 5.6 years. Acta Orthop, 76 (5), pp. 654-661. | Show Abstract | Read more

BACKGROUND: Aseptic loosening of elbow replacements, seen in long-term follow-up, remains a problem. In this study, we attempted to determine the influence of cementing technique, prosthetic position, different component sizes, use of a bone plug, and intraoperative fractures on the development and progression of radiolucent lines and aseptic loosening. METHODS: We studied standard radiographs of 125 primary Souter-Strathclyde total elbow prostheses using the Wrightington method. Additionally, 104 preoperative radiographs were available for analysis. We used a Markow statistical model to detect relationships between all factors described above. RESULTS: After a mean follow-up time of 5.5 (2-19) years, 21 (17%) prostheses had loosened radiographically (10-year survival: 65%). When the humeral component was tilted more medially or more anteriorly, we found development of radiolucent lines at the medial condyle and at the posterior side of the humeral component. However, the progression of these lines was not influenced by these positions. No other prognostic factors for radiolucent lines or aseptic loosening were found. INTERPRETATION: Despite the small number of elbows studied, the weak influence of prosthetic position on aseptic loosening gives more ground for a multifactorial cause for aseptic loosening of the Souter-Strathclyde total elbow prosthesis.

Mekonnen Y, Geskus RB, Hendriks JCM, Messele T, Borghans J, Miedema F, Wolday D, Coutinho RA, Dukers NHTM. 2005. Low CD4 T cell counts before HIV-1 seroconversion do not affect disease progression in Ethiopian factory workers. J Infect Dis, 192 (5), pp. 739-748. | Show Abstract | Read more

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-uninfected Ethiopians have lower CD4 T cell counts than do other populations in Africa and industrialized countries. We studied whether this unique immunological profile results in shorter survival times in HIV-1-infected Ethiopians. METHODS: Data from an open cohort study of 149 HIV-1-infected factory workers in Ethiopia for 1997-2002 were used. To estimate survival times, a continuous-time Markov model was designed on the basis of CD4 T cell counts and World Health Organization clinical staging. By use of a random-effects model, decline in CD4 T cell counts was compared between HIV-1-infected Ethiopian and Dutch individuals. RESULTS: Median survival times were in the range of 9.1-13.7 years, depending on the approach used. This range is similar to that for populations in industrialized countries before the advent of antiretroviral therapy. Ethiopians had a lower annual decline in CD4 T cell counts than did Dutch individuals, which remained when groups with similar CD4 T cell count categories were compared. Moreover, the slower decline in CD4 T cell counts was not due merely to lower HIV-1 RNA loads or an absence of syncytium-inducing/X4 HIV-1 subtype C strains in Ethiopians. CONCLUSIONS: Low baseline CD4 T cell counts do not imply shorter survival times in Ethiopians than in other populations, presumably because of a slower decline in CD4 T cell counts.

Termorshuizen F, Krol A, Prins M, Geskus R, van den Brink W, van Ameijden EJC. 2005. Prediction of relapse to frequent heroin use and the role of methadone prescription: an analysis of the Amsterdam Cohort Study among drug users. Drug Alcohol Depend, 79 (2), pp. 231-240. | Show Abstract | Read more

The risk of relapse into frequent heroin use was studied among 732 participants of the Amsterdam Cohort Study (ACS) on HIV/AIDS among drug users, who experienced an episode of abstinence from or occasional use of heroin. Participants of the ACS were recruited primarily from easy access ("low-threshold") methadone programs. The duration of abstinence/occasional use and relative risks (RR) of relapse were estimated by analyzing 1577 episodes by means of survival analysis using characteristics of patients and methadone treatment as covariates. The majority of episodes (85.8%) were followed by relapse within 5 years. Less education, intense use of heroin prior to the episode of abstinence or well-controlled use, occasional use of heroin and intense use of cocaine during the episode, and having a drug-using partner or having no partner were significantly associated with a higher risk of relapse. Among frequent attendees of a "low-threshold" methadone program, relapse was associated with the daily dose of methadone: RR for dosages <40 and 40-60 mg, compared with doses of >100mg, were 1.45 (P<0.01) and 1.59 (P<0.01), respectively. No beneficial influence was revealed of methadone dosage or program attendance in itself on the risk of relapse into cocaine. High doses of methadone in a harm-reduction setting extend the duration of an episode of no or occasional use of heroin. Other factors, such as no occasional use of heroin during the episode, no use of cocaine, and having a non-using partner, seem to be equally important.

Geskus RB, Meyer L, Hubert J-B, Schuitemaker H, Berkhout B, Rouzioux C, Theodorou ID, Delfraissy J-F, Prins M, Coutinho RA. 2005. Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development. J Acquir Immune Defic Syndr, 39 (3), pp. 321-326. | Show Abstract | Read more

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.

Kivelä PS, Krol A, Salminen MO, Geskus RB, Suni JI, Anttila V-J, Liitsola K, Zetterberg V, Miedema F, Berkhout B et al. 2005. High plasma HIV load in the CRF01-AE outbreak among injecting drug users in Finland. Scand J Infect Dis, 37 (4), pp. 276-283. | Show Abstract | Read more

An explosive outbreak of HIV-1 caused by the recombinant subtype AE (CRF01-AE) was detected in 1998 among Finnish injecting drug users (IDUs). These IDUs were compared with IDUs from the Amsterdam Cohort Study (ACS) infected with subtype B, to detect possible differences between 2 western IDU cohorts infected with different subtypes. Markers for progression (viral load and CD4+lymphocyte count) were compared between 93 IDUs with CRF01-AE and 63 IDUs with subtype B. Only persons with a seroconversion interval =2 y were included. During 48 months of follow-up, both cohorts were similar in CD4+ cell decline, but the Finnish IDUs had 0.34-0.94 log10 copies/ml higher viral loads. The Amsterdam IDUs had a low viral load (<1000 copies/ml) significantly more often than the Finnish IDUs. The difference could not be explained by the use of antiretrovirals. The higher viral load may have contributed to the rapid spread of the recombinant virus in the Finnish outbreak.

Van der Bij AK, Kloosterboer N, Prins M, Boeser-Nunnink B, Geskus RB, Lange JMA, Coutinho RA, Schuitemaker H. 2005. GB virus C coinfection and HIV-1 disease progression: The Amsterdam Cohort Study. J Infect Dis, 191 (5), pp. 678-685. | Show Abstract | Read more

BACKGROUND: The effect that GB virus C (GBV-C) coinfection has on human immunodeficiency virus type 1 (HIV-1) disease progression is controversial and therefore was studied in 326 homosexual men from the prospective Amsterdam Cohort Studies who had an accurately estimated date of HIV-1 seroconversion and were followed up for a median period of 8 years. METHODS: A first plasma sample, obtained shortly after HIV-1 seroconversion, and a last plasma sample, obtained before 1996, were tested for GBV-C RNA and envelope protein-2 antibodies. The effect that GBV-C has on HIV-1 disease progression was studied by use of time-dependent Cox proportional-hazards models with adjustment for baseline variables and time-updated HIV-1 RNA and CD4(+) cell count. RESULTS: Men who lost GBV-C RNA between collection of the first sample and collection of the last sample had a nearly 3-fold-higher risk of HIV-1 disease progression than did men who had never had GBV-C RNA. This effect became much smaller after adjustment for time-updated CD4(+) cell count. CONCLUSION: Rather than a positive effect of GBV-C RNA presence, a negative effect of GBV-C RNA loss on HIV-1 disease progression was found, which disappeared after adjustment for time-updated CD4(+) cell count. We therefore hypothesize that GBV-C RNA persistence depends on the presence of a sufficient number of CD4(+) cells--and that the CD4(+) cell decrease associated with HIV-1 disease progression is a cause, not a consequence, of GBV-C RNA loss.

van der Lugt JCT, Geskus RB, Rozing PM. 2005. Primary Souter-Strathclyde total elbow prosthesis in rheumatoid arthritis. Surgical technique. J Bone Joint Surg Am, 87 Suppl 1 (Pt 1), pp. 67-77. | Show Abstract | Read more

BACKGROUND: Total elbow arthroplasty is a well-established treatment for the painful elbow joint in patients with rheumatoid arthritis. We present the results of what we believe to be the first prospective study of the Souter-Strathclyde total elbow prosthesis. METHODS: Between June 1982 and December 2000, 204 primary total elbow prostheses were inserted in 166 patients who had rheumatoid arthritis. No patient was lost to follow-up. The mean duration of follow-up was 6.4 years. All patients were examined preoperatively, at one and two years postoperatively, and at regular intervals thereafter. RESULTS: Six of the 204 elbows had pain at rest at the time of the latest follow-up. Ten patients (ten elbows) without previous neurological symptoms had development of paresthesias in the distribution of the ulnar nerve postoperatively. Patients who had pain at rest or at night and those who had ulnar nerve symptoms preoperatively were found to have a significant chance of having the same complaints postoperatively. Pain at rest or at night and a decrease in function during the follow-up period were associated with humeral loosening. Twenty-four elbows had revision of the total elbow prosthesis because of loosening of the humeral component (ten), loosening after fracture (six), dislocation (four), infection (two), restricted range of motion (one), or fracture of the middle part of the humeral shaft, proximal to the prosthesis (one). One prosthesis was removed because of humeral loosening, and eight were removed because of deep infection. Another five prostheses were radiographically loose at the time of the latest follow-up. The rate of implant survival, according to the method of Kaplan-Meier, was 77.4% after ten years and 65.2% after eighteen years. CONCLUSIONS: Total elbow replacement is associated with a high complication rate and therefore may be warranted only for seriously disabled patients. Currently, the results associated with the Souter-Strathclyde total elbow prosthesis are comparable with the results associated with other prostheses, but loosening of the humeral component remains a concern.

van der Bij AK, Prins M, Geskus RG. 2004. Response to 'GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality' by Bjorkman et al. AIDS, 18 (17), pp. 2344-2345.

van der Lugt JCT, Geskus RB, Rozing PM. 2004. Influence of previous open synovectomy on the outcome of Souter-Strathclyde total elbow prosthesis. Rheumatology (Oxford), 43 (10), pp. 1240-1245. | Show Abstract | Read more

OBJECTIVES: Open synovectomy of the elbow joint is often performed in early stages of rheumatoid arthritis. Because of poor long-term results after synovectomy, insertion of a total elbow prosthesis is commonly used as a secondary procedure. The aim of this study is to evaluate the influence of previous synovectomy on the outcome after placement of a total elbow prosthesis. METHODS: We inserted 204 primary Souter-Strathclyde total elbow prostheses for rheumatoid arthritis. Two groups could be distinguished: group A with previous synovectomy 3.9 yr (mean) before the elbow replacement (n = 33) and group B without previous synovectomy (n = 171). The mean follow-up was 5.8 yr for group A and 6.3 yr for group B. All patients were assessed clinically and radiologically before the operation, 1 and 2 years later and then at regular intervals. The effect of previous synovectomy was analysed via a Cox model and a generalized linear mixed model for binomial data with multivariate normal random effects. RESULTS: No statistically significant effect of previous synovectomy on pain, function or complaints of the ulnar nerve could be found post-operatively. The post-operative flexion was significantly higher in group B than in group A. The complication-rates were similar for both groups. The overall survival rate for respectively group A and B with revision as endpoint was 66.9% (s.e. 13.4) versus 79.6 (s.e. 4.3) after 10 yr. CONCLUSIONS: Previous synovectomy does not diminish the outcome after total elbow prosthesis in this series and could therefore be considered in early, painful stages of rheumatoid destruction of the elbow joint.

Smit C, Geskus R, Uitenbroek D, Mulder D, Van Den Hoek A, Coutinho RA, Prins M. 2004. Declining AIDS mortality in Amsterdam: contributions of declining HIV incidence and effective therapy. Epidemiology, 15 (5), pp. 536-542. | Show Abstract | Read more

INTRODUCTION: We aimed to evaluate the impact of highly active antiretroviral therapy (HAART) on AIDS mortality, taking into account earlier HIV incidence patterns. METHODS: Using AIDS Surveillance data (1982-2000), we calculated the observed course of the AIDS epidemic among homosexual men in Amsterdam, The Netherlands. We used the HIV incidence patterns (1980-2000) among homosexual men participating in the hepatitis B vaccine trial and the Amsterdam Cohort Study and those attending the Amsterdam sexual transmitted infections clinic, together with the time from seroconversion to AIDS and death in the pre-HAART era, to estimate the natural course of the AIDS epidemic if HAART had not been introduced. RESULTS: The estimated course of the AIDS epidemic without the benefits of HAART showed a decline in AIDS mortality, but this estimated decline was not as strong as the observed decline. Taking into account the HIV incidence over calendar time, we estimated that 331 deaths among homosexual men were prevented by HAART between 1996 and 2000 in Amsterdam. CONCLUSION: The decline in AIDS mortality was the result of both HAART and a decline in the HIV incidence in the early 1980s. When evaluating the effect of HAART on mortality, changes in HIV incidence must also be considered.

Xiridou M, Geskus R, de Wit J, Coutinho R, Kretzschmar M. 2004. Primary HIV infection as source of HIV transmission within steady and casual partnerships among homosexual men. AIDS, 18 (9), pp. 1311-1320. | Show Abstract | Read more

OBJECTIVE: To assess the contribution of primary or acute HIV infection to the transmission of HIV among homosexual men in Amsterdam and to investigate how the initiation of treatment during primary HIV infection (PHI) can affect the incidence of HIV infection. METHODS: A mathematical model describing HIV transmission among homosexual men was developed. In the model, men are involved in both steady and casual partnerships. Infectivity is higher during PHI than during chronic HIV infection. Highly active antiretroviral therapy reduces infectivity and increases the time to the development of AIDS. Its effect is enhanced if treatment is initiated during PHI. HIV incidence and the fraction of transmission attributed to PHI were calculated for different levels of treatment efficacy. RESULTS: Primary infections account for 35% of HIV transmissions from casual partners and 6% of transmissions from steady partners. Among all new infections, only 11% occurs during PHI. Therefore, the effect of treatment during PHI on the incidence of HIV is limited. However, in a community with higher risky behaviour among casual partners, the fraction of transmission attributed to PHI increases to 25%. CONCLUSION: Primary infections play a more important role in transmission from casual partners than in transmission from steady partners. Therefore, in communities in which steady partners account for the majority of new infections and the epidemic is at an advanced phase, the contribution of PHI to the transmission of HIV is rather small and the effect of early treatment on the incidence of HIV is limited.

van der Lugt JCT, Geskus RB, Rozing PM. 2004. Primary Souter-Strathclyde total elbow prosthesis in rheumatoid arthritis. J Bone Joint Surg Am, 86-A (3), pp. 465-473. | Show Abstract | Read more

BACKGROUND: Total elbow arthroplasty is a well-established treatment for the painful elbow joint in patients with rheumatoid arthritis. We present the results of what we believe to be the first prospective study of the Souter-Strathclyde total elbow prosthesis. METHODS: Between June 1982 and December 2000, 204 primary total elbow prostheses were inserted in 166 patients who had rheumatoid arthritis. No patient was lost to follow-up. The mean duration of follow-up was 6.4 years. All patients were examined preoperatively, at one and two years postoperatively, and at regular intervals thereafter. RESULTS: Six of the 204 elbows had pain at rest at the time of the latest follow-up. Ten patients (ten elbows) without previous neurological symptoms had development of paresthesias in the distribution of the ulnar nerve postoperatively. Patients who had pain at rest or at night and those who had ulnar nerve symptoms preoperatively were found to have a significant chance of having the same complaints postoperatively. Pain at rest or at night and a decrease in function during the follow-up period were associated with humeral loosening. Twenty-four elbows had revision of the total elbow prosthesis because of loosening of the humeral component (ten), loosening after fracture (six), dislocation (four), infection (two), restricted range of motion (one), or fracture of the middle part of the humeral shaft, proximal to the prosthesis (one). One prosthesis was removed because of humeral loosening, and eight were removed because of deep infection. Another five prostheses were radiographically loose at the time of the latest follow-up. The rate of implant survival, according to the method of Kaplan-Meier, was 77.4% after ten years and 65.2% after eighteen years. CONCLUSIONS: Total elbow replacement is associated with a high complication rate and therefore may be warranted only for seriously disabled patients. Currently, the results associated with the Souter-Strathclyde total elbow prosthesis are comparable with the results associated with other prostheses, but loosening of the humeral component remains a concern. LEVEL OF EVIDENCE: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.

Stolte IG, Dukers NHTM, Geskus RB, Coutinho RA, de Wit JBF. 2004. Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active antiretroviral therapy: a longitudinal study. AIDS, 18 (2), pp. 303-309. | Show Abstract | Read more

OBJECTIVE: To investigate longitudinally the association between highly active antiretroviral therapy (HAART)-related beliefs and the change from protected to unprotected anal intercourse with casual partners on an individual level. METHODS: The study population included 217 HIV-negative homosexual men participating in the Amsterdam Cohort Study from September 1999 to May 2002, including five data waves with a 6-month interval. The selection criteria were: being under 31 years of age, having had anal sex with casual partners in the preceding 6 months, and participating in at least two data waves. Information was collected on the individual change from protected to unprotected receptive anal intercourse (URAI) and unprotected insertive anal intercourse (UIAI) and the level of agreement with different HAART-related beliefs. RESULTS: The majority of men disagreed with the three treatment-belief factors that resulted from the principal component analysis: perceiving less HIV/AIDS threat since HAART, perceiving less need for safe sex since HAART, and perceiving high effectiveness of HAART in curing HIV/AIDS. Multivariate analyses revealed that the more men inclined to agree with the belief 'perceiving less HIV/AIDS threat', the more likely they were to change to URAI (adjusted OR 1.60; 95% CI 1.16-2.22). CONCLUSION: Homosexual men are quite realistic about the effectiveness of HAART, the continued need for condom use, and the HIV/AIDS threat since HAART. However, a tendency towards agreement with 'perceiving less HIV/AIDS threat' was found to predict an individuals' change to URAI. This finding supports the hypothesis of a causal relationship between decreased HIV/AIDS threat since HAART and a change to URAI.

Mekonnen Y, Sanders E, Aklilu M, Tsegaye A, Rinke de Wit TF, Schaap A, Wolday D, Geskus R, Coutinho RA, Fontanet AL. 2003. Evidence of changes in sexual behaviours among male factory workers in Ethiopia. Ethiop Med J, 41 Suppl 1 pp. 51-59. | Show Abstract

OBJECTIVE: To assess changes in sexual behaviours among male factory workers in Ethiopia. DESIGN: Open cohort studies in two factories near Addis Ababa. DATA AND METHODS: At intake and biannual follow-up visits, data were collected on sexual behaviours including casual sex, sex with commercial sex workers (CSW), condom use, and history of sexually transmitted diseases (STDs) as indicated by genital discharge and genital ulcer. Health education, HIV testing, and counselling were offered to all participants. RESULTS: Between February 1997 and December 1999, 1124 males were enrolled in the two cohort studies. At intake, the prevalence of casual sex in the past year, sex with CSWs, condom use with the last casual partner, history of genital discharge in the past 5 years, and history of genital ulcer in the past 5 years were 9.7, 43.4, 38.8 (Akaki site only), 10.6 and 2.1%, respectively. At the Wonji site, the intake prevalence of casual sex, sex with CSW, and history of genital discharge decreased significantly by calendar year between 1997 and 1999. At both sites combined, between the first and the fourth follow-up visits, there was a decline in the proportion of males reporting recent causal sex (from 17.5 to 3.5%, P < 0.001), sex with CSWs (from 11.2 to 0.75%, P < 0.001), and genital discharge (from 2.1 to 0.6%, P = 0.004). CONCLUSION: There was a decline over time in risky sexual behaviours reported by cohort participants. Part of this decline occurred independently of cohort interventions.

Xiridou M, Geskus R, De Wit J, Coutinho R, Kretzschmar M. 2003. The contribution of steady and casual partnerships to the incidence of HIV infection among homosexual men in Amsterdam. AIDS, 17 (7), pp. 1029-1038. | Show Abstract | Read more

OBJECTIVE: To assess the relative contribution of steady and casual partnerships to the incidence of HIV infection among homosexual men in Amsterdam, and to determine the effect of increasing sexually risky behaviours among both types of partners in the era of highly active antiretroviral therapy (HAART). METHODS: A mathematical model was developed for the spread of HIV infection among young homosexual men in Amsterdam after the introduction of HAART. The model describes the formation of both steady and casual partnerships. Behavioural parameters were estimated separately for steady and casual partners from the Amsterdam Cohort Study among young homosexual men. HIV incidence and the fraction of new infections attributed to casual contacts were calculated from the model, allowing for uncertainty in the increases in risky behaviour, the effect of HAART, and levels of HIV testing and HAART administration. RESULTS: Currently, 86% (range 74-90%) of new HIV infections occur within steady partnerships. A reduction of 75-99% in infectivity caused by HAART will be counterbalanced by increases of 50% (range 30-80%) in risky behaviour with steady partners, but not by increases of up to 100% with casual partners. If HIV testing is increased from 42 to 80% and HAART administration from 70 to 85%, then even an increase of 100% in risk-taking with steady partners will not outweigh the effect of HAART. CONCLUSION: Most new HIV infections among homosexual men in Amsterdam occur within steady relationships. Prevention measures should address risky behaviour, specifically with steady partners, and the promotion of HIV testing.

Geskus RB, Miedema FA, Goudsmit J, Reiss P, Schuitemaker H, Coutinho RA. 2003. Prediction of residual time to AIDS and death based on markers and cofactors. J Acquir Immune Defic Syndr, 32 (5), pp. 514-521. | Show Abstract | Read more

A model was constructed that estimates the probability of an HIV-infected individual developing AIDS or dying within a certain time span if left untreated, based on the most recent CD4 lymphocyte count, HIV-1 RNA load, and HIV-1 phenotype, together with age, time since seroconversion, and two genetic cofactors. The model helps clinicians in deciding when to start highly active antiretroviral treatment (HAART). Data from the Amsterdam Cohort Study among homosexual men restricted to individuals with an estimated date of seroconversion (N = 280) were used. Individual predictions based on several combinations of marker and cofactor values were obtained, and their accuracy was measured using two indices of predictive value. CD4 lymphocyte count and HIV RNA load have the highest predictive value and act independently. The predictive value of the HIV phenotype is only slightly lower and greatly enhances predictions at high CD4 counts. The CCR5-Delta32 and CCR2-64I alleles have no additional predictive value. Some predictive value is lost by not knowing time since seroconversion, and some effect of calendar period is present. In summary, for prognosis, the markers CD4 count, HIV-1 RNA load, and HIV-1 phenotype (at a high CD4 count) are equally important, and the genetic cofactors considered are of no use.

Mekonnen Y, Dukers NH, Sanders E, Dorigo W, Wolday D, Schaap A, Geskus RB, Coutinho RA, Fontanet A. 2003. Simple markers for initiating antiretroviral therapy among HIV-infected Ethiopians. AIDS, 17 (6), pp. 815-819. | Show Abstract | Read more

BACKGROUND: We explored the relevance of simple markers (clinical or laboratory markers not requiring sophisticated laboratories) in the decision of initiation of therapy in resource-poor settings. METHODS: Among HIV-infected Ethiopian cohort participants, simple markers predicting short-term death were examined using time-dependent Cox proportional hazards models. Timing of hypothetical treatment was compared between guidelines using the simple markers (based on presence of at least one marker), guidelines recommended by the United States Department of Health and Human Services (based on CD4 cell count and viral load), and guidelines for resource-limited settings recommended by the World Health Organization (WHO). RESULTS: From February 1997 to August 2001, 35 deaths were recorded among 155 HIV-positive participants. Simple independent predictors of death were low body mass index, HIV-related conditions, anaemia, and lymphocyte count < 1500 x 106/l. In such time as was covered by our study, 135 (87%) of 155 cohort participants would have had the same management under both the simple markers and the DHHS guidelines, i.e., would have been treated (n = 114, 74%) or not treated (n = 21, 14%). Of the 114 participants hypothetically treated under either set of guidelines, 91 (80%) would have started treatment at the same time. Application of the WHO guidelines for resource-limited settings (without CD4 cell counts) would have resulted in 11 participants dying without ever meeting a treatment indication during regular follow-up visits. CONCLUSION: Simple markers for the initiation of highly active antiretroviral therapy were identified among HIV-infected Ethiopian patients. The validity of these markers for monitoring patients' improvement following therapy remains to be evaluated.

Bogaards JA, Weverling GJ, Geskus RB, Miedema F, Lange JMA, Bossuyt PMM, Goudsmit J. 2003. Low versus high CD4 cell count as starting point for introduction of antiretroviral treatment in resource-poor settings: a scenario-based analysis. Antivir Ther, 8 (1), pp. 43-50. | Show Abstract

OBJECTIVE: To evaluate CD4 cell count-driven strategies for the initiation of highly active antiretroviral therapy (HAART) in terms of the reduction of the incidence of AIDS-defining events in resource-poor settings. METHODS: Data from the Amsterdam Cohort Study on HIV infection and AIDS were used to estimate the hazard of AIDS in untreated HIV-1 infection and after initiation of HAART, respectively, conditional on CD4 cell count. Different strategies for initiating therapy were compared by calculating the expected HAART administration rate and 1-year cumulative AIDS incidence in three different population settings, varying in the stage of HIV-1 infection at the time of presentation. RESULTS: Among 695 HIV-1-infected cohort participants, the 1-year AIDS incidence density (ID) ranged from 3.2 per 100 person-years for CD4 cell counts 600-700 cells/mm3, to 31.9 per 100 person-years for CD4 cell counts 100-200 cells/mm3 and 77.9 per 100 person-years for CD4 cell counts below 100 cells/mm3. Upon initiation of HAART, the ID in the lowest CD4 strata declined to 13.3 and 16.3 per 100 person-years, respectively. Extrapolated to developing countries, supply of HAART to patients presenting with HIV-1 infection below 200 CD4 cells/mm3 is expected to give an administration rate of 67%, while the AIDS incidence will drop from over 30% to almost 10%. CONCLUSIONS: Introduction of HAART in populations with advanced HIV-1 infection can accomplish a threefold reduction of the AIDS incidence when HAART is administered to patients with CD4 cell counts below 200 cells/mm3. In a hospital-based setting in resource-poor environments this ensures an efficient treatment allocation.

Mekonnen Y, Sanders E, Aklilu M, Tsegaye A, Rinke de Wit TF, Schaap A, Wolday D, Geskus R, Coutinho RA, Fontanet AL. 2003. Evidence of changes in sexual behaviours among male factory workers in Ethiopia. AIDS, 17 (2), pp. 223-231. | Show Abstract | Read more

OBJECTIVE: To assess changes in sexual behaviours among male factory workers in Ethiopia. DESIGN: Open cohort studies in two factories near Addis Ababa. DATA AND METHODS: At intake and biannual follow-up visits, data were collected on sexual behaviours including casual sex, sex with commercial sex workers (CSW), condom use, and history of sexually transmitted diseases (STDs) as indicated by genital discharge and genital ulcer. Health education, HIV testing, and counselling were offered to all participants. RESULTS: Between February 1997 and December 1999, 1124 males were enrolled in the two cohort studies. At intake, the prevalence of casual sex in the past year, sex with CSWs, condom use with the last casual partner, history of genital discharge in the past 5 years, and history of genital ulcer in the past 5 years were 9.7, 43.4, 38.8 (Akaki site only), 10.6 and 2.1%, respectively. At the Wonji site, the intake prevalence of casual sex, sex with CSW, and history of genital discharge decreased significantly by calendar year between 1997 and 1999. At both sites combined, between the first and the fourth follow-up visits, there was a decline in the proportion of males reporting recent casual sex (from 17.5 to 3.5%, < 0.001), sex with CSWs (from 11.2 to 0.75%, < 0.001), and genital discharge (from 2.1 to 0.6%, = 0.004). CONCLUSION: There was a decline over time in risky sexual behaviours reported by cohort participants. Part of this decline occurred independently of cohort interventions.

&NA;. 2002. FAST TRACK: HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: using a novel approach for detecting recent infections AIDS, 16 (12), pp. 1707-1707. | Read more

Rinke de Wit TF, Tsegaye A, Wolday D, Hailu B, Aklilu M, Sanders E, Hagos M, Kliphuis A, Pollakis G, Krol A et al. 2002. Primary HIV-1 subtype C infection in Ethiopia. J Acquir Immune Defic Syndr, 30 (5), pp. 463-470. | Show Abstract | Read more

Between 1997 and 2001, 1624 Ethiopian factory workers were enrolled in prospective HIV-1 cohorts in Ethiopia, at Akaki and Wonji towns. HIV-1 seroprevalence at intake was 11.8% (Akaki) and 7.1% (Wonji). HIV-1 incidence was .75 per 100 person-years (Akaki) and .35 per 100 person-years (Wonji). During follow up, CD4 T-cell counts remained significantly lower and CD8 T-cell counts significantly higher in Ethiopian seroconverters compared with Dutch seroconverters. Viral loads were lower in Ethiopian seroconverters versus Dutch seroconverters in the first months after seroconversion, subsequently increasing to similar levels. All 20 Ethiopian seroconverters were infected with HIV-1 subtype C (15 with sub-cluster C' and 5 with sub-cluster C). Viral loads were higher in sub-cluster C'-infected Ethiopian seroconverters. One subject demonstrated a window period of at least 204 days, combined with a high preseroconversion viral load and no decline of CD4 T cells over a follow-up period of at least 3 years.

Geskus RB. 2002. Markers and residual time to AIDS. Neth J Med, 60 (7 Suppl), pp. 27-32. | Show Abstract

The value of immunological and virological markers as predictors of progression to AIDS, or death by AIDS, is a topic of much current interest. Mostly, the influence of markers is investigated in a time-dependent or a baseline proportional hazard model, relating time-varying or baseline marker values to the instantaneous AIDS risk. Low CD4 numbers have been shown to increase the AIDS risk. Based on this finding, the decision to start treatment has mainly been based on a person's CD4 count. Over the last couple of years, high viral load has been added as a criterion to start treatment. Relative hazards do not directly reveal information on time to AIDS. A better approach is to base the decision to start treatment on an estimate of a person's residual time to AIDS or death by AIDS. Discrimination and calibration are introduced as criteria to compare prediction models. Two models to predict residual time to AIDS are discussed. One is a proportional hazards model based on baseline marker values; the other one is a combined model of a time-dependent proportional hazards model and a longitudinal model for marker development.

Dukers NHTM, Spaargaren J, Geskus RB, Beijnen J, Coutinho RA, Fennema HSA. 2002. HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: using a novel approach for detecting recent infections. AIDS, 16 (10), pp. F19-F24. | Show Abstract | Read more

OBJECTIVE: Dramatic increases have occurred in sexually transmitted diseases (STD) and in sexual risk behaviour among homosexual men in Amsterdam and internationally. We investigated whether these trends indicate a resurgence of the HIV epidemic. METHODS: HIV incidence was determined among homosexual attendees of an STD clinic in Amsterdam, who had participated in semi-annual anonymous unlinked cross-sectional HIV prevalence studies from 1991 to 2001. Stored HIV-seropositive samples were tested with a less-sensitive HIV assay and, if non-reactive, were further tested for the presence of antiretroviral drugs, indicative of the use of highly active antiretroviral therapy. Seropositive men who tested non-reactive on the less-sensitive assay and had not used antiretroviral drugs were classified as recently infected (< 170 days). Annual HIV incidence and its changes were examined. RESULTS: Among 3090 homosexual participants (median age 34 years), 454 were HIV infected, of whom 37 were recently infectioned. From 1991 to 2001 the overall incidence was 3.0 infections/100 person-years. Incidence increased over time (P = 0.02) and, strikingly, the increase was evident in older (> or = 34 years) men (P < 0.01), but not in the young. Of men recently infected, 84% (n = 31) were unaware of their infection and 70.3% (n = 26) had a concurrent STD. These 26 men reportedly had sex with a total of 315 men in the preceding 6 months. CONCLUSION: HIV incidence is increasing among homosexual attendees of an STD clinic. It is imperative to trace recently infected individuals, because they are highly infectious, and can thus play a key role in the spread of HIV.

Geskus RB. 2002. A new proof of a theorem on M-matrices Linear Algebra and its Applications, 348 (1-3), pp. 139-144. | Show Abstract | Read more

We provide a new and simpler proof of the following result by J.P. Milaszewicz and L.P. Moledo [Linear Algebra Appl. 195 (1993) 1]. Consider the equation Ax = y, with A a nonsingular M-matrix. Suppose that yK ≠ 0 for each nucleus K, and that x i > 0 whenever y i < 0. Then x has only positive coordinates. The same method is used to prove their results on bounds for the solutions. Moreover, the conditions are weakened. © 2002 Elsevier Science Inc. All rights reserved.

Maas J, Termorshuizen F, Geskus RB, Goettsch W, Coutinho RA, Miedema F, Van Loveren H. 2002. Amsterdam Cohort Study on HIV and AIDS: impact of exposure to UVR as estimated by means of a 2-year retrospective questionnaire on immune parameters in HIV positive males. Int J Hyg Environ Health, 205 (5), pp. 373-377. | Show Abstract | Read more

We studied a group of HIV-infected homosexuals who participated in the Amsterdam Cohort Study on HIV and AIDS to investigate whether greater exposure to sunlight is associated with a less favorable course of some important immunological parameters. This was done because ultraviolet radiation (UVR) is potentially harmful to the cellular immunity and may enhance viral replication. The exposure to UVR was estimated by means of a 2-year retrospective questionnaire in 1997. Both a 2-year cumulative estimate and estimates by 3-monthly episodes were calculated. The associations with CD4+ T-cell count, CD4+/CD8+ T-cell ratio, and T-cell reactivity were investigated. First, the associations between the cumulative estimate and the individual slopes of these parameters during the 2 years covered by the questionnaire were explored by means of a robust regression analysis. Secondly, the short-term association with the estimate by episode was examined by means of a linear mixed-effect model for repeated measurements (LME). No statistically significant associations with the cumulative estimate were found. Although a trend to lower values of the immunological parameters studied after short-term greater exposure in the LME model was observed, the differences were not statistically significant either. These findings suggest that exposure to sunlight does not have a suppressive effect on the above mentioned immunological parameters in HIV-infected persons.

Termorshuizen F, Geskus RB, Roos MT, Coutinho RA, Van Loveren H. 2002. Seasonal influences on immunological parameters in HIV-infected homosexual men: searching for the immunomodulating effects of sunlight. Int J Hyg Environ Health, 205 (5), pp. 379-384. | Show Abstract | Read more

In view of the capacity of ultraviolet radiation (UVR) to induce suppression of various immunological parameters and to enhance the viral replication of HIV, we investigated whether seasonal influences on immunological parameters that are relevant for HIV infection could be identified. As the sunny season is associated with high levels of ambient UVR, a decline of immunological parameters and an increase of the HIV viral load during the summer months might ensue. We analysed the immunological data of the HIV-infected homosexual men who participated in the Amsterdam Cohort Study on HIV infection and AIDS (1984-1996; n = 556). The effect of season on the individual development of various immunological parameters in time was examined by means of a random effects model for repeated measurements. Lower levels in the mean number of CD4+ T cells and the mean CD4+/CD8+ ratio were found during summer and spring, respectively (P = 0.0001/0.0001). For the CD8+ T cells, high mean values were observed both in April and September (P = 0.0001). The highest T-cell reactivity values were found during the summer (P = 0.0001). No effect of season on the viral load was established. The seasonal effect on CD4+ T cells seemed to be more pronounced at a more advanced stage of the HIV infection. It is concluded that the lower CD4+ T-cell counts during summer support the notion that solar UVR may have a suppressive effect on the cellular immunity of HIV-infected persons. However, whether this observation can be attributed to the effect of ambient UVR solely is questionable, as the other immunological parameters follow different seasonal courses and other reports suggest that both internal and environmental factors influence immunological parameters.

Prins M, Geskus RB, Coutinho RA. 2001. [Roaming through methodology. XXXV. Bias in prevalent cohort studies of the natural course of disease]. Ned Tijdschr Geneeskd, 145 (45), pp. 2170-2172. | Show Abstract

The natural history of infectious diseases with a long asymptomatic incubation period has mainly been studied in cohorts of individuals already infected at study entry: the so-called prevalent cohort study. Because the time of infection is usually unknown in the prevalent cohort, in standard survival analysis it is common to use the time since entry into the cohort instead of the time since infection to study risk factors for disease progression. However, the use of the time since study entry may bias results. The two most important sources of bias are onset confounding and differential length-bias sampling. Because bias may occur, results derived from a prevalent cohort are not directly comparable to results derived from an incident cohort where the moment of infection is known.

Davidovich U, de Wit J, Albrecht N, Geskus R, Stroebe W, Coutinho R. 2001. Increase in the share of steady partners as a source of HIV infection: a 17-year study of seroconversion among gay men. AIDS, 15 (10), pp. 1303-1308. | Show Abstract | Read more

OBJECTIVES: To examine the share of steady versus casual partners as the source of HIV infection in gay male seroconversions between 1984 and 2000 and the effect of age at seroconversion on the source of HIV transmission. METHODS: The sample consisted of 144 seroconverstors from the Amsterdam Cohort Study among Homosexual Men. Questionnaires and post-seroconversion interviews were used to determine the source of HIV transmission. RESULTS: Analysis revealed an interaction effect between calendar year and age at seroconversion (P < 0.05). Younger seroconverters had higher odds ratios [odds ratio, 11.33; 95% confidence interval, 1.77--72.13] to be infected by their steady partner late in the AIDS epidemic: 15% (three of 20) between 1984 and 1987 versus 67% (six of nine) between 1994 and 2000. No such time effect was present for older seroconverters who were consistently more likely to be infected by a casual partner: 79% (37 of 47) between 1984 and 1987, and 83% (15 of 18) between 1994 and 2000. CONCLUSIONS: Young gay seroconverters today are more likely to have contracted HIV from a steady partner than from a casual partner, compared with early in the AIDS epidemic and compared also with older gay seroconverters. There is a pressing need for preventive measures addressing sexual risk behaviour within steady relationships among younger gay men.

Geskus RB. 2001. Methods for estimating the AIDS incubation time distribution when date of seroconversion is censored. Stat Med, 20 (5), pp. 795-812. | Show Abstract | Read more

In most cohort studies on HIV infection and AIDS, data on time from seroconversion to AIDS or death are doubly censored, both at the time origin and at the endpoint of interest. In epidemiological research, the most frequently adopted approach is to restrict the analysis to persons with narrow seroconversion intervals and to impute the midpoint of this interval as date of seroconversion. For many cohort studies, the consequence is that a substantial proportion of the data is not used. We consider four methods that are expected to be less biased when all cohort data are used: two imputation methods, conditional mean and multiple imputation, and two likelihood maximization methods. We derive the likelihood structure of the cohort data and clarify its dependence on study design. All methods are applied to data from the Amsterdam cohort study among injection drug users. In a simulation study the data generation process of this cohort study is imitated. The performance of midpoint, conditional mean and multiple imputation are compared. With midpoint imputation, both an analysis using the full data set, as well as one restricted to the cases with small seroconversion intervals, is performed. Conditional mean imputation comes out as the preferred method. It gives best results with respect to mean squared error. Moreover, when confidence intervals are computed through standard methods that ignore the uncertainty in the imputed date of seroconversion, coverage probabilities are almost correct.

Dukers NH, Geskus RB, Coutinho RA. 2001. Mucosal shedding of human herpesvirus 8. N Engl J Med, 344 (9), pp. 691.

Geskus RB. 2000. On the inclusion of prevalent cases in HIV/AIDS natural history studies through a marker-based estimate of time since seroconversion. Stat Med, 19 (13), pp. 1753-1769. | Show Abstract | Read more

In most cohort studies of HIV infection and AIDS, seroprevalent cases provide a substantial amount of information. Inclusion of these people in natural history studies requires a fairly unbiased method to estimate their seroconversion distribution. When a cohort-based estimate is not feasible, an alternative is to estimate individual seroconversion distributions, based on marker values at entry. In this paper, a non-parametric marker-based estimation method is developed. The method is applied to data from the Amsterdam cohort study on homosexual men. For seroprevalent cases who entered the study between October 1984 and April 1985, individual seroconversion distributions are estimated based on their first measured CD4 count. In subsequent survival analyses, dates of seroconversion are estimated via conditional mean imputation. Inclusion of these seroprevalent cases greatly improves the quality of the data. Age at seroconversion is a significant cofactor for disease progression, a result not found when analysis is restricted to those who seroconvert. To incorporate the uncertainty in the imputed date of seroconversion, a bootstrap procedure is developed for the computation of p-values and confidence intervals. In our analyses, standard procedures, which ignore the uncertainty in the imputed date of seroconversion, perform almost as well.

Dukers NH, Renwick N, Prins M, Geskus RB, Schulz TF, Weverling GJ, Coutinho RA, Goudsmit J. 2000. Risk factors for human herpesvirus 8 seropositivity and seroconversion in a cohort of homosexual men. Am J Epidemiol, 151 (3), pp. 213-224. | Show Abstract | Read more

Sexual and nonsexual modes of transmission of human herpesvirus 8 (HHV8) have been suggested, but specific routes remain unclear. Therefore, the objective of this study was to assess risk factors for HHV8 seropositivity and determine specific sexual practices associated with HHV8 seroconversion. Sera from 1,458 homosexual men (Amsterdam Cohort Study, 1984-1996) were tested for antibodies to HHV8 with a modified version of an enzyme immunoassay, using recombinant HHV8 lytic phase capsid (ORF65) and latent phase nuclear (ORF73) proteins. HHV8 seroprevalence at study entry was 20.9% (305/1,458); was highest among those with positive human immunodeficiency virus (HIV) status, no steady partner, and southern European or Latin American nationality; and increased with older age and higher number of sexual partners. During follow-up, 215 men seroconverted for HHV8 (incidence: 3.6/100 person-years). Both prevalence and incidence rates remained more or less stable during the study period. Orogenital insertive sex (odds ratio (OR) = 5.95; 95% confidence interval (CI): 2.88, 12.29) or orogenital receptive sex (OR = 4.29; 95% CI: 2.11, 8.71) with more than five partners in the past 6 months, older age (OR = 2.89; 95% CI: 1.13, 7.34, when older than 45 years), and preceding HIV infection (OR = 2.47; 95% CI: 1.53, 3.99) were independent predictors for HHV8 seroconversion. The authors found strong evidence for orogenital transmission of HHV8 among homosexual men.

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Geskus R, Groeneboom P. 1999. Asymptotically optimal estimation of smooth functionals for interval censoring, case 2 Annals of Statistics, 27 (2), pp. 627-674. | Show Abstract

For a version of the interval censoring model, case 2, in which the observation intervals are allowed to be arbitrarily small, we consider estimation of functionals that are differentiable along Hellinger differentiable paths. The asymptotic information lower bound for such functionals can be represented as the squared L 2 -norm of the canonical gradient in the observation space. This canonical gradient has an implicit expression as a solution of an integral equation that does not belong to one of the standard types. We study an extended version of the integral equation that can also be used for discrete distribution functions like the nonparametric maximum likelihood estimator (NPMLE), and derive the asymptotic normality and efficiency of the NPMLE from properties of the solutions of the integral equations.

Geskus RB, Groeneboom P. 1997. Asymptotically optimal estimation of smooth functionals for interval censoring, part 2 Statistica Neerlandica, 51 (2), pp. 201-219. | Show Abstract | Read more

Estimation in the interval censoring model is considered. A class of smooth functionals is introduced, of which the mean is an example. We consider case 2, with two observation times for each unobservable event time, in the situation that the observation times cannot become arbitrarily close to each other. It is proved that the nonparametric maximum likelihood estimator of the functional asymptotically reaches the information lower bound.

Spijkerman IJ, Langendam MW, Veugelers PJ, van Ameijden EJ, Keet IP, Geskus RB, van den Hoek A, Coutinho RA. 1996. Differences in progression to AIDS between injection drug users and homosexual men with documented dates of seroconversion. Epidemiology, 7 (6), pp. 571-577. | Show Abstract | Read more

We compared rates of progression to AIDS for 99 injection drug users and 120 homosexual men with documented dates of HIV-1 seroconversion. The crude risk of developing AIDS was higher among homosexual men than injection drug users [relative hazard (RH) = 2.4; 95% confidence interval (CI) = 1.3-4.4]. The relative hazard was slightly smaller among participants with a seroconversion interval of < or = 1 year (RH = 2.2; 95% CI = 1.0-5.2). The effect was partially explained by the inclusion of Kaposi's sarcoma in the AIDS case definition. Excluding those with Kaposi's sarcoma, the relative hazard was 2.0 (95% CI = 1.1-3.8). Using the 1993 AIDS case definition decreased the effect (RH = 1.9; 95% CI = 1.1-3.4). Finally, the high pre-AIDS mortality among injection drug users could partially explain the difference in progression rate between injection drug users and homosexual men. Combining the effect of the above-mentioned factors resulted in a relative hazard of 1.3 (95% CI = 0.7-2.6). Thus, the slower progression to AIDS among injection drug users compared with homosexual men was largely explained by differences in the spectrum of AIDS-defining illnesses, pre-AIDS mortality, and length of seroconversion interval.

Geskus RB, Groeneboorn P. 1996. Asymptotically optimal estimation of smooth functionals for interval censoring, part 1 Statistica Neerlandica, 50 (1), pp. 69-88. | Show Abstract | Read more

Estimation in the interval censoring model is considered. A class of smooth functionals is introduced, of which the mean is an example. The asymptotic information lower bound for such functionals can be represented as an inner product of two functions. In case 1, i.e. one observation time per unobservable event time, both functions can be given explicitly. We mainly consider case 2, with two observation times for each unobservable event time, in the situation that the observation times can not become arbitrarily close to each other. For case 2, one of the functions in the inner product can only be given implicitly as solution to a Fredholm integral equation. We study properties of this solution and, in a sequel to this paper, prove that the nonparametric maximum likelihood estimator of the functional asymptotically reaches the information lower bound.

Mai NT, Dobbs N, Phu NH, Colas RA, Thao LT, Thuong NT, Nghia HD, Hanh NH, Hang NT, Heemskerk AD et al. 2018. A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife, 7 | Show Abstract | Read more

Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.

de Vries EM, Wang J, Williamson KD, Leeflang MM, Boonstra K, Weersma RK, Beuers U, Chapman RW, Geskus RB, Ponsioen CY. 2017. A novel prognostic model for transplant-free survival in primary sclerosing cholangitis. Gut, pp. gutjnl-2016-313681-gutjnl-2016-313681. | Show Abstract | Read more

OBJECTIVE: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. DESIGN: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. RESULTS: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. CONCLUSION: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.

Thao LTP, Heemskerk AD, Geskus RB, Mai NTH, Ha DTM, Chau TTH, Phu NH, Chau NVV, Caws M, Lan NH et al. 2018. Prognostic Models for 9-Month Mortality in Tuberculous Meningitis. Clin Infect Dis, 66 (4), pp. 523-532. | Show Abstract | Read more

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection. Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/). Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone. Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care.

van Santen DK, van der Helm JJ, Del Amo J, Meyer L, D'Arminio Monforte A, Price M, Béguelin CA, Zangerle R, Sannes M, Porter K et al. 2017. Lack of decline in hepatitis C virus incidence among HIV-positive men who have sex with men during 1990–2014 Journal of Hepatology, 67 (2), pp. 255-262. | Show Abstract | Read more

© 2017 European Association for the Study of the Liver Background & Aims Hepatitis C virus (HCV) incidence among HIV-positive men who have sex with men (MSM) has increased since 2000, although there are regional differences. We aimed to 1) estimate trends in HCV incidence among HIV-positive MSM, 2) assess the association between incidence and geographical region, age and HIV-related measurements and, 3) assess temporal changes from HIV seroconversion to HCV infection. Methods Data was used from MSM with well-estimated dates of HIV seroconversion from the CASCADE Collaboration (1990–2014). Smoothly varying trends in HCV incidence over time were allowed, using restricted cubic splines. The association of calendar year, age, CD4 count (lagged), HIV RNA (lagged), geographical region and HIV infection stage (recent vs. chronic) with HCV incidence were assessed using Poisson regression. Results Of 5,941 MSM, 337 acquired HCV during follow-up. HCV incidence significantly increased from 0.7/1,000 person-years in 1990 to 18/1,000 person-years in 2014. Recent calendar years, younger age, recent HIV infection and higher HIV RNA levels were significantly associated with HCV incidence, while CD4 count was not. Trends differed by geographical region; while incidence appeared to have stabilized in Western Europe and remained stable in Southern Europe, it continued to increase in Northern Europe in recent years. Time from HIV to HCV infection significantly decreased over time (p < 0.001). Conclusions HCV has continued to spread among HIV-positive MSM in recent years, but trends differ by geographical region. Interventions to decrease the risk of HCV acquisition and increase early diagnosis are warranted. Lay summary Hepatitis C virus infection continues to spread among HIV-positive men who have sex with men, especially among younger individuals. However, trends seem to differ by European region in recent years. Furthermore, men who have sex with men with a higher HIV RNA load were more likely to get infected with the hepatitis C virus. During recent HIV infection, MSM appear to be at higher risk of acquiring hepatitis C.

Geskus RB, González C, Torres M, Del Romero J, Viciana P, Masiá M, Blanco JR, Iribarren M, De Sanjosé S, Hernández-Novoa B et al. 2016. Incidence and clearance of anal high-risk human papillomavirus in HIV-positive men who have sex with men: estimates and risk factors. AIDS, 30 (1), pp. 37-44. | Show Abstract | Read more

BACKGROUND: To estimate incidence and clearance of high-risk human papillomavirus (HR-HPV), and their risk factors, in men who have sex with men (MSM) recently infected by HIV in Spain; 2007-2013. METHODS: Multicenter cohort. HR-HPV infection was determined and genotyped with linear array. Two-state Markov models and Poisson regression were used. RESULTS: We analysed 1570 HR-HPV measurements of 612 MSM over 13 608 person-months (p-m) of follow-up. Median (mean) number of measurements was 2 (2.6), median time interval between measurements was 1.1 years (interquartile range: 0.89-1.4). Incidence ranged from 9.0 [95% confidence interval (CI) 6.8-11.8] per 1000 p-m for HPV59 to 15.9 (11.7-21.8) per 1000 p-m for HPV51. HPV16 and HPV18 had slightly above average incidence: 11.9/1000 p-m and 12.8/1000 p-m. HPV16 showed the lowest clearance for both 'prevalent positive' (15.7/1000 p-m; 95% CI 12.0-20.5) and 'incident positive' infections (22.1/1000 p-m; 95% CI 11.8-41.1). More sexual partners increased HR-HPV incidence, although it was not statistically significant. Age had a strong effect on clearance (P-value < 0.001) due to the elevated rate in MSM under age 25; the effect of HIV-RNA viral load was more gradual, with clearance rate decreasing at higher HIV-RNA viral load (P-value 0.008). CONCLUSION: No large variation in incidence by HR-HPV type was seen. The most common incident types were HPV51, HPV52, HPV31, HPV18 and HPV16. No major variation in clearance by type was observed, with the exception of HPV16 which had the highest persistence and potentially, the strongest oncogenic capacity. Those aged below 25 or with low HIV-RNA- viral load had the highest clearance.

Gras L, de Wolf F, Smit C, Prins M, van der Meer JTM, Vanhommerig JW, Zwinderman AH, Schinkel J, Geskus RB, ATHENA national observational cohort and the MOSAIC study. 2015. Changes in HIV RNA and CD4 cell count after acute HCV infection in chronically HIV-infected individuals. J Acquir Immune Defic Syndr, 68 (5), pp. 536-542. | Show Abstract | Read more

OBJECTIVE: Little is known about the impact of acute hepatitis C virus (HCV) co-infection on HIV-1 disease progression. We investigated CD4 cell count and HIV RNA concentration changes after HCV infection in individuals chronically infected with HIV-1. METHODS: We selected individuals that had the last negative and first positive HCV RNA test less than 1 year apart. Bivariate linear mixed-effects regression was used to model trends in HIV RNA level and CD4 cell count from 2 years before the last negative HCV RNA test until the first of the following dates: start of anti-HCV medication, change in combination antiretroviral therapy (cART) status, and end of follow-up. RESULTS: At the estimated time of HCV co-infection, of 89 individuals, 63 (71%) were cART-treated and 26 (29%) were not on cART. In persons on cART, median CD4 cell count declined from 587 to 508 cells per cubic millimeter (P < 0.0001) during the first 5 months after HCV infection and returned to 587 cells per cubic millimeter after 2.2 years. Also, the probability of an HIV RNA >50 copies per milliliter peaked to 18.6% at HCV co-infection, with lower probabilities 6 months before (3.5%, P = 0.006 compared with peak probability) and after (2.9%, P = 0.009). In persons not on cART, no significant impact of HCV co-infection on trends in the HIV RNA level or CD4 cell count was observed. CONCLUSIONS: Acute HCV infection in cART-treated, chronically HIV-infected patients was associated with a temporary decrease in CD4 cell counts and increased risk of HIV viremia >50 copies per milliliter. This may increase the risk of further HIV transmission.

Geskus RB. 2014. Which individuals make dropout informative? Stat Methods Med Res, 23 (1), pp. 91-106. | Show Abstract | Read more

Markers are internal host factors that measure the current disease or recovery status of an individual. Individuals with more advanced disease progression are more likely to drop out, e.g. because they die. Marker data after dropout are missing. Such missingness is certainly not completely at random. A mixed effects model can be used if missingness of the marker data depends on measured marker values only (missing at random). If missingness is not at random, such models yield biased results. We describe various approaches that jointly model the marker development and dropout risk and may eliminate bias. One example of such a model is a random effects selection model. Based on a real data set with frequent follow-up, we compare results from a random effects model and a random effects selection model. Results are remarkably similar. In a simulation study, we investigate how the bias in the parameter estimates from a random effects model depends on the frequency of measurements and the time between the last measurement and the dropout or censoring time. Results from the simulation study confirm that the bias is small if follow-up is frequent.

Musoro JZ, Zwinderman AH, Puhan MA, ter Riet G, Geskus RB. 2014. Validation of prediction models based on lasso regression with multiply imputed data. BMC Med Res Methodol, 14 (1), pp. 116. | Show Abstract | Read more

BACKGROUND: In prognostic studies, the lasso technique is attractive since it improves the quality of predictions by shrinking regression coefficients, compared to predictions based on a model fitted via unpenalized maximum likelihood. Since some coefficients are set to zero, parsimony is achieved as well. It is unclear whether the performance of a model fitted using the lasso still shows some optimism. Bootstrap methods have been advocated to quantify optimism and generalize model performance to new subjects. It is unclear how resampling should be performed in the presence of multiply imputed data. METHOD: The data were based on a cohort of Chronic Obstructive Pulmonary Disease patients. We constructed models to predict Chronic Respiratory Questionnaire dyspnea 6 months ahead. Optimism of the lasso model was investigated by comparing 4 approaches of handling multiply imputed data in the bootstrap procedure, using the study data and simulated data sets. In the first 3 approaches, data sets that had been completed via multiple imputation (MI) were resampled, while the fourth approach resampled the incomplete data set and then performed MI. RESULTS: The discriminative model performance of the lasso was optimistic. There was suboptimal calibration due to over-shrinkage. The estimate of optimism was sensitive to the choice of handling imputed data in the bootstrap resampling procedure. Resampling the completed data sets underestimates optimism, especially if, within a bootstrap step, selected individuals differ over the imputed data sets. Incorporating the MI procedure in the validation yields estimates of optimism that are closer to the true value, albeit slightly too larger. CONCLUSION: Performance of prognostic models constructed using the lasso technique can be optimistic as well. Results of the internal validation are sensitive to how bootstrap resampling is performed.

van der Helm J, Geskus R, Sabin C, Meyer L, Del Amo J, Chêne G, Dorrucci M, Muga R, Porter K, Prins M, CASCADE Collaboration in EuroCoord. 2013. Effect of HCV infection on cause-specific mortality after HIV seroconversion, before and after 1997. Gastroenterology, 144 (4), pp. 751-760.e2. | Show Abstract | Read more

BACKGROUND & AIMS: Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the duration of HIV infection. METHODS: We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural. RESULTS: Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease. CONCLUSIONS: Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression.

Andersen PK, Geskus RB, de Witte T, Putter H. 2012. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol, 41 (3), pp. 861-870. | Show Abstract | Read more

BACKGROUND: In studies of all-cause mortality, the fundamental epidemiological concepts of rate and risk are connected through a well-defined one-to-one relation. An important consequence of this relation is that regression models such as the proportional hazards model that are defined through the hazard (the rate) immediately dictate how the covariates relate to the survival function (the risk). METHODS: This introductory paper reviews the concepts of rate and risk and their one-to-one relation in all-cause mortality studies and introduces the analogous concepts of rate and risk in the context of competing risks, the cause-specific hazard and the cause-specific cumulative incidence function. RESULTS: The key feature of competing risks is that the one-to-one correspondence between cause-specific hazard and cumulative incidence, between rate and risk, is lost. This fact has two important implications. First, the naïve Kaplan-Meier that takes the competing events as censored observations, is biased. Secondly, the way in which covariates are associated with the cause-specific hazards may not coincide with the way these covariates are associated with the cumulative incidence. An example with relapse and non-relapse mortality as competing risks in a stem cell transplantation study is used for illustration. CONCLUSION: The two implications of the loss of one-to-one correspondence between cause-specific hazard and cumulative incidence should be kept in mind when deciding on how to make inference in a competing risks situation.

Geskus RB. 2011. Cause-specific cumulative incidence estimation and the fine and gray model under both left truncation and right censoring. Biometrics, 67 (1), pp. 39-49. | Show Abstract | Read more

Summary The standard estimator for the cause-specific cumulative incidence function in a competing risks setting with left truncated and/or right censored data can be written in two alternative forms. One is a weighted empirical cumulative distribution function and the other a product-limit estimator. This equivalence suggests an alternative view of the analysis of time-to-event data with left truncation and right censoring: individuals who are still at risk or experienced an earlier competing event receive weights from the censoring and truncation mechanisms. As a consequence, inference on the cumulative scale can be performed using weighted versions of standard procedures. This holds for estimation of the cause-specific cumulative incidence function as well as for estimation of the regression parameters in the Fine and Gray proportional subdistribution hazards model. We show that, with the appropriate filtration, a martingale property holds that allows deriving asymptotic results for the proportional subdistribution hazards model in the same way as for the standard Cox proportional hazards model. Estimation of the cause-specific cumulative incidence function and regression on the subdistribution hazard can be performed using standard software for survival analysis if the software allows for inclusion of time-dependent weights. We show the implementation in the R statistical package. The proportional subdistribution hazards model is used to investigate the effect of calendar period as a deterministic external time varying covariate, which can be seen as a special case of left truncation, on AIDS related and non-AIDS related cumulative mortality.

Prognostic survival models and adaptive trial designs in tuberculous meningitis

The whole project is focused on patients with tuberculous meningitis. The first aim is to develop a model that predicts mortality within the first nine months after diagnosis, combining patient data with clinical and laboratory examinations. Results from a model that only uses information collected at baseline (i.e. diagnosis) have been published. A paper that compares different methods of model construction has been submitted. Currently, we investigate the added value of time-updated ...

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