Dr Raph Hamers

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health and Immunology & Infectious Disease
Keywords: HIV, tuberculosis, infectious diseases, global health, epidemiology and clinical trials
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Raph Hamers is an infectious disease physician and clinical immunologist based at the Eijkman-Oxford Clinical Research Unit (EOCRU) in Jakarta, Indonesia.

EOCRU was created in 2007 by agreement between the Eijkman Institute for Molecular Biolology (EIMB, Ministry of Science & Technology) and the University of Oxford to collaborate on clinical, laboratory, and field research on infectious diseases of public health importance in Indonesia, and is part of the Oxford University Clinical Research Unit in Vietnam (OUCRU). EOCRU head of Unit is Prof. Kevin Baird.

His research to date has been centred on the clinical management, epidemiology and public health aspects of HIV (antiretroviral treatment, drug-resistant HIV, molecular epidemiology, chronic immune dysregulation, affordable diagnostics), with over 10 years of experience in research projects in sub-Saharan Africa. He holds a PhD (Cum Laude) from the University of Amsterdam, is the recipient of a post-doctoral fellowship from the Netherlands Organization for Scientific Research through the Innovational Research Incentives Scheme (Veni), and holds honorary positions at the Departments of Global Health and Internal Medicine of the Academic Medical Center, University of Amsterdam. His major areas of interest are in HIV and opportunistic infections, tuberculosis, antimicrobial drug resistance, diagnostics, and in multidisciplinary approaches to improve health outcomes in low-resource settings.

He is the Manager of the newly established Universities of Indonesia and Oxford Clinical Research Laboratory (IOCRL), situated on the Salemba campus of the Faculty of Medicine Universitas Indonesia (FKUI) in central Jakarta. IOCRL provides an integrated medium for broader engagement with its principal partners (FKUI, EIMB, Oxford tropical network, and others) in training, education, public engagement, and development of a broader collaborative clinical research agenda. The IOCRL facility serves as the administrative, regulatory, and technical hub for clinical trials. Ongoing/planned clinical trials at IOCRL include: i) adjunctive dexamethasone in tuberculous meningitis in HIV-infected adults (ACT-HIV); ii) Tafenoquine for the radical cure of Plasmodium vivax malaria (INSPECTOR); iii) Plasmodium falciparum sporozoite vaccine.

Name Department Institution Country
Professor J. Kevin Baird Tropical Medicine Oxford University, Jakarta Indonesia
Professor Guy Thwaites Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr H Rogier van Doorn Tropical Medicine Oxford University, Hanoi Vietnam
Evelyne Kestelyn Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Mary Chambers Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Dr Darma Imran Neurology Cipto Mangunkusumo Hospital Indonesia
Professor Reinout van Crevel Nijmegen Netherlands
Associate Professor Rob Aernoutse Pharmacology Radboud University Medical Center Netherlands
Dr Erlina Burlan Pulomonology Persahabatan Hospital Indonesia
Inzaule SC, Hamers RL, Calis J, Boerma R, Sigaloff K, Zeh C, Mugyenyi P, Akanmu S, Rinke de Wit TF. 2018. When prevention of mother-to-child HIV transmission fails: preventing pretreatment drug resistance in African children. AIDS, 32 (2), pp. 143-147. | Read more

Gupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, Kaleebu P, Watera C, Aghokeng A, Mutenda N et al. 2017. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis, | Show Abstract | Read more

BACKGROUND: Pretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs. METHODS: This study was a systematic review and meta-regression analysis. We assessed regional prevalence of pretreatment drug resistance and risk of pretreatment drug resistance in people initiating ART who reported previous ART exposure. We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs. We searched for studies in PubMed and Embase and conference abstracts and presentations from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference, and the International Drug Resistance Workshop for the period Jan 1, 2001, to Dec 31, 2016. To assess the prevalence of drug resistance within a specified region at any specific timepoint, we extracted study level data and pooled prevalence estimates within the region using an empty logistic regression model with a random effect at the study level. We used random effects meta-regression to relate sampling year to prevalence of pretreatment drug resistance within geographical regions. FINDINGS: We identified 358 datasets that contributed data to our analyses, representing 56 044 adults in 63 countries. Prevalence estimates of pretreatment NNRTI resistance in 2016 were 11·0% (7·5-15·9) in southern Africa, 10·1% (5·1-19·4) in eastern Africa, 7·2% (2·9-16·5) in western and central Africa, and 9·4% (6·6-13·2) in Latin America and the Caribbean. There were substantial increases in pretreatment NNRTI resistance per year in all regions. The yearly increases in the odds of pretreatment drug resistance were 23% (95% CI 16-29) in southern Africa, 17% (5-30) in eastern Africa, 17% (6-29) in western and central Africa, 11% (5-18) in Latin America and the Caribbean, and 11% (2-20) in Asia. Estimated increases in the absolute prevalence of pretreatment drug resistance between 2015 and 2016 ranged from 0·3% in Asia to 1·8% in southern Africa. INTERPRETATION: Pretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHO's 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition. FUNDING: Bill & Melinda Gates Foundation and World Health Organization.

Inzaule SC, Hamers RL, Paredes R, Yang C, Schuurman R, de Wit TFR. 2017. The evolving landscape of HIV drug resistance diagnostics for expanding testing in resource-limited settings AIDS Reviews, 19 (4), pp. 179-189. | Show Abstract

© 2017, Publicaciones Permanyer. All rights reserved. Global scale-up of antiretroviral treatment has dramatically changed the prospects of HIV/AIDS disease, rendering life-long chronic care and treatment a reality for millions of HIV-infected patients. Affordable technologies to monitor antiretroviral treatment are needed to ensure long-term durability of limited available drug regimens. HIV drug resistance tests can complement existing strategies in optimizing clinical decision-making for patients with treatment failure, in addition to facilitating population-based surveillance of HIV drug resistance. This review assesses the current landscape of HIV drug resistance technologies and discusses the strengths and limitations of existing assays available for expanding testing in resource-limited settings. These include sequencing-based assays (Sanger sequencing assays and nextgeneration sequencing), point mutation assays, and genotype-free data-based prediction systems. Sanger assays are currently considered the gold standard genotyping technology, though only available at a limited number of resource-limited setting reference and regional laboratories, but high capital and test costs have limited their wide expansion. Point mutation assays present opportunities for simplified laboratory assays, but HIV genetic variability, extensive codon redundancy at or near the mutation target sites with limited multiplexing capability have restricted their utility. Next-generation sequencing, despite high costs, may have potential to reduce the testing cost significantly through multiplexing in high-throughput facilities, although the level of bioinformatics expertise required for data analysis is currently still complex and expensive and lacks standardization. Web-based genotype-free prediction systems may provide enhanced antiretroviral treatment decision-making without the need for laboratory testing, but require further clinical field evaluation and implementation scientific research in resource-limited settings.

Paredes R, Tzou PL, van Zyl G, Barrow G, Camacho R, Carmona S, Grant PM, Gupta RK, Hamers RL, Harrigan PR et al. 2017. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation. PLoS One, 12 (7), pp. e0181357. | Show Abstract | Read more

INTRODUCTION: HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. METHODS: An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs). RESULTS: There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required. CONCLUSIONS: The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

Inzaule SC, Hamers RL, Mukui I, Were K, Owiti P, Kwaro D, Rinke de Wit TF, Zeh C. 2017. Emergence of untreatable, multidrug-resistant HIV-1 in patients failing second-line therapy in Kenya AIDS, 31 (10), pp. 1495-1498. | Show Abstract | Read more

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. We performed a countrywide assessment of HIV drug resistance among 123 patients with virological failure on second-line antiretroviral therapy (ART) in Kenya. The percentage of patients harbouring intermediate-to-high-level resistance was 27% for lopinavir-ritonavir, 24% for atazanavir-ritonavir and 7% for darunavir-ritonavir, and 25% had complete loss of activity to all available first and second-line drugs. Overall, one in four patients failing second-line ART have completely exhausted available antiretrovirals in Kenya, highlighting the need for increased access to third-line drugs.

Rhee S-Y, Varghese V, Holmes SP, Van Zyl GU, Steegen K, Boyd MA, Cooper DA, Nsanzimana S, Saravanan S, Charpentier C et al. 2017. Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration. EBioMedicine, 18 pp. 225-235. | Show Abstract | Read more

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Gregson J, Kaleebu P, Marconi VC, van Vuuren C, Ndembi N, Hamers RL, Kanki P, Hoffmann CJ, Lockman S, Pillay D et al. 2017. Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study. Lancet Infect Dis, 17 (3), pp. 296-304. | Show Abstract | Read more

BACKGROUND: HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART. METHODS: We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs. FINDINGS: Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL [IQR 21·0-128·0] in patients with TAMS vs 95·0 cells per μL [37·0-177·0] in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0·0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13-1·47; p<0·0001) INTERPRETATION: TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains. FUNDING: The Wellcome Trust.

Bijker R, Jiamsakul A, Kityo C, Kiertiburanakul S, Siwale M, Phanuphak P, Akanmu S, Chaiwarith R, Wit FW, Sim BL et al. 2017. Adherence to antiretroviral therapy for HIV in sub-Saharan Africa and Asia: a comparative analysis of two regional cohorts. J Int AIDS Soc, 20 (1), pp. 21218. | Show Abstract | Read more

INTRODUCTION: Our understanding of how to achieve optimal long-term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV-positive persons receiving ART who were enrolled in a bi-regional cohort in sub-Saharan Africa and Asia. METHODS: This multicentre prospective study of adults starting first-line ART assessed patient-reported adherence at follow-up clinic visits using a 30-day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six-month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. RESULTS: Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06-1.53;p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8-0.9;p = 0.003), use of concomitant medication (OR 1.8, 1.0-3.2;p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1-1.7;p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4-0.9;p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9-2.6;p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low- and lower-middle-income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3-2.0;p < 0.001), compared to those in upper-middle or high-income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3-7.7;p < 0.001) and Asia (OR 9.0, 95% CI 5.0-16.2;p < 0.001). Patient-reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. CONCLUSION: Psychosocial factors and health system resources may explain regional differences. Adherence-enhancing interventions should address patient-reported barriers tailored to local settings, prioritizing the first years of ART.

Smoleń-Dzirba J, Rosińska M, Janiec J, Beniowski M, Cycoń M, Bratosiewicz-Wąsik J, Wąsik TJ. 2017. The Evolving Landscape of HIV Drug Resistance Diagnostics for Expanding Testing in Resource-Limited Settings. AIDS Rev, 19 (4), pp. 219-230. | Show Abstract

Global scale-up of antiretroviral treatment has dramatically changed the prospects of HIV/AIDS disease, rendering life-long chronic care and treatment a reality for millions of HIV-infected patients. Affordable technologies to monitor antiretroviral treatment are needed to ensure long-term durability of limited available drug regimens. HIV drug resistance tests can complement existing strategies in optimizing clinical decision-making for patients with treatment failure, in addition to facilitating population-based surveillance of HIV drug resistance. This review assesses the current landscape of HIV drug resistance technologies and discusses the strengths and limitations of existing assays available for expanding testing in resource-limited settings. These include sequencing-based assays (Sanger sequencing assays and nextgeneration sequencing), point mutation assays, and genotype-free data-based prediction systems. Sanger assays are currently considered the gold standard genotyping technology, though only available at a limited number of resource-limited setting reference and regional laboratories, but high capital and test costs have limited their wide expansion. Point mutation assays present opportunities for simplified laboratory assays, but HIV genetic variability, extensive codon redundancy at or near the mutation target sites with limited multiplexing capability have restricted their utility. Next-generation sequencing, despite high costs, may have potential to reduce the testing cost significantly through multiplexing in high-throughput facilities, although the level of bioinformatics expertise required for data analysis is currently still complex and expensive and lacks standardization. Web-based genotype-free prediction systems may provide enhanced antiretroviral treatment decision-making without the need for laboratory testing, but require further clinical field evaluation and implementation scientific research in resource-limited settings.

Hamers RL, Paredes R. 2016. Next-generation sequencing and HIV drug resistance surveillance The Lancet HIV, 3 (12), pp. e553-e554. | Read more

Inzaule SC, Ondoa P, Peter T, Mugyenyi PN, Stevens WS, de Wit TFR, Hamers RL. 2016. Affordable HIV drug-resistance testing for monitoring of antiretroviral therapy in sub-Saharan Africa. Lancet Infect Dis, 16 (11), pp. e267-e275. | Show Abstract | Read more

Increased provision of antiretroviral therapy in sub-Saharan Africa has led to a growing number of patients with therapy failure and acquired drug-resistant HIV, driving the demand for more costly further lines of antiretroviral therapy. In conjunction with accelerated access to viral load monitoring, feasible and affordable technologies to detect drug-resistant HIV could help maximise the durability and rational use of available drug regimens. Potential low-cost technologies include in-house Sanger and next-generation sequencing in centralised laboratories, and point mutation assays and genotype-free systems that predict response to antiretroviral therapy at point-of-care. Strengthening of centralised high-throughput laboratories, including efficient systems for sample referral and results delivery, will increase economies-of-scale while reducing costs. Access barriers can be mitigated by standardisation of in-house assays into commercial kits, use of polyvalent instruments, and adopting price-reducing strategies. A stepwise rollout approach should improve feasibility, prioritising WHO-recommended population-based surveillance and management of complex patient categories, such as patients failing protease inhibitor-based antiretroviral therapy. Implementation research, adaptations of existing WHO guidance, and political commitment, will be key to support the appropriate investments and policy changes. In this Personal View, we discuss the potential role of HIV drug resistance testing for population-based surveillance and individual patient management in sub-Saharan Africa. We review the strengths and challenges of promising low-cost technologies and how they can be implemented.

Inzaule SC, Hamers RL, Kityo C, Rinke de Wit TF, Roura M. 2016. Long-Term Antiretroviral Treatment Adherence in HIV-Infected Adolescents and Adults in Uganda: A Qualitative Study. PLoS One, 11 (11), pp. e0167492. | Show Abstract | Read more

BACKGROUND: Long-term success of HIV antiretroviral therapy requires near-perfect adherence, maintained throughout one's lifetime. However, perceptions towards ART and patterns of adherence may change during the life course. We assessed challenges to long-term adherence in adolescents and adults in three regional HIV treatment centers in Uganda. METHODS: We conducted 24 in-depth interviews and 2 focus group discussions with a total of 33 health-care providers and expert clients (HIV patients on long-term ART who assist with adherence support of fellow patients). Interview topics included experiences with patients on long-term treatment with either declining adherence or persistent poor adherence. Transcribed texts were coded and analyzed based on the social-ecological framework highlighting differences and commonalities between adolescents and adults. RESULTS: The overarching themes in adolescents were unstructured treatment holidays, delays in disclosure of HIV status by caretakers, stigma, which was mainly experienced in boarding schools, and diminishing or lack of clinical support. In particular, there was minimal support for early and gradual disclosure for caretakers to the infected children, diminishing clinical support for young adults during transition to adult-based care and declining peer-to-peer support group activities. The predominating theme in adults was challenges with treatment access among temporary economic migrants. Common themes to adults and adolescents were challenges with disclosure in intimate relationships, treatment related factors including side effects, supply of single tablets in place of fixed-dose combined drugs, supply of drug brands with unfavorable taste and missed opportunities for counseling due to shortage of staff. CONCLUSION: Adherence counseling and support should be adapted differently for adolescents and adults and to the emerging life course challenges in long-term treated patients. Programs should also address constraints experienced by temporary economic migrants to ensure continuity of treatment within the host country.

Grijsen ML, Kaderbhai HS, Hamers RL, Masenga JE. 2016. Under fire in Tanzania Nederlands Tijdschrift voor Dermatologie en Venereologie, 26 (9), pp. 538-541.

Boender TS, Kityo CM, Boerma RS, Hamers RL, Ondoa P, Wellington M, Siwale M, Nankya I, Kaudha E, Akanmu AS et al. 2016. Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa. J Antimicrob Chemother, 71 (10), pp. 2918-2927. | Show Abstract | Read more

OBJECTIVES: Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. METHODS: HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. RESULTS: At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all P < 0.001). Acquired drug resistance patterns were similar in adults and children. CONCLUSIONS: Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

Revell AD, Wang D, Wood R, Morrow C, Tempelman H, Hamers RL, Reiss P, van Sighem AI, Nelson M, Montaner JSG et al. 2016. An update to the HIV-TRePS system: the development and evaluation of new global and local computational models to predict HIV treatment outcomes, with or without a genotype. J Antimicrob Chemother, 71 (10), pp. 2928-2937. | Show Abstract | Read more

OBJECTIVES: Optimizing antiretroviral drug combination on an individual basis in resource-limited settings is challenging because of the limited availability of drugs and genotypic resistance testing. Here, we describe our latest computational models to predict treatment responses, with or without a genotype, and compare the potential utility of global and local models as a treatment tool for South Africa. METHODS: Global random forest models were trained to predict the probability of virological response to therapy following virological failure using 29 574 treatment change episodes (TCEs) without a genotype, 3179 of which were from South Africa and were used to develop local models. In addition, 15 130 TCEs including genotypes were used to develop another set of models. The 'no-genotype' models were tested with an independent global test set (n = 1700) plus a subset from South Africa (n = 222). The genotype models were tested with 750 independent cases. RESULTS: The global no-genotype models achieved area under the receiver-operating characteristic curve (AUC) values of 0.82 and 0.79 with the global and South African tests sets, respectively, and the South African models achieved AUCs of 0.70 and 0.79. The genotype models achieved an AUC of 0.84. The global no-genotype models identified more alternative, locally available regimens that were predicted to be effective for cases that failed their new regimen in the South African clinics than the local models. Both sets of models were significantly more accurate predictors of outcomes than genotyping with rules-based interpretation. CONCLUSIONS: These latest global models predict treatment responses accurately even without a genotype, out-performed the local South African models and have the potential to help optimize therapy, particularly in resource-limited settings.

Boender TS, Hamers RL, Ondoa P, Wellington M, Chimbetete C, Siwale M, Labib Maksimos EEF, Balinda SN, Kityo CM, Adeyemo TA et al. 2016. Protease Inhibitor Resistance in the First 3 Years of Second-Line Antiretroviral Therapy for HIV-1 in Sub-Saharan Africa. J Infect Dis, 214 (6), pp. 873-883. | Show Abstract | Read more

BACKGROUND: As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. METHODS: HIV-1-infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. RESULTS: Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based (hazard ratio, 7.10; 95% confidence interval, 3.40-14.83; P < .001) or PI-based (7.59; 3.02-19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49-17.98; P < .001), and suboptimal adherence (3.05; 1.71-5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. CONCLUSIONS: Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Inzaule SC, Weidle PJ, Yang C, Ndiege K, Hamers RL, Rinke de Wit TF, Thomas T, Zeh C. 2016. Prevalence and dynamics of the K65R drug resistance mutation in HIV-1-infected infants exposed to maternal therapy with lamivudine, zidovudine and either nevirapine or nelfinavir in breast milk. J Antimicrob Chemother, 71 (6), pp. 1619-1626. | Show Abstract | Read more

BACKGROUND: K65R is a relatively rare drug resistance mutation (DRM) selected by the NRTIs tenofovir, didanosine, abacavir and stavudine and confers cross-resistance to all NRTIs except zidovudine. Selection by other NRTIs is uncommon. OBJECTIVES: In this study we investigated the frequency of emergence of the K65R mutation and factors associated with it in HIV-1-infected infants exposed to low doses of maternal lamivudine, zidovudine and either nevirapine or nelfinavir ingested through breast milk, using specimens collected from the Kisumu Breastfeeding Study. METHODS: Plasma specimens with viral load ≥1000 copies/mL collected from HIV-infected infants at 0-1, 2, 6, 14, 24 and 36 weeks of age and maternal samples at delivery were tested for HIV drug resistance using Sanger sequencing of the polymerase gene. Factors associated with K65R emergence were assessed using Fisher's exact test and the Wilcoxon rank-sum test. RESULTS: K65R was detected in samples from 6 of the 24 infants (25%) who acquired HIV-1 infection by the age of 6 months. K65R emerged in half of the infants by 6 weeks and in the rest by 14 weeks of age. None of the mothers at delivery or the infants with a positive genotype at first time of positivity had the K65R mutation. Infants with K65R had low baseline CD4 cell counts (P = 0.014), were more likely to have DRMs earlier (≤6 weeks versus ≥14 weeks, P = 0.007) and were more likely to have multiclass drug resistance (P = 0.035). M184V was the most common mutation associated with K65R emergence. K65R had reverted by 3 months after cessation of breastfeeding. CONCLUSIONS: A high rate of K65R emergence may suggest that ingesting low doses of lamivudine via breast milk could select for this mutation. The presence of this mutation may have a negative impact on future responses to NRTI-based ART. More in vitro studies are, however, needed to establish the molecular mechanism for this selection.

TenoRes Study Group. 2016. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study. Lancet Infect Dis, 16 (5), pp. 565-575. | Show Abstract | Read more

BACKGROUND: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. METHODS: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. FINDINGS: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27-1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20-1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]). INTERPRETATION: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. FUNDING: The Wellcome Trust.

Hamers RL. 2016. Enhancement of clinical decision making in HIV care in Africa. Lancet HIV, 3 (2), pp. e59-e60. | Read more

Hamers RL, van Gool T, Goorhuis A. 2016. Benznidazole for Chronic Chagas' Cardiomyopathy. N Engl J Med, 374 (2), pp. 188. | Read more

Inzaule SC, Hamers RL, Zeh CE, Rinke de Wit TF. 2016. Stringent HIV Viral Load Threshold for Virological Failure Using Dried Blood Spots: Is the Perfect the Enemy of the Good? J Acquir Immune Defic Syndr, 71 (1), pp. e30-e33. | Read more

Rhee S-Y, Jordan MR, Raizes E, Chua A, Parkin N, Kantor R, Van Zyl GU, Mukui I, Hosseinipour MC, Frenkel LM et al. 2015. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing. PLoS One, 10 (12), pp. e0145772. | Show Abstract | Read more

The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

Boender TS, Hoenderboom BM, Sigaloff KCE, Hamers RL, Wellington M, Shamu T, Siwale M, Labib Maksimos EEF, Nankya I, Kityo CM et al. 2015. Pretreatment HIV drug resistance increases regimen switches in sub-Saharan Africa. Clin Infect Dis, 61 (11), pp. 1749-1758. | Show Abstract | Read more

BACKGROUND: After the scale-up of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in Africa, increasing numbers of patients have pretreatment drug resistance. METHODS: In a large multicountry cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) ≥1000 cps/mL. Pretreatment drug resistance was defined as a decreased susceptibility to ≥1 prescribed drug. We assessed the effect of pretreatment drug resistance on all-cause mortality, new AIDS events and switch to second-line ART due to presumed treatment failure, using Cox models. RESULTS: Among 2579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (adjusted hazard ratio [aHR] 3.80; 95% confidence interval [CI], 1.49-9.68; P = .005) but was not associated with mortality (aHR 0.75, 95% CI, .24-2.35; P = .617) or new AIDS events (aHR 1.06, 95% CI, .68-1.64; P = .807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL < 1000 cps/mL, 7 (6.6%) with VL ≥ 1000 cps/mL and no drug resistance mutations (DRMs), 46 (43.4%) with VL ≥ 1000 cps/mL and ≥1 DRMs; no HIV RNA data was available for 32 (30.2%) participants. CONCLUSIONS: Given rising pretreatment HIV drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. VL monitoring can improve the accuracy of failure detection and efficiency of switching practices.

Rhee S-Y, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, Hamers RL, Bertagnolio S, de Wit TFR, Aghokeng AF et al. 2015. Correction: Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis PLOS Medicine, 12 (6), pp. e1001845-e1001845. | Read more

Rhee S-Y, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, Hamers RL, Bertagnolio S, Rinke de Wit TF, Aghokeng AF et al. 2015. Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis. PLoS Med, 12 (4), pp. e1001810. | Show Abstract | Read more

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Nichols BE, Sigaloff KCE, Kityo C, Mandaliya K, Hamers RL, Bertagnolio S, Jordan MR, Boucher CAB, Rinke de Wit TF, van de Vijver DAMC. 2014. Averted HIV infections due to expanded antiretroviral treatment eligibility offsets risk of transmitted drug resistance: a modeling study. AIDS, 28 (1), pp. 73-83. | Show Abstract | Read more

BACKGROUND: Earlier antiretroviral therapy initiation can reduce the incidence of HIV-1. This benefit can be offset by increased transmitted drug resistance (TDR). We compared the preventive benefits of reducing incident infections with the potential TDR increase in East Africa. METHODS: A mathematical model was constructed to represent Kampala, Uganda, and Mombasa, Kenya. We predicted the effect of initiating treatment at different immunological thresholds (<350, <500 CD4 cells/μl) on infections averted and mutation-specific TDR prevalence over 10 years compared to initiating treatment at CD4 cell count below 200 cells/μl. RESULTS: When initiating treatment at CD4 cell count below 350 cells/μl, we predict 18 [interquartile range (IQR) 11-31] and 46 (IQR 30-83) infections averted for each additional case of TDR in Kampala and Mombasa, respectively, and 22 (IQR 17-35) and 32 (IQR 21-57) infections averted when initiating at below 500. TDR is predicted to increase most strongly when initiating treatment at CD4 cell count below 500 cells/μl, from 8.3% (IQR 7.7-9.0%) and 12.3% (IQR 11.7-13.1%) in 2012 to 19.0% (IQR 16.5-21.8%) and 19.2% (IQR 17.1-21.5%) in 10 years in Kampala and Mombasa, respectively. The TDR epidemic at all immunological thresholds was comprised mainly of resistance to non-nucleoside reverse transcriptase inhibitors. When 80-100% of individuals with virological failure are timely switched to second-line therapy, TDR is predicted to decline irrespective of treatment initiation threshold. CONCLUSION: Averted HIV infections due to the expansion of antiretroviral treatment eligibility offset the risk of transmitted drug resistance, as defined by more infections averted than TDR gained. The effectiveness of first-line non-nucleoside reverse transcriptase inhibitor-based therapy can be preserved by improving switching practices to second-line therapy.

Revell AD, Wang D, Wood R, Morrow C, Tempelman H, Hamers R, Alvarez-Uria G, Streinu-Cercel A, Ene L, Wensing A et al. 2014. An update to the HIV-TRePS system: the development of new computational models that do not require a genotype to predict HIV treatment outcomes. J Antimicrob Chemother, 69 (4), pp. 1104-1110. | Show Abstract | Read more

OBJECTIVES: The optimal individualized selection of antiretroviral drugs in resource-limited settings is challenging because of the limited availability of drugs and genotyping. Here we describe the development of the latest computational models to predict the response to combination antiretroviral therapy without a genotype, for potential use in such settings. METHODS: Random forest models were trained to predict the probability of a virological response to therapy (<50 copies HIV RNA/mL) following virological failure using the following data from 22,567 treatment-change episodes including 1090 from southern Africa: baseline viral load and CD4 cell count, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. The models were assessed during cross-validation and with an independent global test set of 1000 cases including 100 from southern Africa. The models' accuracy [area under the receiver-operating characteristic curve (AUC)] was evaluated and compared with genotyping using rules-based interpretation systems for those cases with genotypes available. RESULTS: The models achieved AUCs of 0.79-0.84 (mean 0.82) during cross-validation, 0.80 with the global test set and 0.78 with the southern African subset. The AUCs were significantly lower (0.56-0.57) for genotyping. CONCLUSIONS: The models predicted virological response to HIV therapy without a genotype as accurately as previous models that included a genotype. They were accurate for cases from southern Africa and significantly more accurate than genotyping. These models will be accessible via the online treatment support tool HIV-TRePS and have the potential to help optimize antiretroviral therapy in resource-limited settings where genotyping is not generally available.

Nichols BE, Sigaloff KCE, Kityo C, Hamers RL, Baltussen R, Bertagnolio S, Jordan MR, Hallett TB, Boucher CAB, de Wit TFR, van de Vijver DAMC. 2014. Increasing the use of second-line therapy is a cost-effective approach to prevent the spread of drug-resistant HIV: a mathematical modelling study. J Int AIDS Soc, 17 (1), pp. 19164. | Show Abstract | Read more

INTRODUCTION: Earlier antiretroviral therapy (ART) initiation reduces HIV-1 incidence. This benefit may be offset by increased transmitted drug resistance (TDR), which could limit future HIV treatment options. We analyze the epidemiological impact and cost-effectiveness of strategies to reduce TDR. METHODS: We develop a deterministic mathematical model representing Kampala, Uganda, to predict the prevalence of TDR over a 10-year period. We then compare the impact on TDR and cost-effectiveness of: (1) introduction of pre-therapy genotyping; (2) doubling use of second-line treatment to 80% (50-90%) of patients with confirmed virological failure on first-line ART; and (3) increasing viral load monitoring from yearly to twice yearly. An intervention can be considered cost-effective if it costs less than three times the gross domestic product per capita per quality adjusted life year (QALY) gained, or less than $3420 in Uganda. RESULTS: The prevalence of TDR is predicted to rise from 6.7% (interquartile range [IQR] 6.2-7.2%) in 2014, to 6.8% (IQR 6.1-7.6%), 10.0% (IQR 8.9-11.5%) and 11.1% (IQR 9.7-13.0%) in 2024 if treatment is initiated at a CD4 <350, <500, or immediately, respectively. The absolute number of TDR cases is predicted to decrease 4.4-8.1% when treating earlier compared to treating at CD4 <350 due to the preventative effects of earlier treatment. Most cases of TDR can be averted by increasing second-line treatment (additional 7.1-10.2% reduction), followed by increased viral load monitoring (<2.7%) and pre-therapy genotyping (<1.0%). Only increasing second-line treatment is cost-effective, ranging from $1612 to $2234 (IQR $450-dominated) per QALY gained. CONCLUSIONS: While earlier treatment initiation will result in a predicted increase in the proportion of patients infected with drug-resistant HIV, the absolute numbers of patients infected with drug-resistant HIV is predicted to decrease. Increasing use of second-line treatment to all patients with confirmed failure on first-line therapy is a cost-effective approach to reduce TDR. Improving access to second-line ART is therefore a major priority.

Hamers RL, Zaaijer HL, Wallis CL, Siwale M, Ive P, Botes ME, Sigaloff KCE, Hoepelman AIM, Stevens WS, Rinke de Wit TF, PharmAccess African Studies to Evaluate Resistance (PASER). 2013. HIV-HBV coinfection in Southern Africa and the effect of lamivudine- versus tenofovir-containing cART on HBV outcomes. J Acquir Immune Defic Syndr, 64 (2), pp. 174-182. | Show Abstract | Read more

BACKGROUND: This study assessed HIV-hepatitis B virus (HBV) coinfection in southern Africa in terms of prevalence, viral characteristics, occult HBV, and the effect of lamivudine- versus tenofovir-containing first-line combination antiretroviral treatment (cART) on HBV-related outcomes. METHODS: A multicenter prospective cohort of HIV-infected adults in Zambia and South Africa who initiated cART. Outcomes by month 12 on cART were immunological recovery, hepatitis B surface antigen (HBsAg) loss, viral suppression, and drug resistance. We used descriptive statistics, logistic regression, and linear mixed models. RESULTS: Of the 1087 participants, 92 were HBsAg seropositive, yielding a sample-weighted prevalence of 7.4% (95% confidence interval: 5.6 to 9.2), with 76% genotype HBV-A1. The estimated CD4 recovery on cART was similar between HIV monoinfection and HIV-HBV coinfection groups and between lamivudine- and tenofovir-treated participants. HBsAg loss was documented in 20% (4/20) of lamivudine-treated and 18% (3/17) of tenofovir-treated participants (P = 0.305). Viral suppression (HBV-DNA < 20 IU/mL) was achieved in 61.5% (16/26) of lamivudine-treated and 71.4% (15/21) of tenofovir-treated participants (P = 0.477). HBV pol sequencing demonstrated M204I (n = 3) and N236T (n = 1) resistance-associated mutations in 4 of 8 (50%) lamivudine-treated participants and none in tenofovir-treated participants. Occult HBV infection was present in 13.3% before cART, but by month 12, HBV-DNA was below the limit of detection (<15 IU/mL) in 90.5% (19/21) of lamivudine-treated and 100% (18/18) of tenofovir-treated participants (P = 0.179). CONCLUSIONS: Tenofovir-containing first-line cART is preferred for HIV-HBV coinfection in Africa because of a superior resistance profile relative to lamivudine monotherapy. Extended follow-up will be needed to determine long-term complications of occult HBV coinfection. Improved access to HBsAg screening and tenofovir is needed.

Bezemer D, Faria NR, Hassan A, Hamers RL, Mutua G, Anzala O, Mandaliya K, Cane P, Berkley JA, Rinke de Wit TF et al. 2014. HIV Type 1 transmission networks among men having sex with men and heterosexuals in Kenya. AIDS Res Hum Retroviruses, 30 (2), pp. 118-126. | Show Abstract | Read more

We performed a molecular phylogenetic study on HIV-1 polymerase sequences of men who have sex with men (MSM) and heterosexual patient samples in Kenya to characterize any observed HIV-1 transmission networks. HIV-1 polymerase sequences were obtained from samples in Nairobi and coastal Kenya from 84 MSM, 226 other men, and 364 women from 2005 to 2010. Using Bayesian phylogenetics, we tested whether sequences clustered by sexual orientation and geographic location. In addition, we used trait diffusion analyses to identify significant epidemiological links and to quantify the number of transmissions between risk groups. Finally, we compared 84 MSM sequences with all HIV-1 sequences available online at GenBank. Significant clustering of sequences from MSM at both coastal Kenya and Nairobi was found, with evidence of HIV-1 transmission between both locations. Although a transmission pair between a coastal MSM and woman was confirmed, no significant HIV-1 transmission was evident between MSM and the comparison population for the predominant subtype A (60%). However, a weak but significant link was evident when studying all subtypes together. GenBank comparison did not reveal other important transmission links. Our data suggest infrequent intermingling of MSM and heterosexual HIV-1 epidemics in Kenya.

De Luca A, Hamers RL, Schapiro JM. 2013. Antiretroviral treatment sequencing strategies to overcome HIV type 1 drug resistance in adolescents and adults in low-middle-income countries. J Infect Dis, 207 Suppl 2 (suppl 2), pp. S63-S69. | Show Abstract | Read more

Antiretroviral treatment (ART) is expanding to human immunodeficiency virus type 1 (HIV-1)-infected persons in low-middle income countries, thanks to a public health approach. With 3 available drug classes, 2 ART sequencing lines are programmatically foreseen. The emergence and transmission of viral drug resistance represents a challenge to the efficacy of ART. Knowledge of HIV-1 drug resistance selection associated with specific drugs and regimens and the consequent activity of residual drug options are essential in programming ART sequencing options aimed at preserving ART efficacy for as long as possible. This article determines optimal ART sequencing options for overcoming HIV-1 drug resistance in resource-limited settings, using currently available drugs and treatment monitoring opportunities. From the perspective of drug resistance and on the basis of limited virologic monitoring data, optimal sequencing seems to involve use of a tenofovir-containing nonnucleoside reverse-transcriptase inhibitor-based first-line regimen, followed by a zidovudine-containing, protease inhibitor (PI)-based second-line regimen. Other options and their consequences are explored by considering within-class and between-class sequencing opportunities, including boosted PI monotherapies and future options with integrase inhibitors. Nucleoside reverse-transcriptase inhibitor resistance pathways in HIV-1 subtype C suggest an additional reason for accelerating stavudine phase out. Viral load monitoring avoids the accumulation of resistance mutations that significantly reduce the activity of next-line options. Rational use of resources, including broader access to viral load monitoring, will help ensure 3 lines of fully active treatment options, thereby increasing the duration of ART success.

Tang MW, Rhee S-Y, Bertagnolio S, Ford N, Holmes S, Sigaloff KC, Hamers RL, de Wit TFR, Fleury HJ, Kanki PJ et al. 2013. Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine. J Infect Dis, 207 Suppl 2 (suppl_2), pp. S70-S77. | Show Abstract | Read more

BACKGROUND: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Revell AD, Wang D, Wood R, Morrow C, Tempelman H, Hamers RL, Alvarez-Uria G, Streinu-Cercel A, Ene L, Wensing AMJ et al. 2013. Computational models can predict response to HIV therapy without a genotype and may reduce treatment failure in different resource-limited settings. J Antimicrob Chemother, 68 (6), pp. 1406-1414. | Show Abstract | Read more

OBJECTIVES: Genotypic HIV drug-resistance testing is typically 60%-65% predictive of response to combination antiretroviral therapy (ART) and is valuable for guiding treatment changes. Genotyping is unavailable in many resource-limited settings (RLSs). We aimed to develop models that can predict response to ART without a genotype and evaluated their potential as a treatment support tool in RLSs. METHODS: Random forest models were trained to predict the probability of response to ART (≤400 copies HIV RNA/mL) using the following data from 14 891 treatment change episodes (TCEs) after virological failure, from well-resourced countries: viral load and CD4 count prior to treatment change, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. Models were assessed by cross-validation during development, with an independent set of 800 cases from well-resourced countries, plus 231 cases from Southern Africa, 206 from India and 375 from Romania. The area under the receiver operating characteristic curve (AUC) was the main outcome measure. RESULTS: The models achieved an AUC of 0.74-0.81 during cross-validation and 0.76-0.77 with the 800 test TCEs. They achieved AUCs of 0.58-0.65 (Southern Africa), 0.63 (India) and 0.70 (Romania). Models were more accurate for data from the well-resourced countries than for cases from Southern Africa and India (P < 0.001), but not Romania. The models identified alternative, available drug regimens predicted to result in virological response for 94% of virological failures in Southern Africa, 99% of those in India and 93% of those in Romania. CONCLUSIONS: We developed computational models that predict virological response to ART without a genotype with comparable accuracy to genotyping with rule-based interpretation. These models have the potential to help optimize antiretroviral therapy for patients in RLSs where genotyping is not generally available.

Sigaloff KCE, Kayiwa J, Musiime V, Calis JCJ, Kaudha E, Mukuye A, Matama C, Nankya I, Nakatudde L, Dekker JT et al. 2013. Short communication: high rates of thymidine analogue mutations and dual-class resistance among HIV-infected Ugandan children failing first-line antiretroviral therapy. AIDS Res Hum Retroviruses, 29 (6), pp. 925-930. | Show Abstract | Read more

HIV-infected children are at high risk of acquiring drug-resistant viruses, which is of particular concern in settings where antiretroviral drug options are limited. We aimed to assess resistance patterns and predict viral drug susceptibility among children with first-line antiretroviral therapy (ART) failure in Uganda. A cross-sectional analysis of children switching ART regimens due to first-line failure was performed at three clinical sites in Uganda. HIV-RNA determination and genotypic resistance testing on all specimens with HIV-RNA >1,000 copies/ml were performed. Major drug resistance mutations were scored using the 2011 International Antiviral Society-USA list. The Stanford algorithm was used to predict drug susceptibility. At the time of switch, 44 genotypic resistance tests were available for 50 children. All children harbored virus with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance [95% confidence interval (CI) 92-100%] and NRTI resistance was present in 98% (95% CI 88-100%). Forty-six percent (95% CI 30-61%) of children harbored ≥2 thymidine analog mutations. M184V was identified as the only NRTI mutation in 27% (95% CI 15-43%). HIV susceptibility to NRTIs, with the exception of tenofovir, was reduced in ≥60% of children. Ugandan children experiencing first-line ART failure in our study harbored high rates of dual-class and accumulated HIV drug resistance. Methods to prevent treatment failure, including adequate pediatric formulations and alternative second-line treatment options, are urgently needed.

Hamers RL, Kityo C, Sigaloff KC, de Wit TFR. 2013. Pretreatment HIV-1 drug resistance in Africa. Lancet Infect Dis, 13 (6), pp. 476. | Read more

Hamers RL, Sigaloff KC, Kityo C, Mugyenyi P, de Wit TFR. 2013. HIV-1 drug resistance in antiretroviral-naive patients in sub-Saharan Africa. Lancet Infect Dis, 13 (3), pp. 196-197. | Read more

Hamers RL, Sigaloff KCE, Kityo C, Mugyenyi P, de Wit TFR. 2013. Emerging HIV-1 drug resistance after roll-out of antiretroviral therapy in sub-Saharan Africa. Curr Opin HIV AIDS, 8 (1), pp. 19-26. | Show Abstract | Read more

PURPOSE OF REVIEW: This review provides an update of recent data on the development of HIV-1 drug resistance during treatment and its transmission in sub-Saharan Africa after the scale-up of antiretroviral therapy (ART). RECENT FINDINGS: Evidence is accumulating of a rising prevalence of transmitted HIV drug resistance (TDR), predominantly associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs), in east and southern Africa. Pretherapy resistance is associated with first-line therapy failure. Accumulation of resistance mutations during first-line failure can be prevented by early detection and timely switching to second-line ART. Important gaps in service delivery and programme performance, associated with resistance development, affect a considerable proportion of ART programmes, particularly with respect to inadequate supply systems and patient retention. The reduction in new HIV infections associated with earlier use of ART is predicted to outweigh the risk of increasing TDR. Future levels of TDR are estimated to be diminished by improving switching practices to second-line regimens. SUMMARY: TDR is on the rise after the recent scale-up of ART in Africa. To prevent the development and spread of drug resistance and sustain the effectiveness of ART programmes, there is a need to improve drug supply systems, patient retention and access to routine viral load monitoring. Enhanced resistance monitoring is warranted in Africa.

Boender TS, Sigaloff KCE, Kayiwa J, Musiime V, Calis JCJ, Hamers RL, Nakatudde LK, Khauda E, Mukuye A, Ditai J et al. 2012. Barriers to Initiation of Pediatric HIV Treatment in Uganda: A Mixed-Method Study AIDS Research and Treatment, 2012 pp. 1-10. | Show Abstract | Read more

Although the advantages of early infant HIV diagnosis and treatment initiation are well established, children often present late to HIV programs in resource-limited settings. We aimed to assess factors related to the timing of treatment initiation among HIV-infected children attending three clinical sites in Uganda. Clinical and demographic determinants associated with early disease (WHO clinical stages 1-2) or late disease (stages 3-4) stage at presentation were assessed using multilevel logistic r egression. Additionally, semistructured interviews with caregivers and health workers were conducted to qualitatively explore determinants of late disease stage at presentation. Of 306 children initiating first-line regimens, 72% presented late. Risk factors for late presentation were age below 2 years old (OR 2.83, P=0.014), living without parents (OR 3.93, P=0.002), unemployment of the caregiver (OR 4.26, P=0.001), lack of perinatal HIV prophylaxis (OR 5.66, P=0.028), and high transportation costs to the clinic (OR 2.51, P=0.072). Forty-nine interviews were conducted, confirming the identified risk factors and additionally pointing to inconsistent referral from perinatal care, caregivers' unawareness of HIV symptoms, fear, and stigma as important barriers. The problem of late disease at presentation requires a multifactorial approach, addressing both health system and individual-level factors. © 2012 T. Sonia Boender et al.

Gupta RK, Jordan MR, Sultan BJ, Hill A, Davis DHJ, Gregson J, Sawyer AW, Hamers RL, Ndembi N, Pillay D, Bertagnolio S. 2012. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet, 380 (9849), pp. 1250-1258. | Show Abstract | Read more

BACKGROUND: The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. METHODS: We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. FINDINGS: Study-level data were available for 26,102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (-0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region. INTERPRETATION: Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries--no changes in antiretroviral treatment guidelines are warranted at the moment. FUNDING: Bill & Melinda Gates Foundation and the European Community's Seventh Framework Programme.

Sigaloff KCE, Mandaliya K, Hamers RL, Otieno F, Jao IM, Lyagoba F, Magambo B, Kapaata A, Ndembi N, Rinke de Wit TF. 2012. Short communication: High prevalence of transmitted antiretroviral drug resistance among newly HIV type 1 diagnosed adults in Mombasa, Kenya. AIDS Res Hum Retroviruses, 28 (9), pp. 1033-1037. | Show Abstract | Read more

Abstract In view of the recent antiretroviral therapy (ART) scale-up in Kenya, surveillance of transmitted HIV drug resistance (TDR) is important. A cross-sectional survey was conducted among newly HIV-1 diagnosed, antiretroviral-naive adults in Mombasa, Kenya. Surveillance drug resistance mutations (SDRMs) were identified according to the 2009 WHO list. HIV-1 subtypes were determined using REGA and SCUEAL subtyping tools. Genotypic test results were obtained for 68 of 81 participants, and SDRMs were identified in 9 samples. Resistance to nonnucleoside reverse transcriptase inhibitors (K103N) occurred in five participants, yielding a TDR prevalence of 7.4% (95% confidence interval 2.4-16.3%). Frequencies of HIV-1 subtypes were A (70.6%), C (5.9%), D (2.9%), and unique recombinant forms (20.6%). The TDR prevalence found in this survey is higher than previously reported in different regions in Kenya. These findings justify increased vigilance with respect to TDR surveillance in African regions where ART programs are scaled-up in order to inform treatment guidelines.

Hamers RL, Sawyer AW, Tuohy M, Stevens WS, Rinke de Wit TF, Hill AM, ART-A Consortium. 2012. Cost-effectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis. AIDS, 26 (13), pp. 1663-1672. | Show Abstract | Read more

OBJECTIVE: To compare the cost-effectiveness of three different strategies for long-term monitoring of antiretroviral therapy (ART) failure and regimen switching in sub-Saharan Africa: a symptom-based approach, or monitoring of either CD4 cell counts or plasma viral load (pVL). DESIGN: Markov model. SETTING AND PARTICIPANTS: Hypothetical HIV-infected adult population who began first-line ART and subsequently had up to 6 years of follow-up. MAIN OUTCOME MEASURES: Total cost, life expectancy and incremental cost-effectiveness ratio (ICER). RESULTS: A symptom-based approach yielded a life expectancy of 64.0 months at a total cost of US$ 4028 per person. All laboratory-based strategies, at testing intervals of 6 or 12 months, were cost-saving and improved life expectancy, compared with a symptom-based approach. The life-expectancy gain was larger for pVL than for CD4 strategies at 6-monthly (2.3 and 0.9 months, respectively) and 12-monthly testing (2.0 and 0.8 months, respectively). Cost-savings of 6-monthly pVL or CD4 testing were similar (US$ 630 and 621, respectively), whereas 12-monthly CD4 cell counts were more cost-saving than 12-monthly pVL (US$ 1132 and 880, respectively). Testing every 12 months - rather than every 6 months - decreased the ICER by 102% for CD4 cell count and 67% for pVL. These findings were robust to a wide range of deterministic sensitivity analyses, but were sensitive to the specificity and costs of diagnostic tests. CONCLUSION: Additional diagnostic costs are balanced by cost-savings from avoiding unnecessary switching due to misdiagnosis of ART failure. Routine pVL monitoring may be preferred as a replacement for CD4 cell counts because of its additional public-health advantages in preventing drug-resistance, supporting adherence and reducing HIV transmission.

Hamers RL, Kityo C, Lange JMA, de Wit TFR, Mugyenyi P. 2012. Global threat from drug resistant HIV in sub-Saharan Africa. BMJ, 344 (jun18 1), pp. e4159. | Read more

Hamers RL, Sigaloff KCE, Wensing AM, Wallis CL, Kityo C, Siwale M, Mandaliya K, Ive P, Botes ME, Wellington M et al. 2012. Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies. Clin Infect Dis, 54 (11), pp. 1660-1669. | Show Abstract | Read more

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility. METHODS: A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was >1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility. RESULTS: HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried ≥1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with ≥1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine. CONCLUSIONS: Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priority.

Sigaloff KCE, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, Botes ME, Mandaliya K, Wellington M, Osibogun A et al. 2012. Second-line antiretroviral treatment successfully resuppresses drug-resistant HIV-1 after first-line failure: prospective cohort in Sub-Saharan Africa. J Infect Dis, 205 (11), pp. 1739-1744. | Show Abstract | Read more

Little is known about the effect of human immunodeficiency virus type 1 (HIV-1) resistance mutations present at time of regimen switch on the response to second-line antiretroviral therapy in Africa. In adults who switched to boosted protease inhibitor-based regimens after first-line failure, HIV-RNA and genotypic resistance testing was performed at switch and after 12 months. Factors associated with treatment failure were assessed using logistic regression. Of 243 participants, 53% were predicted to receive partially active second-line regimens due to drug resistance. The risk of treatment failure was, however, not increased in these participants. In this African cohort, boosted protease inhibitors successfully resuppressed drug-resistant HIV after first-line failure.

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.

Hamers RL, Straatsma E, Kityo C, Wallis CL, Stevens WS, Sigaloff KCE, Siwale M, Conradie F, Botes ME, Mandaliya K et al. 2012. Building capacity for the assessment of HIV drug resistance: experiences from the PharmAccess African Studies to Evaluate Resistance network. Clin Infect Dis, 54 Suppl 4 (suppl 4), pp. S261-S265. | Show Abstract | Read more

The PharmAccess African Studies to Evaluate Resistance (PASER) network was established as a collaborative partnership of clinical sites, laboratories, and research groups in 6 African countries; its purpose is to build research and laboratory capacity in support of a coordinated effort to assess population-level acquired and transmitted human immunodeficiency virus type-1 drug resistance (HIVDR), thus contributing to the goals of the World Health Organization Global HIV Drug Resistance Network. PASER disseminates information to medical professionals and policy makers and conducts observational research related to HIVDR. The sustainability of the network is challenged by funding limitations, constraints in human resources, a vulnerable general health infrastructure, and high cost and complexity of molecular diagnostic testing. This report highlights experiences and challenges in the PASER network from 2006 to 2010.

Hamers RL, Schuurman R, Sigaloff KCE, Wallis CL, Kityo C, Siwale M, Mandaliya K, Ive P, Botes ME, Wellington M et al. 2012. Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study. Lancet Infect Dis, 12 (4), pp. 307-317. | Show Abstract | Read more

BACKGROUND: The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. METHODS: HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. FINDINGS: Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44-3·14; p<0·0001) and acquired drug-resistance (2·30, 1·55-3·40; p<0·0001) was increased in participants with pretreatment drug resistance to at least one prescribed drug, but not in those with pretreatment drug resistance and fully active ART. CD4 count increased less in participants with pretreatment drug resistance than in those without (35 cells per μL difference after 12 months; 95% CI 13-58; p=0·002). INTERPRETATION: At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. FUNDING: The Netherlands Ministry of Foreign Affairs.

Hamers RL, Oyomopito R, Kityo C, Phanuphak P, Siwale M, Sungkanuparph S, Conradie F, Kumarasamy N, Botes ME, Sirisanthana T et al. 2012. Cohort profile: The PharmAccess African (PASER-M) and the TREAT Asia (TASER-M) monitoring studies to evaluate resistance--HIV drug resistance in sub-Saharan Africa and the Asia-Pacific. Int J Epidemiol, 41 (1), pp. 43-54. | Read more

Hamers RL, Wallis CL, Kityo C, Siwale M, Mandaliya K, Conradie F, Botes ME, Wellington M, Osibogun A, Sigaloff KCE et al. 2011. HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study. Lancet Infect Dis, 11 (10), pp. 750-759. | Show Abstract | Read more

BACKGROUND: There are few data on the epidemiology of primary HIV-1 drug resistance after the roll-out of antiretroviral treatment (ART) in sub-Saharan Africa. We aimed to assess the prevalence of primary resistance in six African countries after ART roll-out and if wider use of ART in sub-Saharan Africa is associated with rising prevalence of drug resistance. METHODS: We did a cross-sectional study in antiretroviral-naive adults infected with HIV-1 who had not started first-line ART, recruited between 2007 and 2009 from 11 regions in Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe. We did population-based sequencing of the pol gene on plasma specimens with greater than 1000 copies per mL of HIV RNA. We identified drug-resistance mutations with the WHO list for transmitted resistance. The prevalence of sequences containing at least one drug-resistance mutation was calculated accounting for the sampling weights of the sites. We assessed the risk factors of resistance with multilevel logistic regression with random coefficients. FINDINGS: 2436 (94.1%) of 2590 participants had a pretreatment genotypic resistance result. 1486 participants (57.4%) were women, 1575 (60.8%) had WHO clinical stage 3 or 4 disease, and the median CD4 count was 133 cells per μL (IQR 62-204). Overall sample-weighted drug-resistance prevalence was 5.6% (139 of 2436; 95% CI 4.6-6.7), ranging from 1.1% (two of 176; 0.0-2.7) in Pretoria, South Africa, to 12.3% (22 of 179; 7.5-17.1) in Kampala, Uganda. The pooled prevalence for all three Ugandan sites was 11.6% (66 of 570; 8.9-14.2), compared with 3.5% (73 of 1866; 2.5-4.5) for all other sites. Drug class-specific resistance prevalence was 2.5% (54 of 2436; 1.8-3.2) for nucleoside reverse-transcriptase inhibitors (NRTIs), 3.3% (83 of 2436; 2.5-4.2) for non-NRTIs (NNRTIs), 1.3% (31 of 2436; 0.8-1.8) for protease inhibitors, and 1.2% (25 of 2436; 0.7-1.7) for dual-class resistance to NRTIs and NNRTIs. The most common drug-resistance mutations were K103N (43 [1.8%] of 2436), thymidine analogue mutations (33 [1.6%] of 2436), M184V (25 [1.2%] of 2436), and Y181C/I (19 [0.7%] of 2436). The odds ratio for drug resistance associated with each additional year since the start of the ART roll-out in a region was 1.38 (95% CI 1.13-1.68; p=0.001). INTERPRETATION: The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda. Resistance surveillance and prevention should be prioritised in settings where ART programmes are scaled up. FUNDING: Ministry of Foreign Affairs of the Netherlands.

Sigaloff KCE, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, Botes ME, Mandaliya K, Wellington M, Osibogun A et al. 2011. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J Acquir Immune Defic Syndr, 58 (1), pp. 23-31. | Show Abstract | Read more

OBJECTIVES: This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. METHODS: Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (≥2 TAMs or Q151M or K65R/K70E). RESULTS: Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA <1000 copies per milliliter occurred in 46.9% of CIF only patients versus 12.4% of patients with targeted VL (P < 0.001). NRTI cross-resistance was observed in 48.0% of 183 specimens available for genotypic analysis, comprising ≥2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. CONCLUSIONS: Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross-resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Africa.

Ndembi N, Hamers RL, Sigaloff KCE, Lyagoba F, Magambo B, Nanteza B, Watera C, Kaleebu P, Rinke de Wit TF. 2011. Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala. AIDS, 25 (7), pp. 905-910. | Show Abstract | Read more

OBJECTIVE: To assess the emergence of transmitted HIV-1 drug resistance (TDR) in Kampala, Uganda, 10 years after the scale-up of antiretroviral treatment (ART) and to compare with a previous survey among antenatal clinic attendees in 2007 (reporting 0% TDR). DESIGN: A cross-sectional survey was conducted among newly HIV-1 diagnosed, antiretroviral-naive young adults attending two large voluntary counseling and testing centers within the geographic area of Kampala. METHODS: Proxy criteria for recent HIV-1 infection were used as defined by the WHO. Population sequencing of the pol gene was performed on plasma samples with HIV-1 RNA at least 1000 copies/ml. Surveillance drug resistance mutations (SDRMs) were identified according to the 2009 WHO list for surveillance of TDR. HIV-1 subtypes were designated using maximum likelihood phylogenetic reconstruction. RESULTS: : Genotypic test results were obtained for 70 of 77 (90.9%) participants. SDRMs were identified in six samples yielding a prevalence of TDR of 8.6% (95% confidence interval 3.2-17.7%). Two had SDRMs to nucleoside reverse-transcriptase inhibitors (D67G and L210W), three had SDRMs to nonnucleoside reverse transcriptase inhibitors (G190A, G190S, and K101E), and one had SDRMs to protease inhibitors (N88D). Frequencies of HIV-1 subtypes were A (36/70, 51.4%), C ( two of 70; 2.9%), D (23/70, 32.9%), and unique recombinant forms (nine of 70, 12.9%). CONCLUSION: This repeated survey suggests an increase in TDR in Kampala, compared with a previous survey. This finding justifies increased vigilance with respect to surveillance of TDR in areas in Africa where ART programs are rolled-out.

Welzen MEB, van den Berk GEL, Hamers RL, Burger DM. 2011. Interaction between antiretroviral drugs and acenocoumarol. Antivir Ther, 16 (2), pp. 249-252. | Show Abstract | Read more

The authors report a case of an HIV type-1-infected patient concomitantly using highly active antiretroviral therapy and acenocoumarol anticoagulant for secondary prevention of recurrent venous thromboembolism. This is the first report of a possible drug interaction between efavirenz and atazanavir/ritonavir with acenocoumarol and also of the uncomplicated concurrent use of raltegravir with acenocoumarol.

Hamers RL, Wensing AM, Back NK, Arcilla MS, Frissen JP. 2011. Multi-nucleoside reverse transcriptase inhibitor resistant HIV type-1 in a patient from Sierra Leone failing stavudine, lamivudine and nevirapine. Antivir Ther, 16 (1), pp. 115-118. | Show Abstract | Read more

We report a 33-year-old HIV type-1 (HIV-1)-infected male from Sierra Leone who harboured extensive drug resistance mutations to all nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs, including the multi-NRTI-resistance Q151M complex, K65R, M184I and Y181I, after using standard first-line generic fixed-dose stavudine, lamivudine and nevirapine (Triomune™) for 36 months. In the context of non-B subtypes in resource-limited countries, first-line stavudine-containing regimens have been associated with more extensive and complex mutation patterns, compared with subtype B viruses. Whether the extensive and complex NRTI resistance patterns found among African patients failing first-line antiretroviral therapy is explained by viral genetic diversity or by different patient monitoring strategies remains to be elucidated. Emerging multi-NRTI resistance in sub-Saharan Africa would not only compromise second-line treatment options and the success of antiretroviral rollout, but could also contribute to the spread of drug-resistant variants worldwide.

Hamers RL, Siwale M, Wallis CL, Labib M, van Hasselt R, Stevens WS, Schuurman R, Wensing AMJ, Van Vugt M, Rinke de Wit TF, PharmAccess African Studies to Evaluate Resistance. 2010. HIV-1 drug resistance mutations are present in six percent of persons initiating antiretroviral therapy in Lusaka, Zambia. J Acquir Immune Defic Syndr, 55 (1), pp. 95-101. | Show Abstract | Read more

OBJECTIVE: To assess the mutational patterns and factors associated with baseline drug-resistant HIV-1 present at initiation of first-line antiretroviral therapy (ART) at 3 sites in Lusaka, Zambia, in 2007-2008. METHODS: Population sequencing of the HIV-1 pol gene was performed in the PharmAccess African Studies to Evaluate Resistance Monitoring cohort. Drug resistance-associated mutations (DRMs) were identified using the WHO 2009 Surveillance DRM list. Multiple logistic regression was used to assess factors associated with baseline resistance. RESULTS: The overall prevalence of baseline resistance was 5.7% [31 of 548 participants; 95% confidence interval (CI): 3.9 to 7.9]; the prevalence of DRMs associated with nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors was 1.1%, 4.0%, and 1.1%, respectively. Resistance prevalence was 5.2% (27 of 523) in antiretroviral-naive and 16.0% (4 of 25) in antiretroviral-experienced (ie, previous use of ART or antiretroviral prophylaxis for prevention of mother-to-child transmission) participants (P = 0.022). Dual-class resistance to NRTIs and NNRTIs was observed in 0.6% of participants. HIV-1 subtype C was identified in 98.0% (537 of 548) of participants. Prior antiretroviral experience (odds ratio: 4.32, CI: 1.34 to 14.0, P = 0.015) and hemoglobin level (highest tertile versus lowest tertile odds ratio: 2.74, CI: 1.09 to 6.89, P = 0.033) were independently associated with baseline resistance. CONCLUSIONS: Baseline resistance may compromise the response to standard NNRTI-based first-line ART in 6% of patients in Lusaka, Zambia. Continuous resistance monitoring is warranted to maintain individual and population-level ART effectiveness.

Revell AD, Wang D, Harrigan R, Hamers RL, Wensing AMJ, Dewolf F, Nelson M, Geretti A-M, Larder BA. 2010. Modelling response to HIV therapy without a genotype: an argument for viral load monitoring in resource-limited settings. J Antimicrob Chemother, 65 (4), pp. 605-607. | Show Abstract | Read more

In the absence of widespread access to individualized laboratory monitoring, which forms an integral part of HIV patient management in resource-rich settings, the roll-out of highly active antiretroviral therapy (HAART) in resource-limited settings has adopted a public health approach based on standard HAART protocols and clinical/immunological definitions of therapy failure. The cost-effectiveness of HIV-1 viral load monitoring at the individual level in such settings has been debated, and questions remain over the long-term and population-level impact of managing HAART without it. Computational models that accurately predict virological response to HAART using baseline data including CD4 count, viral load and genotypic resistance profile, as developed by the Resistance Database Initiative, have significant potential as an aid to treatment selection and optimization. Recently developed models have shown good predictive performance without the need for genotypic data, with viral load emerging as by far the most important variable. This finding provides further, indirect support for the use of viral load monitoring for the long-term optimization of HAART in resource-limited settings.

Hamers RL, Smit PW, Stevens W, Schuurman R, Rinke de Wit TF. 2009. Dried fluid spots for HIV type-1 viral load and resistance genotyping: a systematic review. Antivir Ther, 14 (5), pp. 619-629. | Show Abstract

BACKGROUND: Dried spots on filter paper made of whole blood (dried blood spots; DBS), plasma (dried plasma spots; DPS) or serum (dried serum spots) hold promise as an affordable and practical alternative specimen source to liquid plasma for HIV type-1 (HIV-1) viral load determination and drug resistance genotyping in the context of the rapidly expanding access to antiretroviral therapy (ART) for HIV-1-infected individuals in low- and middle-income countries. This report reviews the current evidence for their utility. METHODS: We systematically searched the English language literature published before 2009 on Medline, the websites of the World Health Organization and US Centers for Disease Control and Prevention, abstracts presented at relevant international conferences and references from relevant articles. RESULTS: Data indicate that HIV-1 viral load determination and resistance genotyping from DBS and DPS is feasible, yielding comparable test performances, even after storage. Limitations include reduced analytical sensitivity resulting from small analyte volumes (approximately 3.5 log(10) copies/ml at 50 microl sample volume), nucleic acid degradation under extreme environmental conditions, impaired efficiency of nucleic acid extraction, potential interference of archived proviral DNA in genotypes obtained from DBS and the excision of spots from the filters in high-volume testing. CONCLUSIONS: This technology offers the advantages of a stable specimen matrix, ease of sample collection and shipment. The current sensitivity in drug resistance testing is appropriate for public health surveillance among pretreatment populations. However, consistently improved analytical sensitivity is needed for their routine application in the therapeutic monitoring of individuals receiving ART, particularly at the onset of treatment failure.

Hamers RL, Beer ID, Kaura H, van Vugt M, Rinke de Wit TF. 2009. Oral Fluid HIV Rapid Testing in Southern Africa Is Suitable for Population-Level Surveillance But May Not Be So for Individual Diagnosis (Invited Response to Scott et al: Can Oral Fluid Testing Be Used to Replace Blood-Based HIV Rapid Testing to Improve Access to Diagnosis in South Africa?) JAIDS Journal of Acquired Immune Deficiency Syndromes, 51 (5), pp. 648-649. | Read more

Hamers RL, Van Den Berg FG, Groeneveld ABJ. 2009. Acute necrotizing pancreatitis following inadvertent extensive splenic artery embolisation for trauma. Br J Radiol, 82 (973), pp. e11-e14. | Show Abstract | Read more

We present a case of splenic artery embolisation (SAE) after traumatic splenic injury that was complicated by acute necrotizing pancreatitis, caused by inadvertently extensive embolisation of the splenic artery. Although SAE is increasingly used for splenic preservation in trauma, there is insufficient knowledge on its efficacy and pitfalls. This report aims to draw attention to a rare but potentially serious complication of SAE.

Hamers RL, Derdelinckx I, van Vugt M, Stevens W, Rinke de Wit TF, Chuurman R. 2008. Erratum: The status of HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa (Antiviral Therapy vol. 13 (625-639)) Antiviral Therapy, 13 (8), pp. 1129.

Hamers RL, Derdelinckx I, van Vugt M, Stevens W, Rinke de Wit TF, Schuurman R, PharmAccess African Studies to Evaluate Resistance Programme. 2008. The status of HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa. Antivir Ther, 13 (5), pp. 625-639. | Show Abstract

Access to highly active antiretroviral therapy (HAART) for persons infected with HIV in sub-Saharan Africa has greatly improved over the past few years. However, data on long-term clinical outcomes of Africans receiving HAART, patterns of HIV resistance to antiretroviral drugs and implications of HIV type-1 (HIV-1) subtype diversity in Africa for resistance, are limited. In resource-limited settings, concerns have been raised that deficiencies in health systems could create the conditions for accelerated development of resistance. Coordinated surveillance systems are being established to assess the emergence of resistance and the factors associated with resistance development, and to create the possibility for adjusting treatment guidelines as necessary. The purpose of this report is to review the literature on HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa, in relation to the drug regimens used in Africa, HIV-1 subtype diversity and overall prevalence of resistance. The report focuses on resistance associated with treatment, prevention of mother-to-child transmission and transmitted resistance. It also outlines priorities for public health action and research.

Hamers RL, de Beer IH, Kaura H, van Vugt M, Caparos L, Rinke de Wit TF. 2008. Diagnostic accuracy of 2 oral fluid-based tests for HIV surveillance in Namibia. J Acquir Immune Defic Syndr, 48 (1), pp. 116-118. | Read more

Hamers RL, Rinke De Wit TF, Schellekens OP, Van Vugt M. 2008. Treatment of AIDS in Africa (2) Nederlands Tijdschrift voor Geneeskunde, 152 (11), pp. 654.

Hamers RL, Schuurman R, van Vugt M, Derdelinckx I, Rinke de Wit TF. 2007. [AIDS treatment in Africa: the risk of antiretroviral resistance]. Ned Tijdschr Geneeskd, 151 (48), pp. 2666-2671. | Show Abstract

--In recent years, implementation of antiretroviral therapy in developing countries with a high prevalence of HIV-1 has been recognised as a public health priority. Consequently, the availability ofantiretroviral combination therapy for people with HIV is increasing rapidly in sub-Saharan Africa. --HIV treatment programmes are implemented according to the standardised, simplified public health guidelines developed by the World Health Organization (WHO). --However, the implementation of treatment programmes in Africa is hindered by several factors, including the lack of adequate immunological and virological laboratory monitoring, insufficient support for adherence to therapy, vulnerable health care systems and the use of suboptimal drug combinations. --These suboptimal treatment conditions increase the risk that resistant virus strains will emerge that are less susceptible to standard first-line combination therapy, thus threatening the long-term success of the treatment programmes. --The WHO has initiated HIVResNet, an international expert advisory board that has developed a global strategy for surveillance and prevention of antiretroviral drug resistance. --The Dutch initiative known as 'PharmAccess African studies to evaluate resistance' (PASER) is contributing to this strategy by creating a surveillance network in sub-Saharan Africa.

Hamers R, Bontemps S, van den Akker M, Souza R, Penaforte J, Chavannes N. 2006. Chronic obstructive pulmonary disease in Brazilian primary care: Diagnostic competence and case-finding. Prim Care Respir J, 15 (5), pp. 299-306. | Show Abstract | Read more

AIMS: The developing world is particularly at risk of an increasing health burden due to an increased prevalence of Chronic Obstructive Pulmonary Disease (COPD) secondary to increasing tobacco consumption. However, research is scarce. The objectives of this study were to assess the current competence for diagnosing COPD in primary care in a resource-limited setting in Brazil, and to develop a local patient profile for case-finding. METHODS: 34 general practitioners (GPs) in five areas of northern Brazil recruited adult patients with principal complaints of cough and/or shortness of breath who then had spirometry (n = 142). RESULTS: For the dichotomous variable 'COPD' the degree of agreement between GP diagnosis (n = 64, 18.3%) and spirometric outcome (n = 36, 25.4%) was poor, with Kappa = 0.055 (SE 0.087) and DOR = 1.35. False-positive and false-negative diagnosis proportions were 19.8% and 75%, respectively. Independent risk factors were 'smoking history of more than five pack years' and 'presence of both dyspnoea and cough'. It requires the testing of 2.2 smokers with more than five pack years to detect one patient at risk. CONCLUSIONS: COPD is a common yet underdiagnosed disease in Brazilian primary care. Spirometry improves diagnostic competence and case-finding substantially. If applied in a pre-selected high-risk population, we believe spirometry can be a cost-effective diagnostic tool for case-finding in the resource-limited setting. This study provides important baseline information for effective guideline implementation.

Paredes R, Tzou PL, van Zyl G, Barrow G, Camacho R, Carmona S, Grant PM, Gupta RK, Hamers RL, Harrigan PR et al. 2017. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation. PLoS One, 12 (7), pp. e0181357. | Show Abstract | Read more

INTRODUCTION: HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. METHODS: An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs). RESULTS: There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required. CONCLUSIONS: The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

Bijker R, Jiamsakul A, Kityo C, Kiertiburanakul S, Siwale M, Phanuphak P, Akanmu S, Chaiwarith R, Wit FW, Sim BL et al. 2017. Adherence to antiretroviral therapy for HIV in sub-Saharan Africa and Asia: a comparative analysis of two regional cohorts. J Int AIDS Soc, 20 (1), pp. 21218. | Show Abstract | Read more

INTRODUCTION: Our understanding of how to achieve optimal long-term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV-positive persons receiving ART who were enrolled in a bi-regional cohort in sub-Saharan Africa and Asia. METHODS: This multicentre prospective study of adults starting first-line ART assessed patient-reported adherence at follow-up clinic visits using a 30-day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six-month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. RESULTS: Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06-1.53;p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8-0.9;p = 0.003), use of concomitant medication (OR 1.8, 1.0-3.2;p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1-1.7;p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4-0.9;p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9-2.6;p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low- and lower-middle-income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3-2.0;p < 0.001), compared to those in upper-middle or high-income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3-7.7;p < 0.001) and Asia (OR 9.0, 95% CI 5.0-16.2;p < 0.001). Patient-reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. CONCLUSION: Psychosocial factors and health system resources may explain regional differences. Adherence-enhancing interventions should address patient-reported barriers tailored to local settings, prioritizing the first years of ART.

Inzaule SC, Ondoa P, Peter T, Mugyenyi PN, Stevens WS, de Wit TFR, Hamers RL. 2016. Affordable HIV drug-resistance testing for monitoring of antiretroviral therapy in sub-Saharan Africa. Lancet Infect Dis, 16 (11), pp. e267-e275. | Show Abstract | Read more

Increased provision of antiretroviral therapy in sub-Saharan Africa has led to a growing number of patients with therapy failure and acquired drug-resistant HIV, driving the demand for more costly further lines of antiretroviral therapy. In conjunction with accelerated access to viral load monitoring, feasible and affordable technologies to detect drug-resistant HIV could help maximise the durability and rational use of available drug regimens. Potential low-cost technologies include in-house Sanger and next-generation sequencing in centralised laboratories, and point mutation assays and genotype-free systems that predict response to antiretroviral therapy at point-of-care. Strengthening of centralised high-throughput laboratories, including efficient systems for sample referral and results delivery, will increase economies-of-scale while reducing costs. Access barriers can be mitigated by standardisation of in-house assays into commercial kits, use of polyvalent instruments, and adopting price-reducing strategies. A stepwise rollout approach should improve feasibility, prioritising WHO-recommended population-based surveillance and management of complex patient categories, such as patients failing protease inhibitor-based antiretroviral therapy. Implementation research, adaptations of existing WHO guidance, and political commitment, will be key to support the appropriate investments and policy changes. In this Personal View, we discuss the potential role of HIV drug resistance testing for population-based surveillance and individual patient management in sub-Saharan Africa. We review the strengths and challenges of promising low-cost technologies and how they can be implemented.

Revell AD, Wang D, Wood R, Morrow C, Tempelman H, Hamers RL, Reiss P, van Sighem AI, Nelson M, Montaner JSG et al. 2016. An update to the HIV-TRePS system: the development and evaluation of new global and local computational models to predict HIV treatment outcomes, with or without a genotype. J Antimicrob Chemother, 71 (10), pp. 2928-2937. | Show Abstract | Read more

OBJECTIVES: Optimizing antiretroviral drug combination on an individual basis in resource-limited settings is challenging because of the limited availability of drugs and genotypic resistance testing. Here, we describe our latest computational models to predict treatment responses, with or without a genotype, and compare the potential utility of global and local models as a treatment tool for South Africa. METHODS: Global random forest models were trained to predict the probability of virological response to therapy following virological failure using 29 574 treatment change episodes (TCEs) without a genotype, 3179 of which were from South Africa and were used to develop local models. In addition, 15 130 TCEs including genotypes were used to develop another set of models. The 'no-genotype' models were tested with an independent global test set (n = 1700) plus a subset from South Africa (n = 222). The genotype models were tested with 750 independent cases. RESULTS: The global no-genotype models achieved area under the receiver-operating characteristic curve (AUC) values of 0.82 and 0.79 with the global and South African tests sets, respectively, and the South African models achieved AUCs of 0.70 and 0.79. The genotype models achieved an AUC of 0.84. The global no-genotype models identified more alternative, locally available regimens that were predicted to be effective for cases that failed their new regimen in the South African clinics than the local models. Both sets of models were significantly more accurate predictors of outcomes than genotyping with rules-based interpretation. CONCLUSIONS: These latest global models predict treatment responses accurately even without a genotype, out-performed the local South African models and have the potential to help optimize therapy, particularly in resource-limited settings.

TenoRes Study Group. 2016. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study. Lancet Infect Dis, 16 (5), pp. 565-575. | Show Abstract | Read more

BACKGROUND: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. METHODS: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. FINDINGS: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27-1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20-1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]). INTERPRETATION: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. FUNDING: The Wellcome Trust.

Gupta RK, Jordan MR, Sultan BJ, Hill A, Davis DHJ, Gregson J, Sawyer AW, Hamers RL, Ndembi N, Pillay D, Bertagnolio S. 2012. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet, 380 (9849), pp. 1250-1258. | Show Abstract | Read more

BACKGROUND: The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. METHODS: We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. FINDINGS: Study-level data were available for 26,102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (-0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region. INTERPRETATION: Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries--no changes in antiretroviral treatment guidelines are warranted at the moment. FUNDING: Bill & Melinda Gates Foundation and the European Community's Seventh Framework Programme.

Hamers RL, Sawyer AW, Tuohy M, Stevens WS, Rinke de Wit TF, Hill AM, ART-A Consortium. 2012. Cost-effectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis. AIDS, 26 (13), pp. 1663-1672. | Show Abstract | Read more

OBJECTIVE: To compare the cost-effectiveness of three different strategies for long-term monitoring of antiretroviral therapy (ART) failure and regimen switching in sub-Saharan Africa: a symptom-based approach, or monitoring of either CD4 cell counts or plasma viral load (pVL). DESIGN: Markov model. SETTING AND PARTICIPANTS: Hypothetical HIV-infected adult population who began first-line ART and subsequently had up to 6 years of follow-up. MAIN OUTCOME MEASURES: Total cost, life expectancy and incremental cost-effectiveness ratio (ICER). RESULTS: A symptom-based approach yielded a life expectancy of 64.0 months at a total cost of US$ 4028 per person. All laboratory-based strategies, at testing intervals of 6 or 12 months, were cost-saving and improved life expectancy, compared with a symptom-based approach. The life-expectancy gain was larger for pVL than for CD4 strategies at 6-monthly (2.3 and 0.9 months, respectively) and 12-monthly testing (2.0 and 0.8 months, respectively). Cost-savings of 6-monthly pVL or CD4 testing were similar (US$ 630 and 621, respectively), whereas 12-monthly CD4 cell counts were more cost-saving than 12-monthly pVL (US$ 1132 and 880, respectively). Testing every 12 months - rather than every 6 months - decreased the ICER by 102% for CD4 cell count and 67% for pVL. These findings were robust to a wide range of deterministic sensitivity analyses, but were sensitive to the specificity and costs of diagnostic tests. CONCLUSION: Additional diagnostic costs are balanced by cost-savings from avoiding unnecessary switching due to misdiagnosis of ART failure. Routine pVL monitoring may be preferred as a replacement for CD4 cell counts because of its additional public-health advantages in preventing drug-resistance, supporting adherence and reducing HIV transmission.

Hamers RL, Schuurman R, Sigaloff KCE, Wallis CL, Kityo C, Siwale M, Mandaliya K, Ive P, Botes ME, Wellington M et al. 2012. Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study. Lancet Infect Dis, 12 (4), pp. 307-317. | Show Abstract | Read more

BACKGROUND: The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. METHODS: HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. FINDINGS: Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44-3·14; p<0·0001) and acquired drug-resistance (2·30, 1·55-3·40; p<0·0001) was increased in participants with pretreatment drug resistance to at least one prescribed drug, but not in those with pretreatment drug resistance and fully active ART. CD4 count increased less in participants with pretreatment drug resistance than in those without (35 cells per μL difference after 12 months; 95% CI 13-58; p=0·002). INTERPRETATION: At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. FUNDING: The Netherlands Ministry of Foreign Affairs.

Hamers RL, Wallis CL, Kityo C, Siwale M, Mandaliya K, Conradie F, Botes ME, Wellington M, Osibogun A, Sigaloff KCE et al. 2011. HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study. Lancet Infect Dis, 11 (10), pp. 750-759. | Show Abstract | Read more

BACKGROUND: There are few data on the epidemiology of primary HIV-1 drug resistance after the roll-out of antiretroviral treatment (ART) in sub-Saharan Africa. We aimed to assess the prevalence of primary resistance in six African countries after ART roll-out and if wider use of ART in sub-Saharan Africa is associated with rising prevalence of drug resistance. METHODS: We did a cross-sectional study in antiretroviral-naive adults infected with HIV-1 who had not started first-line ART, recruited between 2007 and 2009 from 11 regions in Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe. We did population-based sequencing of the pol gene on plasma specimens with greater than 1000 copies per mL of HIV RNA. We identified drug-resistance mutations with the WHO list for transmitted resistance. The prevalence of sequences containing at least one drug-resistance mutation was calculated accounting for the sampling weights of the sites. We assessed the risk factors of resistance with multilevel logistic regression with random coefficients. FINDINGS: 2436 (94.1%) of 2590 participants had a pretreatment genotypic resistance result. 1486 participants (57.4%) were women, 1575 (60.8%) had WHO clinical stage 3 or 4 disease, and the median CD4 count was 133 cells per μL (IQR 62-204). Overall sample-weighted drug-resistance prevalence was 5.6% (139 of 2436; 95% CI 4.6-6.7), ranging from 1.1% (two of 176; 0.0-2.7) in Pretoria, South Africa, to 12.3% (22 of 179; 7.5-17.1) in Kampala, Uganda. The pooled prevalence for all three Ugandan sites was 11.6% (66 of 570; 8.9-14.2), compared with 3.5% (73 of 1866; 2.5-4.5) for all other sites. Drug class-specific resistance prevalence was 2.5% (54 of 2436; 1.8-3.2) for nucleoside reverse-transcriptase inhibitors (NRTIs), 3.3% (83 of 2436; 2.5-4.2) for non-NRTIs (NNRTIs), 1.3% (31 of 2436; 0.8-1.8) for protease inhibitors, and 1.2% (25 of 2436; 0.7-1.7) for dual-class resistance to NRTIs and NNRTIs. The most common drug-resistance mutations were K103N (43 [1.8%] of 2436), thymidine analogue mutations (33 [1.6%] of 2436), M184V (25 [1.2%] of 2436), and Y181C/I (19 [0.7%] of 2436). The odds ratio for drug resistance associated with each additional year since the start of the ART roll-out in a region was 1.38 (95% CI 1.13-1.68; p=0.001). INTERPRETATION: The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda. Resistance surveillance and prevention should be prioritised in settings where ART programmes are scaled up. FUNDING: Ministry of Foreign Affairs of the Netherlands.

Sigaloff KCE, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, Botes ME, Mandaliya K, Wellington M, Osibogun A et al. 2011. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J Acquir Immune Defic Syndr, 58 (1), pp. 23-31. | Show Abstract | Read more

OBJECTIVES: This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. METHODS: Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (≥2 TAMs or Q151M or K65R/K70E). RESULTS: Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA <1000 copies per milliliter occurred in 46.9% of CIF only patients versus 12.4% of patients with targeted VL (P < 0.001). NRTI cross-resistance was observed in 48.0% of 183 specimens available for genotypic analysis, comprising ≥2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. CONCLUSIONS: Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross-resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Africa.

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