Professor J. Kevin Baird

Research Area: Clinical Epidemiology
Technology Exchange: Drug discovery, Medical statistics and Microscopy (Video)
Scientific Themes: Tropical Medicine & Global Health
Keywords: infections, malaria, influenza, typhoid, clinical studies and surveillance
Web Links:
Relapse of Plasmodium vivax in Indonesian soldiers repatriated to Java from their duties in malarious eastern Indonesia. 'AS' group received no primaquine, and the graph plots the cumulative incidence to first relapse after first confirmed P. vivax attack on Java. 'QN+PQ' and 'DHA-PP+PQ' each received primaquine with quinine or an artemisinin combined therapy.

Relapse of Plasmodium vivax in Indonesian soldiers repatriated to Java from their duties in ...

The Eijkman-Oxford Clinical Research Unit (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. EIMB and EOCRU undertake joint collaborative research endeavors principally in the field of malariology, and especially involving the parasite species Plasmodium vivax.  Together with partners in the Faculty of Medicine, University of Indonesia and the health services division of the Indonesian Army, EOCRU and EIMB have developed a clinical trial model for clinical interventions for preventing and treating malaria – young soldiers based in malaria-free areas of Java being deployed to heavily malarious outer islands of Indonesia for routine duties, but who return to Java after 6 months to a year. The clinical trials team composed of all these partners have successfully executed 2 trials of primaquine therapy against relapse of vivax malaria, and now plan for a third involving tafenoquine, all of which have been genrously funded by the Medicines for Malaria Venture, Geneva. The Unit is a partner in the IMPROV multi-centre clinical trial of primaquine against relapse of vivax malaria based at the Oxford unit in Bangkok (MORU). The Unit also conducts basic laboratory bench, clinical, and field research on the diagnosis and epidemiology of glucose-6-phosphate dehydrogenase deficiency (G6PDd), and polymorphisms in cytochrome P450 2D6 (CYP2D6). Both of these factors profoundly impact the prevention and treatment of Plasmodium vivax malaria.  EOCRU represents the Asia Pacific region for the Malaria Atlas Project, and engages directly with those partners in numerous technical endeavors of geospatial modeling, managed principally be Wellcome Trust Fellow Dr. Iqbal Elyazar.

Name Department Institution Country
Sangkot Marzuki Indonesian Academy of Sciences, Jakarta Indonesia
Amin Soebandrio Eijkman Institute of Molecular Biology, Jakarta Indonesia
Hera Sudoyo Eijkman Institute for Molecular Biology, Jakarta Indonesia
Professor Inge Sutanto Parasitology Faculty of Medicine, University of Indonesia, Jakarta Indonesia
Pratiwi Sudarmono Faculty of Medicine, University of Indonesia, Jakarta Indonesia
Irawan Yusuf Faculty of Medicine, Hasannudin University, Makassar Indonesia
Hadi Yusuf Hasan Sadikin Hospital, Bandung Indonesia
Diky Oktavianus Internal Medicine Karitas Hospital, Sumba Indonesia
Erni N Nelwan Internal Medicine Faculty of Medicine, U. Indonesia Jakarta Indonesia
Asyik Surya Malaria Control Ministry of Health, Jakarta Indonesia
Dr Michael Bangs Malaria Control PT Freeport Indonesia, Timika Indonesia
Bagus Tjahjono Health Army of the Republic of Indonesia, Jakarta Indonesia
Soroy Lardo Health Army of the Republic of Indonesia, Jakarta Indonesia
Dr Rintis Noviyanti Eijkman Institute for Molecular Biology, Jakarta Indonesia
Din Syafruddin Malaria Eijkman Institute for Molecular Biology, Jakarta Indonesia
Alida Harahap Blood disorders Eijkman Institute of Molecular Biology, Jakarta Indonesia
Putji Taslim Public Health Hasanuddin University, Makassar Indonesia
Unknown Wirawan Public Health Udayana University, Makassar Indonesia
Dr Ayodhia Pitaloka Pasaribu University of Sumatera Utara Indonesia
Eddy Wirawan Parasitology Faculty of MEdicine, U. Indonesia, Jakarta Indonesia
Ivo Mueller Infections Walter & Eliza Hall Institute, Melbourne Australia
Denise Doolan Immunology Queensland Institute for Medical Research, Brisbane Australia
Professor James McCarthy Malaria University of Queensland Australia
Dennis Shanks Australian Army Malaria Research Institute, Brisbane Australia
Professor Richard Price Tropical Medicine Oxford University, Asia Pacific Australia
Hien Tran Tinh Malaria Oxford University Clinical Research Unit, Ho Chi Minh City Vietnam
Professor Guy Thwaites Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Hong Nguyen Van Malaria National Institute of Malaria, Parasitology & Entom, Hanoi Vietnam
Kheng Sim Malaria Pasteur Institute Cambodia, Phnom Penh Cambodia
Didier Menard Malaria Pasteur Institute Cambodia, Phnom Penh Cambodia
Professor Sir Nicholas J White FRS Tropical Medicine Oxford University, Bangkok Thailand
Arjen Dundoorp Malaria Mahidol-Oxford Research Unit, Bangkok Thailand
Professor Stuart Blacksell Tropical Medicine Oxford University, Bangkok Thailand
Professor Yoel Lubell Tropical Medicine Oxford University, Bangkok Thailand
Dr Robert Taylor Tropical Medicine Oxford University, Bangkok Thailand
Dr Lorenz Von Seidlein Tropical Medicine Oxford University, Bangkok Thailand
Professor François H Nosten Tropical Medicine Oxford University, Mae Sot Thailand
Germana Bancone Shoklo Malaria Research Unit, Mae Sot Thailand
Bruce Russell Singapore Immunology Group, A-Star Singapore
Ari Satyagraha Biochemistry Eijkman Institute of Molecular Biology, Jakarta Indonesia
Antonius Pudjiadi Cipto Mangunkusumo Hospital, Jakarta Indonesia
Yohana Sorontou Faculty of Medicine, Cendrawasih University, Jayapura Indonesia
Rita Kustriastuti Infectious Diseases Control, Ministry of Health Indonesia
Erlina Burhan Friendship Hospital, Jakarta Indonesia
Dewi Murniati Sulianti Suroso Infectious Diseases Hospital, Jakarta Indonesia
Joost Philippa Wildlife Conservation Society, Jakarta Indonesia
William Rogers US NAMRU-2 Indonesia
Professor Jeremy Farrar Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Peter Horby Tropical Medicine Oxford University, Old Road Campus Research Building United Kingdom
Kasia Stepniewska Mahidol-Oxford Research Unit, Bangkok Thailand
Srivicha Krudsood Faculty of Trop Med, Mahidol University, Bangkok Thailand
Bruce Russell Vivax Laboratory School of Medicine, National University of Singapore Singapore
Laurent RENIA Singapore Immunology Network Singapore
Eva Christophel Infections Western Pacific Regional Office, WHO, Manila Philippines
Lasse Vestergaard Malaria Western Pacifica Regional Office, WHO, Manila Philippines
Joan Ingram Medicine Auckland Cit Hospital, Auckland New Zealand
Kim Jung Yeon Malaria Disease Control Diversion, Seoul South Korea
Dr Neena Valecha National Institute for Malaria Research India
Kavitha Saravu Katsurba Medical College, Manipal India
Dhanpat Kochar Medicine S.P. Medical College, Bikaner India
Professor Bob W Snow Tropical Medicine Oxford University, Nairobi Kenya
Professor Simon Hay Big Data Institute Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Peter Gething Big Data Institute Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Dr Catherine Moyes Big Data Institute Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Rosalind Howes Malaria Atlas Project Dept. Zoology, Univeristy of Oxford United Kingdom
Katherine Battle Malaria Atlas Project Dept. Zoology, Univeristy of Oxford United Kingdom
Professor Philippe J Guerin Tropical Medicine Oxford University, NDM Research Building United Kingdom
Mark Harrison Wellcome Unit for the History of Medicine, U. Oxford United Kingdom
Justin Green GlaxoSmithKline, Uxbridge United Kingdom
Pascal Ringwald Malaria World Health Organization, Geneva Switzerland
Richard Cibulkis Malaria World Health Organization, Geneva Switzerland
Andrea Bosman Malaria World Health Organization, Geneva Switzerland
Stephan Duparc Medicines for Malaria Venture, Geneva Switzerland
Valerie LeMayeur Sanofi (pharmaceuticals), Paris France
Marco Corsi Sigma Tau Pharmaceuticals Italy
Luco Luzzatto Instituto Toscano Tumori, Florence Italy
Stephen L. Hoffman Sanaria Inc., Rockville, Maryland United States
Young S. Hong AccessBio Inc., Somerset, New Jersey United States
Peter Zimmerman Case Western Reserve University, Cleveland United States
Liwang Ciu Pennsylvania State Univeristy United States
David Wesche Bill & Melinda Gates Foundation, Seattle United States
Baird JK. 2017. Malaria control by commodities without practical malariology BMC PUBLIC HEALTH, 17 (1), | Show Abstract | Read more

© 2017 The Author(s). Malaria remains a serious clinical and public health problem, the object of an ongoing technological and humanitarian struggle to abate the very substantial harm done. The manner by which humanity approached malaria control changed abruptly and profoundly after 1945 with the advent of the insecticide DDT. Malariologists in the first half of the twentieth century conceived precise modifications to natural or man-made environments aimed at making those less hospitable to specific anopheline mosquito vector species. This practical malariology achieved very significant reductions in burdens of morbidity and mortality, but the revolutionary insecticide eliminated the need for its specialized knowledge and diverse practices. By 1970 mosquito resistance to DDT and perceived environmental concerns precipitated the collapse of what had been a vigorous global campaign to eradicate malaria. Humanity did not then revitalize practical malariology but turned to another commodity as the foundation of control strategy, the war-spurred suite of synthetic antimalarial drugs developed in the 1940s and 1950s. When those drugs became lost to parasite resistance in the latter twentieth century, malaria resurged globally. Since 2005, tens of billions of dollars mobilized new commodities to control malaria: point-of-care diagnostics, effective artemisinin-based treatments, and longer-lasting insecticide treated bed nets. The know-how of practical malariology is not part of that ongoing commodities-based strategy. This article examines contemporary malaria control in the broad strokes of a strategy mitigating the consequences of infection contrasted to that of the abandoned practical malariology strategy of prevention. The inherent risks and limitations of over-reliance upon commodities in striving to control malaria may prompt consideration of a strategic posture inclusive of the proven methods of practical malariology.

Baird JK. 2017. Rational malaria chemoprophylaxis - The position of primaquine. Travel Med Infect Dis, 17 pp. 3-4. | Read more

Baird JK. 2017. Management of Plasmodium vivax risk and illness in travelers. Trop Dis Travel Med Vaccines, 3 (1), pp. 7. | Show Abstract | Read more

Malaria poses an exceptionally complex problem for providers of travel medicine services. Perceived high risk of exposure during travel typically prompts prescribing protective antimalarial drugs. Suppressive chemoprophylactic agents have dominated strategy for that practice for over 70 years. This broad class of therapeutic agents kills parasites after they emerge from the liver and attempt development in red blood cells. The dominance of suppressive chemoprophylaxis in travel medicine stems largely from the view of Plasmodium falciparum as the utmost threat to the patient - these drugs are poorly suited to preventing Plasmodium vivax and Plasmodium ovale due to inactivity against the latent liver stages of these species not produced by P. falciparum. Those hypnozoites awaken to cause multiple clinical attacks called relapses in the months following infection. Causal prophylactic agents kill parasites as they attempt development in hepatic cells. The only drug proven effective for causal prophylaxis against P. vivax is primaquine. That drug is not widely recommended for primary prophylaxis for travelers despite preventing both primary attacks of all the plasmodia and relapses of P. vivax. The long-held perception of P. vivax as causing a benign malaria in part explains the dominance of suppressive chemoprophylaxis strategies poorly suited to its prevention. Recent evidence from both travelers and patients hospitalized in endemic areas reveals P. vivax as a pernicious clinical threat capable of progression to severe disease syndromes associated with fatal outcomes. Effective prevention of clinical attacks of vivax malaria following exposure during travel requires primary causal prophylaxis or post-travel presumptive anti-relapse therapy following suppressive prophylaxis.

Thriemer K, Ley B, Bobogare A, Dysoley L, Alam MS, Pasaribu AP, Sattabongkot J, Jambert E, Domingo GJ, Commons R et al. 2017. Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group. Malar J, 16 (1), pp. 141. | Show Abstract | Read more

The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia-Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by  the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.

Ding XC, Ade MP, Baird JK, Cheng Q, Cunningham J, Dhorda M, Drakeley C, Felger I, Gamboa D, Harbers M et al. 2017. Defining the next generation of Plasmodium vivax diagnostic tests for control and elimination: Target product profiles. PLoS Negl Trop Dis, 11 (4), pp. e0005516. | Show Abstract | Read more

The global prevalence of malaria has decreased over the past fifteen years, but similar gains have not been realized against Plasmodium vivax because this species is less responsive to conventional malaria control interventions aimed principally at P. falciparum. Approximately half of all malaria cases outside of Africa are caused by P. vivax. This species places dormant forms in human liver that cause repeated clinical attacks without involving another mosquito bite. The diagnosis of acute patent P. vivax malaria relies primarily on light microscopy. Specific rapid diagnostic tests exist but typically perform relatively poorly compared to those for P. falciparum. Better diagnostic tests are needed for P. vivax. To guide their development, FIND, in collaboration with P. vivax experts, identified the specific diagnostic needs associated with this species and defined a series of three distinct target product profiles, each aimed at a particular diagnostic application: (i) point-of-care of acutely ill patients for clinical care purposes; (ii) point-of-care asymptomatic and otherwise sub-patent residents for public health purposes, e.g., mass screen and treat campaigns; and (iii) ultra-sensitive not point-of-care diagnosis for epidemiological research/surveillance purposes. This report presents and discusses the rationale for these P. vivax-specific diagnostic target product profiles. These contribute to the rational development of fit-for-purpose diagnostic tests suitable for the clinical management, control and elimination of P. vivax malaria.

Baird JK. 2017. Telling the human story of Asia's invisible malaria burden. Lancet, 389 (10071), pp. 781-782. | Read more

Baird JK. 2017. Asia-Pacific malaria is singular, pervasive, diverse and invisible. Int J Parasitol, 47 (7), pp. 371-377. | Show Abstract | Read more

Malaria in the Asia-Pacific region has been targeted for elimination by the year 2030. This article asks the question, "by what means?" in the context of proven technical strategies and tools against key challenges imposed by the distinct character of the Asia-Pacific malaria problem. The misperception of malaria in the Asia-Pacific region as a less serious but otherwise essentially similar problem to African malaria lulls us into rote application of the same tools and strategies. Those now mitigating the harm done by malaria in Africa will not suffice to eliminate malaria in the Asia-Pacific region - these tasks and the problems are fundamentally distinct. This article describes the singular characteristics of Asia-Pacific malaria and the bearing of those upon the technical strategy of malaria elimination. Most of the tools needed for that endeavour do not yet exist and spirited calls for elimination within the next 14years may discourage the patience and investments needed to conceive, optimise and validate them.

Baird JK. 2016. Attacking Plasmodium vivax. Am J Trop Med Hyg, 95 (6 Suppl), pp. 1-3. | Show Abstract | Read more

Discussions beginning in 2012 ultimately led to a landmark document from the World Health Organization (WHO) titled, Control and Elimination of Plasmodium vivax: A Technical Brief, published in July 2015. That body of work represents multiple expert consultations coordinated by the WHO Global Malaria Program, along with technical consensus gathering from national malaria control programs via the WHO regional offices around the globe. That document thus represents thoroughly vetted state-of-the-art recommendations for dealing specifically with P. vivax, the first assembly of such by the WHO. This supplement to the journal was commissioned by the WHO and compiles the very substantial body of evidence and analysis informing those recommendations. This introductory narrative to the supplement provides the historical and technological context of global strategy for combatting P. vivax and reducing the burdens of morbidity and mortality it imposes.

Surjadjaja C, Surya A, Baird JK. 2016. Epidemiology of Plasmodium vivax in Indonesia. Am J Trop Med Hyg, 95 (6 Suppl), pp. 121-132. | Show Abstract | Read more

Endemic malaria occurs across much of the vast Indonesian archipelago. All five species of Plasmodium known to naturally infect humans occur here, along with 20 species of Anopheles mosquitoes confirmed as carriers of malaria. Two species of plasmodia cause the overwhelming majority and virtually equal shares of malaria infections in Indonesia: Plasmodium falciparum and Plasmodium vivax The challenge posed by P. vivax is especially steep in Indonesia because chloroquine-resistant strains predominate, along with Chesson-like strains that relapse quickly and multiple times at short intervals in almost all patients. Indonesia's hugely diverse human population carries many variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency, most of them exhibiting severely impaired enzyme activity. Therefore, the patients most likely to benefit from primaquine therapy by preventing aggressive relapse, may also be most likely to suffer harm without G6PD deficiency screening. Indonesia faces the challenge of controlling and eventually eliminating malaria across > 13,500 islands stretching > 5,000 km and an enormous diversity of ecological, ethnographic, and socioeconomic settings, and extensive human migrations. This article describes the occurrence of P. vivax in Indonesia and the obstacles faced in eliminating its transmission.

Baird JK, Valecha N, Duparc S, White NJ, Price RN. 2016. Diagnosis and Treatment of Plasmodium vivax Malaria. Am J Trop Med Hyg, 95 (6 Suppl), pp. 35-51. | Show Abstract | Read more

The diagnosis and treatment of Plasmodium vivax malaria differs from that of Plasmodium falciparum malaria in fundamentally important ways. This article reviews the guiding principles, practices, and evidence underpinning the diagnosis and treatment of P. vivax malaria.

Bassat Q, Velarde M, Mueller I, Lin J, Leslie T, Wongsrichanalai C, Baird JK. 2016. Key Knowledge Gaps for Plasmodium vivax Control and Elimination. Am J Trop Med Hyg, 95 (6 Suppl), pp. 62-71. | Show Abstract | Read more

There is inadequate understanding of the biology, pathology, transmission, and control of Plasmodium vivax, the geographically most widespread cause of human malaria. During the last decades, study of this species was neglected, in part due to the erroneous belief that it is intrinsically benign. In addition, many technical challenges in culturing the parasite also hampered understanding its fundamental biology and molecular and cellular responses to chemotherapeutics. Research on vivax malaria needs to be substantially expanded over the next decade to accelerate its elimination and eradication. This article summarizes key knowledge gaps identified by researchers, national malaria control programs, and other stakeholders assembled by the World Health Organization to develop strategies for controlling and eliminating vivax malaria. The priorities presented in this article emerged in these technical discussions, and were adopted by expert consensus of the authors. All involved understood the priority placed upon pragmatism in this research agenda, that is, focus upon tools delivering better prevention, diagnosis, treatment, and surveillance of P. vivax.

Howes RE, Battle KE, Mendis KN, Smith DL, Cibulskis RE, Baird JK, Hay SI. 2016. Global Epidemiology of Plasmodium vivax. Am J Trop Med Hyg, 95 (6 Suppl), pp. 15-34. | Show Abstract | Read more

Plasmodium vivax is the most widespread human malaria, putting 2.5 billion people at risk of infection. Its unique biological and epidemiological characteristics pose challenges to control strategies that have been principally targeted against Plasmodium falciparum Unlike P. falciparum, P. vivax infections have typically low blood-stage parasitemia with gametocytes emerging before illness manifests, and dormant liver stages causing relapses. These traits affect both its geographic distribution and transmission patterns. Asymptomatic infections, high-risk groups, and resulting case burdens are described in this review. Despite relatively low prevalence measurements and parasitemia levels, along with high proportions of asymptomatic cases, this parasite is not benign. Plasmodium vivax can be associated with severe and even fatal illness. Spreading resistance to chloroquine against the acute attack, and the operational inadequacy of primaquine against the multiple attacks of relapse, exacerbates the risk of poor outcomes among the tens of millions suffering from infection each year. Without strategies accounting for these P. vivax-specific characteristics, progress toward elimination of endemic malaria transmission will be substantially impeded.

Boni MF, White NJ, Baird JK. 2016. The Community As the Patient in Malaria-Endemic Areas: Preempting Drug Resistance with Multiple First-Line Therapies. PLoS Med, 13 (3), pp. e1001984. | Show Abstract | Read more

Maciej F. Boni and colleagues propose deploying multiple first-line combination therapies against malaria within a community to delay drug-resistance evolution.

Satyagraha AW, Sadhewa A, Elvira R, Elyazar I, Feriandika D, Antonjaya U, Oyong D, Subekti D, Rozi IE, Domingo GJ et al. 2016. Assessment of Point-of-Care Diagnostics for G6PD Deficiency in Malaria Endemic Rural Eastern Indonesia. PLoS Negl Trop Dis, 10 (2), pp. e0004457. | Show Abstract | Read more

BACKGROUND: Patients infected by Plasmodium vivax or Plasmodium ovale suffer repeated clinical attacks without primaquine therapy against latent stages in liver. Primaquine causes seriously threatening acute hemolytic anemia in patients having inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency. Access to safe primaquine therapy hinges upon the ability to confirm G6PD normal status. CareStart G6PD, a qualitative G6PD rapid diagnostic test (G6PD RDT) intended for use at point-of-care in impoverished rural settings where most malaria patients live, was evaluated. METHODOLOGY/PRINCIPAL FINDINGS: This device and the standard qualitative fluorescent spot test (FST) were each compared against the quantitative spectrophotometric assay for G6PD activity as the diagnostic gold standard. The assessment occurred at meso-endemic Panenggo Ede in western Sumba Island in eastern Indonesia, where 610 residents provided venous blood. The G6PD RDT and FST qualitative assessments were performed in the field, whereas the quantitative assay was performed in a research laboratory at Jakarta. The median G6PD activity ≥ 5 U/gHb was 9.7 U/gHb and was considered 100% of normal activity. The prevalence of G6PD deficiency by quantitative assessment (<5 U/gHb) was 7.2%. Applying 30% of normal G6PD activity as the cut-off for qualitative testing, the sensitivity, specificity, positive predictive value, and negative predictive value for G6PD RDT versus FST among males were as follows: 100%, 98.7%, 89%, and 100% versus 91.7%, 92%, 55%, and 99%; P = 0.49, 0.001, 0.004, and 0.24, respectively. These values among females were: 83%, 92.7%, 17%, and 99.7% versus 100%, 92%, 18%, and 100%; P = 1.0, 0.89, 1.0 and 1.0, respectively. CONCLUSIONS/SIGNIFICANCE: The overall performance of G6PD RDT, especially 100% negative predictive value, demonstrates suitable safety for G6PD screening prior to administering hemolytic drugs like primaquine and many others. Relatively poor diagnostic performance among females due to mosaic G6PD phenotype is an inherent limitation of any current practical screening methodology.

Baird JK. 2015. Point-of-care G6PD diagnostics for Plasmodium vivax malaria is a clinical and public health urgency. BMC Med, 13 (1), pp. 296. | Show Abstract | Read more

Malaria caused by Plasmodium vivax threatens over 2 billion people globally and sickens tens of millions annually. Recent clinical evidence discredits the long-held notion of this infection as intrinsically benign revealing an often threatening course associated with mortality. Most acute attacks by this species derive from latent forms in the human liver called hypnozoites. Radical cure for P. vivax malaria includes therapy aimed both at the acute attack (blood schizontocidal) and against future attacks (hypnozoitocidal). The only hypnozoitocide available is primaquine, a drug causing life-threatening acute hemolytic anemia in patients with the inherited blood disorder glucose-6-phosphate dehydrogenase (G6PD) deficiency. This disorder affects 400 million people worldwide, at an average prevalence of 8 % in malaria-endemic nations. In the absence of certain knowledge regarding the G6PD status of patients infected by P. vivax, providers must choose between the risk of harm caused by primaquine and that caused by the parasite by withholding therapy. Resolving this dilemma requires the availability of point-of-care G6PD diagnostics practical for use in the impoverished rural tropics where the vast majority of malaria patients seek care.

Nelwan EJ, Ekawati LL, Tjahjono B, Setiabudy R, Sutanto I, Chand K, Ekasari T, Djoko D, Basri H, Taylor WR et al. 2015. Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia. BMC Med, 13 (1), pp. 294. | Show Abstract | Read more

BACKGROUND: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide. METHODS: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ. RESULTS: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively. CONCLUSIONS: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.

Abreha T, Alemayehu B, Assefa A, Awab GR, Baird JK, Bezabih B, Cheah PY, Day NP, Devine A, Dorda M et al. 2015. Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens BMC INFECTIOUS DISEASES, 15 (1), | Show Abstract | Read more

© 2015 The IMPROV Study Group. Background: Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients. Design: This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8 weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events. Discussion: This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir. Trial registration: ClinicalTrials.gov Identifier: NCT01814683. Registered March 18, 2013

Anstey NM, Auburn S, Baird JK, Battle KE, Bobogare A, Chancellor A, Chasombat S, Cheng Q, Domingo GJ, Drakeley CJ et al. 2015. Targeting vivax malaria in the Asia Pacific: The Asia Pacific Malaria Elimination Network Vivax Working Group MALARIA JOURNAL, 14 (1), | Show Abstract | Read more

© 2015 World Health Organization; licensee BioMed Central. The Asia Pacific Malaria Elimination Network (APMEN) is a collaboration of 18 country partners committed to eliminating malaria from within their borders. Over the past 5 years, APMEN has helped to build the knowledge, tools and in-country technical expertise required to attain this goal. At its inaugural meeting in Brisbane in 2009, Plasmodium vivax infections were identified across the region as a common threat to this ambitious programme; the APMEN Vivax Working Group was established to tackle specifically this issue. The Working Group developed a four-stage strategy to identify knowledge gaps, build regional consensus on shared priorities, generate evidence and change practice to optimize malaria elimination activities. This case study describes the issues faced and the solutions found in developing this robust strategic partnership between national programmes and research partners within the Working Group. The success of the approach adopted by the group may facilitate similar applications in other regions seeking to deploy evidence-based policy and practice.

Ley B, Luter N, Espino FE, Devine A, Kalnoky M, Lubell Y, Thriemer K, Baird JK, Poirot E, Conan N et al. 2015. The challenges of introducing routine G6PD testing into radical cure: a workshop report. Malar J, 14 (1), pp. 377. | Show Abstract | Read more

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.

Nguyen TD, Olliaro P, Dondorp A, Baird JK, Lam HM, Farrar J, Thwaites GE, White NJ, Boni MF. 2015. Optimal population-level deployment of artemisinin combination therapies TROPICAL MEDICINE & INTERNATIONAL HEALTH, 20 pp. 182-182.

Kheng S, Muth S, Taylor WR, Tops N, Kosal K, Sothea K, Souy P, Kim S, Char CM, Vanna C et al. 2015. Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency. BMC Med, 13 (1), pp. 203. | Show Abstract | Read more

BACKGROUND: Primaquine is used to prevent Plasmodium vivax relapse; however, it is not implemented in many malaria-endemic countries, including Cambodia, for fear of precipitating primaquine-induced acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Reluctance to use primaquine is reinforced by a lack of quality safety data. This study was conducted to assess the tolerability of a primaquine regimen in Cambodian severely deficient G6PD variants to ascertain whether a weekly primaquine could be given without testing for G6PDd. METHODS: From January 2013 to January 2014, Cambodians with acute vivax malaria were treated with dihydroartemisinin/piperaquine on days (D) 0, 1 and 2 with weekly doses of primaquine 0.75 mg/kg for 8 weeks (starting on D0, last dose on D49), and followed until D56. Participants' G6PD status was confirmed by G6PD genotype and measured G6PD activity. The primary outcome was treatment completion without primaquine toxicity defined as any one of: (1) severe anaemia (haemoglobin [Hb] <7 g/dL), (2) a >25 % fractional fall in Hb from D0, (3) the need for a blood transfusion, (4) haemoglobinuria, (5) acute kidney injury (an increase in baseline serum creatinine >50 %) or (6) methaemoglobinaemia >20 %. RESULTS: We enrolled 75 patients with a median age of 24 years (range 5-63); 63 patients (84 %) were male. Eighteen patients were G6PDd (17/18 had the Viangchan variant) and had D0 G6PD activity ranging from 0.1 to 1.5 U/g Hb (median 0.85 U/g Hb). In the 57 patients with normal G6PD (G6PDn), D0 G6PD activity ranged from 6.9 to 18.5 U/g Hb (median 12 U/g Hb). Median D0 Hb concentrations were similar (P = 0.46) between G6PDd (13 g/dL, range 9.6-16) and G6PDn (13.5 g/dL, range 9-16.3) and reached a nadir on D2 in both groups: 10.8 g/dL (8.2-15.3) versus 12.4 g/dL (8.8-15.2) (P = 0.006), respectively. By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049). One of these G6PDd patients required a blood transfusion (D0-D5 Hb, 10.0-7.2 g/dL). No patients developed severe anaemia, haemoglobinuria, a methaemoglobin concentration >4.9 %, or acute kidney injury. CONCLUSIONS: Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion. Weekly primaquine in G6PDd patients mandates medical supervision and pre-treatment screening for G6PD status. The feasibility of implementing a package of G6PDd testing and supervised primaquine should be explored. TRIAL REGISTRATION: The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.

Battle KE, Guerra CA, Golding N, Duda KA, Cameron E, Howes RE, Elyazar IR, Baird JK, Reiner RC, Gething PW et al. 2015. Global database of matched Plasmodium falciparum and P. vivax incidence and prevalence records from 1985-2013. Sci Data, 2 pp. 150012. | Show Abstract | Read more

Measures of clinical incidence are necessary to help estimate the burden of a disease. Incidence is a metric not commonly measured in malariology because the longitudinal surveys required are costly and labour intensive. This database is an effort to collate published incidence records obtained using active case detection for Plasmodium falciparum and Plasmodium vivax malaria. The literature search methods, data abstraction procedures and data processing procedures are described here. A total of 1,680 spatio-temporally unique incidence records were collected for the database: 1,187 for P. falciparum and 493 for P. vivax. These data were gathered to model the relationship between clinical incidence and prevalence of infection and can be used for a variety of modelling exercises including the assessment of change in disease burden in relation to age and control interventions. The subset of data that have been used for such modelling exercises are described and identified.

Tanner M, Greenwood B, Whitty CJ, Ansah EK, Price RN, Dondorp AM, von Seidlein L, Baird JK, Beeson JG, Fowkes FJ et al. 2015. Malaria eradication and elimination: views on how to translate a vision into reality. BMC Med, 13 (1), pp. 167. | Show Abstract | Read more

Although global efforts in the past decade have halved the number of deaths due to malaria, there are still an estimated 219 million cases of malaria a year, causing more than half a million deaths. In this forum article, we asked experts working in malaria research and control to discuss the ways in which malaria might eventually be eradicated. Their collective views highlight the challenges and opportunities, and explain how multi-factorial and integrated processes could eventually make malaria eradication a reality.

Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. 2015. Global extent of chloroquine-resistant Plasmodium vivax - Authors' reply. Lancet Infect Dis, 15 (6), pp. 630-631. | Read more

Battle KE, Cameron E, Guerra CA, Golding N, Duda KA, Howes RE, Elyazar IR, Price RN, Baird JK, Reiner RC et al. 2015. Defining the relationship between Plasmodium vivax parasite rate and clinical disease. Malar J, 14 (1), pp. 191. | Show Abstract | Read more

BACKGROUND: Though essential to the development and evaluation of national malaria control programmes, precise enumeration of the clinical illness burden of malaria in endemic countries remains challenging where local surveillance systems are incomplete. Strategies to infer annual incidence rates from parasite prevalence survey compilations have proven effective in the specific case of Plasmodium falciparum, but have yet to be developed for Plasmodium vivax. Moreover, defining the relationship between P. vivax prevalence and clinical incidence may also allow levels of endemicity to be inferred for areas where the information balance is reversed, that is, incident case numbers are more widely gathered than parasite surveys; both applications ultimately facilitating cartographic estimates of P. vivax transmission intensity and its ensuring disease burden. METHODS: A search for active case detection surveys was conducted and the recorded incidence values were matched to local, contemporary parasite rate measures and classified to geographic zones of differing relapse phenotypes. A hierarchical Bayesian model was fitted to these data to quantify the relationship between prevalence and incidence while accounting for variation among relapse zones. RESULTS: The model, fitted with 176 concurrently measured P. vivax incidence and prevalence records, was a linear regression of the logarithm of incidence against the logarithm of age-standardized prevalence. Specific relationships for the six relapse zones where data were available were drawn, as well as a pooled overall relationship. The slope of the curves varied among relapse zones; zones with short predicted time to relapse had steeper slopes than those observed to contain long-latency relapse phenotypes. CONCLUSIONS: The fitted relationships, along with appropriate uncertainty metrics, allow for estimates of clinical incidence of known confidence to be made from wherever P. vivax prevalence data are available. This is a prerequisite for cartographic-based inferences about the global burden of morbidity due to P. vivax, which will be used to inform control efforts.

Baird JK. 2015. Still defining optimal primaquine therapy against relapse after 63 years of continuous use. Travel Med Infect Dis, 13 (3), pp. 215-216. | Read more

Satyagraha AW, Sadhewa A, Baramuli V, Elvira R, Ridenour C, Elyazar I, Noviyanti R, Coutrier FN, Harahap AR, Baird JK. 2015. G6PD deficiency at Sumba in Eastern Indonesia is prevalent, diverse and severe: implications for primaquine therapy against relapsing Vivax malaria. PLoS Negl Trop Dis, 9 (3), pp. e0003602. | Show Abstract | Read more

Safe treatment of Plasmodium vivax requires diagnosis of both the infection and status of erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity because hypnozoitocidal therapy against relapse requires primaquine, which causes a mild to severe acute hemolytic anemia in G6PD deficient patients. Many national malaria control programs recommend primaquine therapy without G6PD screening but with monitoring due to a broad lack of G6PD deficiency screening capacity. The degree of risk in doing so hinges upon the level of residual G6PD activity among the variants present in any given area. We conducted studies on Sumba Island in eastern Indonesia in order to assess the potential threat posed by primaquine therapy without G6PD screening. We sampled 2,033 residents of three separate districts in western Sumba for quantitative G6PD activity and 104 (5.1%) were phenotypically deficient (<4.6U/gHb; median normal 10U/gHb). The villages were in two distinct ecosystems, coastal and inland. A positive correlation occurred between the prevalence of malaria and G6PD deficiency: 5.9% coastal versus inland 0.2% for malaria (P<0.001), and 6.7% and 3.1% for G6PD deficiency (P<0.001) at coastal and inland sites, respectively. The dominant genotypes of G6PD deficiency were Vanua Lava, Viangchan, and Chatham, accounting for 98.5% of the 70 samples genotyped. Subjects expressing the dominant genotypes all had less than 10% of normal enzyme activities and were thus considered severe variants. Blind administration of anti-relapse primaquine therapy at Sumba would likely impose risk of serious harm.

Nguyen TD, Olliaro P, Dondorp AM, Baird JK, Lam HM, Farrar J, Thwaites GE, White NJ, Boni MF. 2015. Optimum population-level use of artemisinin combination therapies: a modelling study. Lancet Glob Health, 3 (12), pp. e758-e766. | Show Abstract | Read more

BACKGROUND: Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. METHODS: With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. FINDINGS: Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. INTERPRETATION: Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. FUNDING: Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.

Baird JK, Dewi M, Subekti D, Elyazar I, Satyagraha AW. 2015. Noninferiority of glucose-6-phosphate dehydrogenase deficiency diagnosis by a point-of-care rapid test vs the laboratory fluorescent spot test demonstrated by copper inhibition in normal human red blood cells Translational Research, 165 (6), pp. 677-688. | Show Abstract | Read more

© 2015 Elsevier Inc. All rights reserved. All rights reserved. Tens of millions of patients diagnosed with vivax malaria cannot safely receive primaquine therapy against repeated attacks caused by activation of dormant liver stages called hypnozoites. Most of these patients lack access to screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency, a highly prevalent disorder causing serious acute hemolytic anemia with primaquine therapy. We optimized CuCl inhibition of G6PD in normal red blood cells (RBCs) to assess G6PD diagnostic technologies suited to point of care in the impoverished rural tropics. The most widely applied technology for G6PD screening - the fluorescent spot test (FST) - is impractical in that setting. We evaluated a new point-of-care G6PD screening kit (CareStart G6PD, CSG) against FST using graded CuCl treatments to simulate variable hemizygous states, and varying proportions of CuCl-treated RBC suspensions to simulate variable heterozygous states of G6PD deficiency. In experiments double-blinded to CuCl treatment, technicians reading FST and CSG test (n = 269) classified results as positive or negative for deficiency. At G6PD activity ≤40% of normal (n = 112), CSG test was not inferior to FST in detecting G6PD deficiency (P = 0.003), with 96% vs 90% (P = 0.19) sensitivity and 75% and 87% (P = 0.01) specificity, respectively. The CSG test costs less, requires no specialized equipment, laboratory skills, or cold chain for successful application, and performs as well as the FST standard of care for G6PD screening. Such a device may vastly expand access to primaquine therapy and aid in mitigating the very substantial burden of morbidity and mortality imposed by the hypnozoite reservoir of vivax malaria.

Yuan L, Wang Y, Parker DM, Gupta B, Yang Z, Liu H, Fan Q, Cao Y, Xiao Y, Lee MC et al. 2015. Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar. Antimicrob Agents Chemother, 59 (2), pp. 1230-1235. | Show Abstract | Read more

Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating.

Syafruddin D, Bangs MJ, Sidik D, Elyazar I, Asih PB, Chan K, Nurleila S, Nixon C, Hendarto J, Wahid I et al. 2014. Impact of a spatial repellent on malaria incidence in two villages in Sumba, Indonesia. Am J Trop Med Hyg, 91 (6), pp. 1079-1087. | Show Abstract | Read more

A randomized, double-blinded, placebo-controlled study was conducted to examine the effect of spatial repellent (SR) in households at risk of malaria in Indonesia. Following presumptive radical cure for malaria in 180 adult men representing sentinels of new infection in four clusters within two villages, all households were given either metofluthrin or placebo mosquito coils. Weekly blood smear screening and human-landing mosquito catches were done throughout the 6 months intervention. Malaria infections occurred in 61 subjects living in placebo households and 31 subjects living in SR coil households, suggesting a 52% protective effect of SR. Likewise, anopheles indoor human landing rates were 32% lower in homes receiving SR coils. Differences in the malaria attack rate between SR- and placebo-treated homes was significant when not accounting for the effects of clustering. When the analysis was adjusted for intra-cluster correlation, the differences between SR- and placebo-treated homes were not statistically significant. The findings provide evidence of SR public health benefit and support a larger trial statistically powered to detect those effects.

Baird JK, Dewi M, Subekti D, Elyazar I, Satyagraha AW. 2015. Noninferiority of glucose-6-phosphate dehydrogenase deficiency diagnosis by a point-of-care rapid test vs the laboratory fluorescent spot test demonstrated by copper inhibition in normal human red blood cells. Transl Res, 165 (6), pp. 677-688. | Show Abstract | Read more

Tens of millions of patients diagnosed with vivax malaria cannot safely receive primaquine therapy against repeated attacks caused by activation of dormant liver stages called hypnozoites. Most of these patients lack access to screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency, a highly prevalent disorder causing serious acute hemolytic anemia with primaquine therapy. We optimized CuCl inhibition of G6PD in normal red blood cells (RBCs) to assess G6PD diagnostic technologies suited to point of care in the impoverished rural tropics. The most widely applied technology for G6PD screening-the fluorescent spot test (FST)-is impractical in that setting. We evaluated a new point-of-care G6PD screening kit (CareStart G6PD, CSG) against FST using graded CuCl treatments to simulate variable hemizygous states, and varying proportions of CuCl-treated RBC suspensions to simulate variable heterozygous states of G6PD deficiency. In experiments double-blinded to CuCl treatment, technicians reading FST and CSG test (n = 269) classified results as positive or negative for deficiency. At G6PD activity ≤40% of normal (n = 112), CSG test was not inferior to FST in detecting G6PD deficiency (P = 0.003), with 96% vs 90% (P = 0.19) sensitivity and 75% and 87% (P = 0.01) specificity, respectively. The CSG test costs less, requires no specialized equipment, laboratory skills, or cold chain for successful application, and performs as well as the FST standard of care for G6PD screening. Such a device may vastly expand access to primaquine therapy and aid in mitigating the very substantial burden of morbidity and mortality imposed by the hypnozoite reservoir of vivax malaria.

Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. 2014. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis, 14 (10), pp. 982-991. | Show Abstract | Read more

BACKGROUND: Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. METHODS: We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. FINDINGS: We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. INTERPRETATION: Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. FUNDING: Wellcome Trust (UK).

Baird JK, RictitE TL, Hoffman SL, Palmieri JR, Franice-Vellasante E, Ohrt C, Punjabi N, Maguire JD, Elyazar I, Dennis DT et al. 2014. Purnomo Projodipuro 11 April 1933-10 May 2013 Obituary COMPARATIVE PARASITOLOGY, 81 (2), pp. 291-294.

Baird JK. 2014. Pernicious and threatening Plasmodium vivax as reality. Am J Trop Med Hyg, 91 (1), pp. 1-2. | Read more

Battle KE, Karhunen MS, Bhatt S, Gething PW, Howes RE, Golding N, Van Boeckel TP, Messina JP, Shanks GD, Smith DL et al. 2014. Geographical variation in Plasmodium vivax relapse. Malar J, 13 (1), pp. 144. | Show Abstract | Read more

BACKGROUND: Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission. METHODS: A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse. RESULTS: Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas. CONCLUSIONS: The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.

Moyes CL, Henry AJ, Golding N, Huang Z, Singh B, Baird JK, Newton PN, Huffman M, Duda KA, Drakeley CJ et al. 2014. Defining the geographical range of the Plasmodium knowlesi reservoir. PLoS Negl Trop Dis, 8 (3), pp. e2780. | Show Abstract | Read more

BACKGROUND: The simian malaria parasite, Plasmodium knowlesi, can cause severe and fatal disease in humans yet it is rarely included in routine public health reporting systems for malaria and its geographical range is largely unknown. Because malaria caused by P. knowlesi is a truly neglected tropical disease, there are substantial obstacles to defining the geographical extent and risk of this disease. Information is required on the occurrence of human cases in different locations, on which non-human primates host this parasite and on which vectors are able to transmit it to humans. We undertook a systematic review and ranked the existing evidence, at a subnational spatial scale, to investigate the potential geographical range of the parasite reservoir capable of infecting humans. METHODOLOGY/PRINCIPAL FINDINGS: After reviewing the published literature we identified potential host and vector species and ranked these based on how informative they are for the presence of an infectious parasite reservoir, based on current evidence. We collated spatial data on parasite occurrence and the ranges of the identified host and vector species. The ranked spatial data allowed us to assign an evidence score to 475 subnational areas in 19 countries and we present the results on a map of the Southeast and South Asia region. CONCLUSIONS/SIGNIFICANCE: We have ranked subnational areas within the potential disease range according to evidence for presence of a disease risk to humans, providing geographical evidence to support decisions on prevention, management and prophylaxis. This work also highlights the unknown risk status of large parts of the region. Within this unknown category, our map identifies which areas have most evidence for the potential to support an infectious reservoir and are therefore a priority for further investigation. Furthermore we identify geographical areas where further investigation of putative host and vector species would be highly informative for the region-wide assessment.

Hwang J, Cullen KA, Kachur SP, Arguin PM, Baird JK. 2014. Severe morbidity and mortality risk from malaria in the United States, 1985-2011. Open Forum Infect Dis, 1 (1), pp. ofu034. | Show Abstract | Read more

BACKGROUND: Recent reports of Plasmodium vivax associated with severe syndromes and mortality from malaria endemic areas questions the "benign" course of non-falciparum malarias. METHODS: We retrospectively analyzed data from patients reported to the US Centers for Disease Control and Prevention with a diagnosis of malaria parasite single-species infection between 1985 and 2011. Patients classified as having severe illness were further classified according to outcome (survival versus death) and clinical syndrome. RESULTS: Among all cases, .9% of Plasmodium falciparum cases resulted in death and 9.3% were classified as severe, whereas .09% of P. vivax cases resulted in death and 1.3% were classified as severe. The odds ratios for severe illness among 15 272 diagnoses of P. falciparum relative to patients diagnosed with P. vivax (n = 12 152), Plasmodium malariae (n = 1254), or Plasmodium ovale (n = 903) was 7.5, 5.7, and 5.0, respectively (P < .0001 for all); in contrast, the corresponding odds ratios for death among those severely ill was 1.6, 1.1, and .8 (P > .1 for all), respectively. Compared with P. vivax (n = 163), the odds of P. falciparum cases classified as severely ill (n = 1416) were 1.9 (P = .0006), .5 (P = .001), and 1.3 times (P = .1) as likely to present as cerebral, acute respiratory distress, and renal syndromes, respectively. CONCLUSIONS: Although less common, patients presenting with non-falciparum even in the United States can develop severe illness, and severe illness in patients having malaria of any species threatens life.

Nixon CP, Nixon CE, Arsyad DS, Chand K, Yudhaputri FA, Sumarto W, Wangsamuda S, Asih PB, Marantina SS, Wahid I et al. 2014. Distance to Anopheles sundaicus larval habitats dominant among risk factors for parasitemia in meso-endemic Southwest Sumba, Indonesia. Pathog Glob Health, 108 (8), pp. 369-380. | Show Abstract | Read more

BACKGROUND: The decline in intensity of malaria transmission in many areas now emphasizes greater importance of understanding the epidemiology of low to moderate transmission settings. Marked heterogeneity in infection risk within these populations creates opportunities to understand transmission and guide resource allocation to greater impact. METHODS: In this study, we examined spatial patterns of malaria transmission in a hypo- to meso-endemic area of eastern Indonesia using malaria prevalence data collected from a cross-sectional socio-demographic and parasitological survey conducted from August to November 2010. An entomological survey performed in parallel, identified, mapped, and monitored local anopheline larval habitats. RESULTS: A single spatial cluster of higher malaria prevalence was detected during the study period (relative risk=2.13; log likelihood ratio=20.7; P<0.001). In hierarchical multivariate regression models, risk of parasitemia was inversely correlated with distance to five Anopheles sundaicus known larval habitats [odds ratio (OR)=0.21; 95% confidence interval (CI)=0.14-0.32; P<0.001], which were located in a geographically restricted band adjacent to the coastline. Increasing distance from these sites predicted increased hemoglobin level across age strata after adjusting for confounders (OR=1.6; 95% CI=1.30-1.98; P<0.001). CONCLUSION: Significant clustering of malaria parasitemia in close proximity to very specific and relatively few An. sundaicus larval habitats has direct implications for local control strategy, policy, and practice. These findings suggest that larval source management could achieve profound if not complete impact in this region.

Ingram RJ, Crenna-Darusallam C, Soebianto S, Noviyanti R, Baird JK. 2014. The clinical and public health problem of relapse despite primaquine therapy: case review of repeated relapses of Plasmodium vivax acquired in Papua New Guinea. Malar J, 13 (1), pp. 488. | Show Abstract | Read more

BACKGROUND: Primaquine is the only drug available for preventing relapse following a primary attack by Plasmodium vivax malaria. This drug imposes several important problems: daily dosing over two weeks; toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; partner blood schizontocides possibly impacting primaquine safety and efficacy; cytochrome P-450 abnormalities impairing metabolism and therapeutic activity; and some strains of parasite may be tolerant or resistant to primaquine. There are many possible causes of repeated relapses in a patient treated with primaquine. CASE DESCRIPTION: A 56-year-old Caucasian woman from New Zealand traveled to New Ireland, Papua New Guinea for two months in 2012. One month after returning home she stopped daily doxycycline prophylaxis against malaria, and one week later she became acutely ill and hospitalized with a diagnosis of Plasmodium vivax malaria. Over the ensuing year she suffered four more attacks of vivax malaria at approximately two-months intervals despite consuming primaquine daily for 14 days after each of those attacks, except the last. Genotype of the patient's cytochrome P-450 2D6 alleles (*5/*41) corresponded with an intermediate metabolizer phenotype of predicted low activity. DISCUSSION: Multiple relapses in patients taking primaquine as prescribed present a serious clinical problem, and understanding the basis of repeated therapeutic failure is a challenging technical problem. This case highlights these issues in a single traveler, but these problems will also arise as endemic nations approach elimination of malaria transmission.

Kevin Baird J. 2013. Malaria caused by Plasmodium vivax: recurrent, difficult to treat, disabling, and threatening to life--the infectious bite preempts these hazards. Pathog Glob Health, 107 (8), pp. 475-479. | Show Abstract | Read more

The maxim 'an ounce of prevention is worth a pound of cure' finds few better demonstrations than with malaria caused by Plasmodium vivax. Thoroughly neglected over the past 60 years, the chemotherapy of this complex infection has been dangerous and ineffective until the present. Work is at last being done, but seeing that translate to real improvements at the periphery of care delivery will take years of deliberate effort. In the meantime, patients face substantial risk of debilitating, threatening, and fatal courses of illness associated with a diagnosis of vivax malaria. For some of the most vulnerable to such outcomes--pregnant women and infants--repeated attacks of acute vivax malaria from a single infectious anopheline bite is now not preventable. One of the few measures than can be immediately applied with rigor is vector control, thereby effectively preventing as many of these difficult and dangerous infections as possible. This commentary emphasizes the dire consequences of infection by P. vivax and the real difficulty of dealing with them. That, in turn, emphasizes the many benefits to be derived by preventing them in the first place.

Baird JK. 2013. THE HUMAN LIVER AS A RESERVOIR OF INFECTION: THE EPIDEMIOLOGY AND CONTROL OF MALARIA CAUSED BY PLASMODIUM VIVAX PATHOGENS AND GLOBAL HEALTH, 107 (8), pp. 400-400.

Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, Sakuntabhai A, Satyagraha AW, Williams TN, Baird JK, Hay SI. 2013. Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malar J, 12 (1), pp. 418. | Show Abstract | Read more

BACKGROUND: Primaquine is essential for malaria control and elimination since it is the only available drug preventing multiple clinical attacks by relapses of Plasmodium vivax. It is also the only therapy against the sexual stages of Plasmodium falciparum infectious to mosquitoes, and is thus useful in preventing malaria transmission. However, the difficulties of diagnosing glucose-6-phosphate dehydrogenase deficiency (G6PDd) greatly hinder primaquine's widespread use, as this common genetic disorder makes patients susceptible to potentially severe and fatal primaquine-induced haemolysis. The risk of such an outcome varies widely among G6PD gene variants. METHODS: A literature review was conducted to identify surveys of G6PD variant frequencies among representative population groups. Informative surveys were assembled into two map series: (1) those showing the relative proportions of the different variants among G6PDd individuals; and (2) those showing allele frequencies of G6PD variants based on population surveys without prior G6PDd screening. RESULTS: Variants showed conspicuous geographic patterns. A limited repertoire of variants was tested for across sub-Saharan Africa, which nevertheless indicated low genetic heterogeneity predominated by the G6PD A(-202A) mutation, though other mutations were common in western Africa. The severe G6PD Mediterranean variant was widespread across western Asia. Further east, a sharp shift in variants was identified, with high variant heterogeneity in the populations of China and the Asia-Pacific where no single variant dominated. CONCLUSIONS: G6PD variants exhibited distinctive region-specific distributions with important primaquine policy implications. Relative homogeneity in the Americas, Africa, and western Asia contrasted sharply with the heterogeneity of variants in China, Southeast Asia and Oceania. These findings will inform rational risk assessments for primaquine in developing public health strategies for malaria control and elimination, and support the future development of regionally targeted policies. The major knowledge gaps highlighted here strongly advocate for further investigation of G6PD variant diversity and their primaquine-sensitivity phenotypes.

Baird JK, Elyazar I, Basri H, Chand K, Hoffman SL, Palmieri JR, Richie TL, Franke-Villasante E, Fryauff DJ, Ohrt C et al. 2013. Purnomo Projodipuro (April 11, 1934-May 10, 2013). Am J Trop Med Hyg, 89 (2), pp. 202-204. | Read more

Elyazar IR, Sinka ME, Gething PW, Tarmidzi SN, Surya A, Kusriastuti R, Winarno, Baird JK, Hay SI, Bangs MJ. 2013. The distribution and bionomics of anopheles malaria vector mosquitoes in Indonesia. Adv Parasitol, 83 pp. 173-266. | Show Abstract | Read more

Malaria remains one of the greatest human health burdens in Indonesia. Although Indonesia has a long and renowned history in the early research and discoveries of malaria and subsequently in the successful use of environmental control methods to combat the vector, much remains unknown about many of these mosquito species. There are also significant gaps in the existing knowledge on the transmission epidemiology of malaria, most notably in the highly malarious eastern half of the archipelago. These compound the difficulty of developing targeted and effective control measures. The sheer complexity and number of malaria vectors in the country are daunting. The difficult task of summarizing the available information for each species and/or species complex is compounded by the patchiness of the data: while relatively plentiful in one area or region, it can also be completely lacking in others. Compared to many other countries in the Oriental and Australasian biogeographical regions, only scant information on vector bionomics and response to chemical measures is available in Indonesia. That information is often either decades old, geographically patchy or completely lacking. Additionally, a large number of information sources are published in Dutch or Indonesian language and therefore less accessible. This review aims to present an updated overview of the known distribution and bionomics of the 20 confirmed malaria vector species or species complexes regarded as either primary or secondary (incidental) malaria vectors within Indonesia. This chapter is not an exhaustive review of each of these species. No attempt is made to specifically discuss or resolve the taxonomic record of listed species in this document, while recognizing the ever evolving revisions in the systematics of species groups and complexes. A review of past and current status of insecticide susceptibility of eight vector species of malaria is also provided.

Baird JK. 2013. Suppressive chemoprophylaxis invites avoidable risk of serious illness caused by Plasmodium vivax malaria. Travel Med Infect Dis, 11 (1), pp. 60-65. | Show Abstract | Read more

Despite inadequacy in preventing vivax malaria after travel, suppressive chemoprophylaxis has dominated travel medicine strategy since the advent of chloroquine in 1946. The lethal threat of falciparum malaria versus the perceived benign consequence of vivax malaria underpins this strategic posture. Recent evidence demonstrating vivax malaria as often pernicious should prompt reconsideration of that posture. Causal prophylaxis kills early developing forms of plasmodia in the liver, thus preventing attacks of falciparum and vivax malaria during travel and delayed onset vivax malaria following travel. Primaquine is the only available drug for this application, and has good evidence of safety, tolerability and efficacy in non-pregnant, G6PD-normal travelers. The primaquine label, however, carries no such indication. Risk of pernicious vivax malaria from all across the endemic regions of the globe, including much of sub-Saharan Africa, should raise consideration of daily primaquine during travel as the preferred front-line option for chemoprophylaxis against malaria in travelers.

Hay SI, Price RN, Baird JK. 2013. The epidemiology of Plasmodium vivax. Preface. Adv Parasitol, 81 pp. xi-xii. | Read more

Howes RE, Battle KE, Satyagraha AW, Baird JK, Hay SI. 2013. G6PD deficiency: global distribution, genetic variants and primaquine therapy. Adv Parasitol, 81 pp. 133-201. | Show Abstract | Read more

Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination.

Baird JK. 2013. Suppressive chemoprophylaxis invites avoidable risk of serious illness caused by Plasmodium vivax malaria Travel Medicine and Infectious Disease, 11 (1), pp. 60-65. | Show Abstract | Read more

Despite inadequacy in preventing vivax malaria after travel, suppressive chemoprophylaxis has dominated travel medicine strategy since the advent of chloroquine in 1946. The lethal threat of falciparum malaria versus the perceived benign consequence of vivax malaria underpins this strategic posture. Recent evidence demonstrating vivax malaria as often pernicious should prompt reconsideration of that posture. Causal prophylaxis kills early developing forms of plasmodia in the liver, thus preventing attacks of falciparum and vivax malaria during travel and delayed onset vivax malaria following travel. Primaquine is the only available drug for this application, and has good evidence of safety, tolerability and efficacy in non-pregnant, G6PD-normal travelers. The primaquine label, however, carries no such indication. Risk of pernicious vivax malaria from all across the endemic regions of the globe, including much of sub-Saharan Africa, should raise consideration of daily primaquine during travel as the preferred front-line option for chemoprophylaxis against malaria in travelers.

Sutanto I, Tjahjono B, Basri H, Taylor WR, Putri FA, Meilia RA, Setiabudy R, Nurleila S, Ekawati LL, Elyazar I et al. 2013. Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia. Antimicrob Agents Chemother, 57 (3), pp. 1128-1135. | Show Abstract | Read more

Radical cure of Plasmodium vivax infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by P. vivax acquired in Papua, Indonesia.

Howes RE, Battle KE, Satyagraha AW, Baird JK, Hay SI. 2013. G6PD Deficiency. Global Distribution, Genetic Variants and Primaquine Therapy Advances in Parasitology, 81 pp. 135-201. | Show Abstract | Read more

Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and. primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination. © 2013 Elsevier Ltd.

Baird JK. 2013. Evidence and implications of mortality associated with acute Plasmodium vivax malaria. Clin Microbiol Rev, 26 (1), pp. 36-57. | Show Abstract | Read more

Vivax malaria threatens patients despite relatively low-grade parasitemias in peripheral blood. The tenet of death as a rare outcome, derived from antiquated and flawed clinical classifications, disregarded key clinical evidence, including (i) high rates of mortality in neurosyphilis patients treated with vivax malaria; (ii) significant mortality from zones of endemicity; and (iii) the physiological threat inherent in repeated, very severe paroxysms in any patient, healthy or otherwise. The very well-documented course of this infection, with the exception of parasitemia, carries all of the attributes of "perniciousness" historically linked to falciparum malaria, including severe disease and fatal outcomes. A systematic analysis of the parasite biomass in severely ill patients that includes blood, marrow, and spleen may ultimately explain this historic misunderstanding. Regardless of how this parasite is pernicious, recent data demonstrate that the infection comes with a significant burden of morbidity and associated mortality. The extraordinary burden of malaria is not heavily weighted upon any single continent by a single species of parasite-it is a complex problem for the entire endemic world, and both species are of fundamental importance. Humanity must rally substantial resources, intellect, and energy to counter this daunting but profound threat.

Battle KE, Gething PW, Elyazar IR, Moyes CL, Sinka ME, Howes RE, Guerra CA, Price RN, Baird KJ, Hay SI. 2012. The global public health significance of Plasmodium vivax. Adv Parasitol, 80 pp. 1-111. | Show Abstract | Read more

Plasmodium vivax occurs globally and thrives in both temperate and tropical climates. Here, we review the evidence of the biological limits of its contemporary distribution and the global population at risk (PAR) of the disease within endemic countries. We also review the most recent evidence for the endemic level of transmission within its range and discuss the implications for burden of disease assessments. Finally, the evidence-base for defining the contemporary distribution and PAR of P. vivax are discussed alongside a description of the vectors of human malaria within the limits of risk. This information along with recent data documenting the severe morbid and fatal consequences of P. vivax infection indicates that the public health significance of P. vivax is likely to have been seriously underestimated.

Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M, Hogg MM, Battle KE, Padilla CD, Baird JK, Hay SI. 2012. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med, 9 (11), pp. e1001339. | Show Abstract | Read more

BACKGROUND: Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk. METHODS AND FINDINGS: Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4-8.8) across MECs, and 5.3% (4.4-6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd. CONCLUSIONS: G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit. Please see later in the article for the Editors' Summary.

Russell B, Suwanarusk R, Malleret B, Costa FT, Snounou G, Kevin Baird J, Nosten F, Rénia L. 2012. Human ex vivo studies on asexual Plasmodium vivax: the best way forward. Int J Parasitol, 42 (12), pp. 1063-1070. | Show Abstract | Read more

The lack of a continuous culture method for Plasmodium vivax has given the impression that investigations on this important species are severely curtailed. However, the use of new or improved ex vivo methods and tools to study fresh and thawed isolates from vivax malaria patients is currently providing useful data on P. vivax, such as sensitivity to antimalarial drugs, invasion mechanisms and pathobiology. This review discusses a practical framework for conducting ex vivo studies on the asexual erythrocytic stages of P. vivax and considers the synergies between ex vivo defined phenotypes, ex vivo derived 'omic' studies and in vivo clinical studies.

Baird JK. 2012. Reinventing primaquine for endemic malaria. Expert Opin Emerg Drugs, 17 (4), pp. 439-444. | Show Abstract | Read more

After sixty years of continuous use, primaquine remains the only therapy licensed for arresting transmission and relapse of malaria. The US Army developed primaquine for soldiers in a wartime crisis setting. Dosing strategies suited to that narrow population were adopted without modification or validation for the broader population of humans exposed to risk of malaria. The poor suitability of these strategies in populations exhibiting greater vulnerability to hemolytic toxicity among glucose-6-phosphate dehydrogenase deficient patients has not been addressed. Primaquine requires chemotherapeutic reinvention delivering less threatening doses by leveraging unexplored co-drug synergies.

Gething PW, Elyazar IR, Moyes CL, Smith DL, Battle KE, Guerra CA, Patil AP, Tatem AJ, Howes RE, Myers MF et al. 2012. A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis, 6 (9), pp. e1814. | Show Abstract | Read more

BACKGROUND: Current understanding of the spatial epidemiology and geographical distribution of Plasmodium vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination. Here we present the first systematic effort to map the global endemicity of this hitherto neglected parasite. METHODOLOGY AND FINDINGS: We first updated to the year 2010 our earlier estimate of the geographical limits of P. vivax transmission. Within areas of stable transmission, an assembly of 9,970 geopositioned P. vivax parasite rate (PvPR) surveys collected from 1985 to 2010 were used with a spatiotemporal Bayesian model-based geostatistical approach to estimate endemicity age-standardised to the 1-99 year age range (PvPR(1-99)) within every 5×5 km resolution grid square. The model incorporated data on Duffy negative phenotype frequency to suppress endemicity predictions, particularly in Africa. Endemicity was predicted within a relatively narrow range throughout the endemic world, with the point estimate rarely exceeding 7% PvPR(1-99). The Americas contributed 22% of the global area at risk of P. vivax transmission, but high endemic areas were generally sparsely populated and the region contributed only 6% of the 2.5 billion people at risk (PAR) globally. In Africa, Duffy negativity meant stable transmission was constrained to Madagascar and parts of the Horn, contributing 3.5% of global PAR. Central Asia was home to 82% of global PAR with important high endemic areas coinciding with dense populations particularly in India and Myanmar. South East Asia contained areas of the highest endemicity in Indonesia and Papua New Guinea and contributed 9% of global PAR. CONCLUSIONS AND SIGNIFICANCE: This detailed depiction of spatially varying endemicity is intended to contribute to a much-needed paradigm shift towards geographically stratified and evidence-based planning for P. vivax control and elimination.

John GK, Douglas NM, von Seidlein L, Nosten F, Baird JK, White NJ, Price RN. 2012. Primaquine radical cure of Plasmodium vivax: a critical review of the literature. Malar J, 11 (1), pp. 280. | Show Abstract | Read more

BACKGROUND: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. METHODS: Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. RESULTS: Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001). CONCLUSIONS: Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.

Nurleila S, Syafruddin D, Elyazar IR, Baird JK. 2012. Serious and fatal illness associated with falciparum and vivax malaria among patients admitted to hospital at West Sumba in eastern Indonesia. Am J Trop Med Hyg, 87 (1), pp. 41-49. | Show Abstract | Read more

Records of 3,449 patients admitted to Karitas Hospital at Waitabula in eastern Indonesia with microscopy-confirmed malaria through 2008 and 2009 were systematically reviewed. Falciparum, vivax, and mixed species malaria occurred among 1,541, 1,837, and 71 admissions, respectively. Among these, 400 (26%), 199 (11%), and 15 (21%) had serious illness. Fatalities occurred in 46 (12%), 18 (9%), and 2 (13%) of these patients, respectively. Although patients with a diagnosis of falciparum malaria were more likely to have serious illness compared with those with vivax malaria (odds ratio [OR] = 2.9; 95% confidence interval [CI]: 2.4-3.5), this diagnosis nonetheless was associated with 32% of serious illness and 27% of fatalities. Among the seriously ill with a diagnosis of falciparum or vivax malaria, no significant difference in risk of death occurred (OR = 1.3; 95% CI: 0.7-2.5). Serious and fatal illness was predominantly anemia or altered mental state syndromes among patients with either of the species diagnoses. Plasmodium vivax was associated with a substantial share of the burden of morbidity and mortality caused by malaria in this hypo- to meso-endemic community.

Elyazar IR, Gething PW, Patil AP, Rogayah H, Sariwati E, Palupi NW, Tarmizi SN, Kusriastuti R, Baird JK, Hay SI. 2012. Plasmodium vivax malaria endemicity in Indonesia in 2010. PLoS One, 7 (5), pp. e37325. | Show Abstract | Read more

BACKGROUND: Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones. Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it. We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010. METHODS: Plasmodium vivax Annual Parasite Incidence data (2006-2008) and temperature masks were used to map P. vivax transmission limits. A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985-2010) for mapping quantitative estimates of contemporary endemicity within those limits. After error-checking a total of 4,457 points were included into a national database of age-standardized 1-99 year old PvPR data. A Bayesian MBG procedure created a predicted PvPR(1-99) endemicity surface with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population surface. RESULTS: We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010. Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas. In western Indonesia, the predicted P. vivax prevalence was uniformly low. Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs. High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua. In general, prediction uncertainty was relatively low in the west and high in the east. CONCLUSION: Most Indonesians living with endemic P. vivax experience relatively low risk of infection. However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection. The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy practices and manageability of P. vivax importation risk, especially in Java and Bali.

Baird JK. 2012. Elimination therapy for the endemic malarias. Curr Infect Dis Rep, 14 (3), pp. 227-237. | Show Abstract | Read more

Most malaria diagnosed outside endemic zones occurs in patients experiencing the consequences of what was likely a single infectious bite by an anopheline mosquito. A single species of parasite is nearly always involved and expert opinion on malaria chemotherapy uniformly prescribes species- and stage-specific treatments. However the vast majority of people experiencing malaria, those resident in endemic zones, do so repeatedly and very often with the involvement of two or more species and stages of parasite. Silent forms of these infections-asymptomatic and beyond the reach of diagnostics-may accumulate to form substantial and unchallenged reservoirs of infection. In such settings treating only the species and stage of malaria revealed by diagnosis and not others may not be sensible or appropriate. Developing therapeutic strategies that address all species and stages independently of diagnostic evidence may substantially improve the effectiveness of the control and elimination of endemic malaria.

Baird JK. 2012. Chemotherapeutics challenges in developing effective treatments for the endemic malarias International Journal for Parasitology: Drugs and Drug Resistance, 2 pp. 256-261. | Show Abstract | Read more

The endemic malarias threaten the several billion people residing where transmission occurs. Chemotherapeutic strategy pitted against these threats hinges upon species- and stage-specific treatments guided by diagnosis and screening against sometime dangerous contraindications. This approach suits malaria as it occurs among travelers in the developed, non-endemic world. However, limiting treatment to that which diagnosis affirms may not be rational in endemic zones. Most of the endemic malarias remain out of diagnostic reach, either by inaccessibility of the parasite stage, insensitivity of the technology, or unavailability of diagnostic services. The partial and fragmented chemotherapeutic attack of malaria guided by confirmed diagnostics leaves most of the endemic malarias unchallenged. Development of elimination therapy, a single course of treatment aimed at all species and stages, would significantly advance progress against the major killers known collectively as malaria. © 2012 Australian Society for Parasitology Published by Elsevier Ltd.

Baird JK. 2012. Chemotherapeutics challenges in developing effective treatments for the endemic malarias INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, 2 pp. 256-261. | Show Abstract | Read more

The endemic malarias threaten the several billion people residing where transmission occurs. Chemotherapeutic strategy pitted against these threats hinges upon species- and stage-specific treatments guided by diagnosis and screening against sometime dangerous contraindications. This approach suits malaria as it occurs among travelers in the developed, non-endemic world. However, limiting treatment to that which diagnosis affirms may not be rational in endemic zones. Most of the endemic malarias remain out of diagnostic reach, either by inaccessibility of the parasite stage, insensitivity of the technology, or unavailability of diagnostic services. The partial and fragmented chemotherapeutic attack of malaria guided by confirmed diagnostics leaves most of the endemic malarias unchallenged. Development of elimination therapy, a single course of treatment aimed at all species and stages, would significantly advance progress against the major killers known collectively as malaria. © 2012.

Baird KJ, Maguire JD, Price RN. 2012. Diagnosis and treatment of Plasmodium vivax malaria. Adv Parasitol, 80 pp. 203-270. | Show Abstract | Read more

Infection by Plasmodium vivax poses unique challenges for diagnosis and treatment. Relatively low numbers of parasites in peripheral circulation may be difficult to confirm, and patients infected by dormant liver stages cannot be diagnosed before activation and the ensuing relapse. Radical cure thus requires therapy aimed at both the blood stages of the parasite (blood schizontocidal) and prevention of subsequent relapses (hypnozoitocidal). Chloroquine and primaquine have been the companion therapies of choice for the treatment of vivax malaria since the 1950s. Confirmed resistance to chloroquine occurs in much of the vivax endemic world and demands the investigation of alternative blood schizontocidal companions in radical cure. Such a shift in practice necessitates investigation of the safety and efficacy of primaquine when administered with those therapies, and the toxicity profile of such combination treatments, particularly in patients with glucose-6-phosphate dehydrogenase deficiency. These clinical studies are confounded by the frequency and timing of relapse among strains of P. vivax, and potentially by differing susceptibilities to primaquine. The inability to maintain this parasite in continuous in vitro culture greatly hinders new drug discovery. Development of safe and effective chemotherapies for vivax malaria for the coming decades requires overcoming these challenges.

Baird JK. 2012. Primaquine toxicity forestalls effective therapeutic management of the endemic malarias International Journal for Parasitology, 42 (12), pp. 1049-1054. | Show Abstract | Read more

Treatment of acutely ill patients, informed by a diagnosis of the species of Plasmodium involved, has long dominated strategic thinking in malaria chemotherapeutics. This bias for both acute illness and access to diagnosis resulted in therapeutic strategies poorly suited to malaria as it occurs in endemic zones. Most of those malarias do not provoke illness and occur beyond diagnostic reach for technical or practical reasons. Therapies effective against all species and stages would likely prove more practical in endemic zones, especially if safely administered without laboratory screening for contraindications. The primary impediment to such therapies is the mild to severe hemolytic toxicity of primaquine in patients with glucose-6-phosphate dehydrogenase deficiency. Primaquine is the only treatment licensed for therapy against relapse caused by dormant liver stages occurring in some species, and against the sexual blood stages responsible for transmission to mosquitoes in all species. Despite being licensed over 50. years ago, no alternative drugs have been developed, and safer dosing regimens of primaquine have not been explored. These failures forestalled the emergence of therapies practical for use in endemic zones, especially in the context of eliminating transmission. © 2012 Australian Society for Parasitology Inc.

Shaikh S, Memon H, Iohano B, Shaikh A, Ahmed I, Baird JK. 2012. Severe disease in children hospitalized with a diagnosis of Plasmodium vivax in south-eastern Pakistan. Malar J, 11 (1), pp. 144. | Show Abstract | Read more

BACKGROUND: Infection by Plasmodium vivax has been considered rarely threatening to life, but recent studies challenge this notion. This study documented the frequency and character of severe illness in paediatric patients admitted to a hospital in south-eastern Pakistan with a laboratory-confirmed diagnosis of vivax malaria. METHODS: An observational study of all 180 paediatric patients admitted with any diagnosis of malaria during 2010 was conducted: 128 P. vivax; 48 Plasmodium falciparum; and four mixed infections of these species. Patients were classified as having severe illness with any of the following indicators: Glascow coma scale <11; ≥2 convulsions; haemoglobin <5g/dL; thrombocytes <50,000/mL; blood glucose <45mg%; >70 breaths/min; or intravenous anti-malarial therapy. Additionally, 64 patients with a diagnosis of vivax malaria were treated during 2009, and the 21 of these having severe illness were included in analyses of the frequency and character of severe illness with that diagnosis. RESULTS: During 2010, 39 (31%) or 37 (77%) patients with a diagnosis of P. vivax or P. falciparum were classified as having severe disease. Including the 2009 records of 64 patients having vivax malaria, a total of 60 (31%) patients with severe illness and a diagnosis of P. vivax were available. Altered mental status (Glascow coma scale score <11; or ≥2 convulsions) dominated at 54% of the 83 indicators of severe illness manifest among the patients with vivax malaria, as was true among the 37 children with a diagnosis of falciparum malaria and being severely ill; 58% of the 72 indicators of severe disease documented among them. No statistically significant difference appeared in frequencies of any other severe disease indicators between patients diagnosed with vivax or falciparum malaria. Despite such similarities, a diagnosis of falciparum malaria nonetheless came with 3.8-fold (95% CI = 1.8-8.1) higher risk of presenting with severe illness, and 8.0-fold (95% CI = 2.1-31) greater likelihood of presenting with three or more severe disease indicators. Two patients did not survive hospitalization, one each with a diagnosis of falciparum or vivax malaria. CONCLUSIONS: Vivax malaria caused a substantial burden of potentially life-threatening morbidity on a paediatric ward in a hospital in south-eastern Pakistan.

Baird JK. 2012. Elimination therapy for the endemic malarias Current Infectious Disease Reports, 14 (3), pp. 227-237. | Show Abstract | Read more

Most malaria diagnosed outside endemic zones occurs in patients experiencing the consequences of what was likely a single infectious bite by an anopheline mosquito. A single species of parasite is nearly always involved and expert opinion on malaria chemotherapy uniformly prescribes species- and stage-specific treatments. However the vast majority of people experiencing malaria, those resident in endemic zones, do so repeatedly and very often with the involvement of two or more species and stages of parasite. Silent forms of these infections-asymptomatic and beyond the reach of diagnostics-may accumulate to form substantial and unchallenged reservoirs of infection. In such settings treating only the species and stage of malaria revealed by diagnosis and not others may not be sensible or appropriate. Developing therapeutic strategies that address all species and stages independently of diagnostic evidence may substantially improve the effectiveness of the control and elimination of endemic malaria. © The Author(s) 2012.

Baird JK. 2012. Primaquine toxicity forestalls effective therapeutic management of the endemic malarias. Int J Parasitol, 42 (12), pp. 1049-1054. | Show Abstract | Read more

Treatment of acutely ill patients, informed by a diagnosis of the species of Plasmodium involved, has long dominated strategic thinking in malaria chemotherapeutics. This bias for both acute illness and access to diagnosis resulted in therapeutic strategies poorly suited to malaria as it occurs in endemic zones. Most of those malarias do not provoke illness and occur beyond diagnostic reach for technical or practical reasons. Therapies effective against all species and stages would likely prove more practical in endemic zones, especially if safely administered without laboratory screening for contraindications. The primary impediment to such therapies is the mild to severe hemolytic toxicity of primaquine in patients with glucose-6-phosphate dehydrogenase deficiency. Primaquine is the only treatment licensed for therapy against relapse caused by dormant liver stages occurring in some species, and against the sexual blood stages responsible for transmission to mosquitoes in all species. Despite being licensed over 50 years ago, no alternative drugs have been developed, and safer dosing regimens of primaquine have not been explored. These failures forestalled the emergence of therapies practical for use in endemic zones, especially in the context of eliminating transmission.

Kim S, Nguon C, Guillard B, Duong S, Chy S, Sum S, Nhem S, Bouchier C, Tichit M, Christophel E et al. 2011. Performance of the CareStart™ G6PD deficiency screening test, a point-of-care diagnostic for primaquine therapy screening. PLoS One, 6 (12), pp. e28357. | Show Abstract | Read more

Development of reliable, easy-to-use, rapid diagnostic tests (RDTs) to detect glucose-6-phosphate dehydrogenase (G6PD) deficiency at point of care is essential to deploying primaquine therapies as part of malaria elimination strategies. We assessed a kit under research and development called CareStart™ G6PD deficiency screening test (Access Bio, New Jersey, USA) by comparing its performance to quantitative G6PD enzyme activity using a standardized spectrophotometric method ('gold standard'). Blood samples (n = 903) were collected from Cambodian adults living in Pailin province, western Cambodia. G6PD enzyme activities ranged from 0 to 20.5 U/g Hb (median 12.0 U/g Hg). Based on a normal haemoglobin concentration and wild-type G6PD gene, the normal values of G6PD enzymatic activity for this population was 3.6 to 20.5 U/g Hg (95(th) percentiles from 5.5 to 17.2 U/g Hg). Ninety-seven subjects (10.7%) had <3.6 U/g Hg and were classified as G6PD deficient. Prevalence of deficiency was 15.0% (64/425) among men and 6.9% (33/478) among women. Genotype was analyzed in 66 G6PD-deficient subjects and 63 of these exhibited findings consistent with Viangchang genotype. The sensitivity and specificity of the CareStart™ G6PD deficiency screening test was 0.68 and 1.0, respectively. Its detection threshold was <2.7 U/g Hg, well within the range of moderate and severe enzyme deficiencies. Thirteen subjects (1.4%, 12 males and 1 female) with G6PD enzyme activities <2 U/g Hg were falsely classified as "normal" by RDT. This experimental RDT test here evaluated outside of the laboratory for the first time shows real promise, but safe application of it will require lower rates of falsely "normal" results.

Myint HY, Berman J, Walker L, Pybus B, Melendez V, Baird JK, Ohrt C. 2011. Review: Improving the therapeutic index of 8-aminoquinolines by the use of drug combinations: review of the literature and proposal for future investigations. Am J Trop Med Hyg, 85 (6), pp. 1010-1014. | Show Abstract | Read more

Because 8-aminoquinolines affect critical survival stages of Plasmodium parasites, treatment and control of malaria could be markedly improved by more widespread use of these drugs; however, hemolytic toxicity, which is widely prevalent in G6PD-deficient patients, severely constrains this use. Primaquine was approved more than 50 years ago after extensive clinical testing. Review of the mid-20th century literature in the light of present understanding of pharmacokinetics and metabolism suggests that manipulation of these factors might dissociate 8-aminoquinoline efficacy from toxicity and lead to an improved therapeutic index.

Elyazar IR, Gething PW, Patil AP, Rogayah H, Kusriastuti R, Wismarini DM, Tarmizi SN, Baird JK, Hay SI. 2011. Plasmodium falciparum malaria endemicity in Indonesia in 2010. PLoS One, 6 (6), pp. e21315. | Show Abstract | Read more

BACKGROUND: Malaria control programs require a detailed understanding of the contemporary spatial distribution of infection risk to efficiently allocate resources. We used model based geostatistics (MBG) techniques to generate a contemporary map of Plasmodium falciparum malaria risk in Indonesia in 2010. METHODS: Plasmodium falciparum Annual Parasite Incidence (PfAPI) data (2006-2008) were used to map limits of P. falciparum transmission. A total of 2,581 community blood surveys of P. falciparum parasite rate (PfPR) were identified (1985-2009). After quality control, 2,516 were included into a national database of age-standardized 2-10 year old PfPR data (PfPR(2-10)) for endemicity mapping. A Bayesian MBG procedure was used to create a predicted surface of PfPR(2-10) endemicity with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population count surface. RESULTS: We estimate 132.8 million people in Indonesia, lived at risk of P. falciparum transmission in 2010. Of these, 70.3% inhabited areas of unstable transmission and 29.7% in stable transmission. Among those exposed to stable risk, the vast majority were at low risk (93.39%) with the reminder at intermediate (6.6%) and high risk (0.01%). More people in western Indonesia lived in unstable rather than stable transmission zones. In contrast, fewer people in eastern Indonesia lived in unstable versus stable transmission areas. CONCLUSION: While further feasibility assessments will be required, the immediate prospects for sustained control are good across much of the archipelago and medium term plans to transition to the pre-elimination phase are not unrealistic for P. falciparum. Endemicity in areas of Papua will clearly present the greatest challenge. This P. falciparum endemicity map allows malaria control agencies and their partners to comprehensively assess the region-specific prospects for reaching pre-elimination, monitor and evaluate the effectiveness of future strategies against this 2010 baseline and ultimately improve their evidence-based malaria control strategies.

Baird JK. 2011. Resistance to chloroquine unhinges vivax malaria therapeutics. Antimicrob Agents Chemother, 55 (5), pp. 1827-1830. | Read more

Baird JK. 2011. Radical cure: the case for anti-relapse therapy against all malarias. Clin Infect Dis, 52 (5), pp. 621-623. | Read more

Elyazar IR, Hay SI, Baird JK. 2011. Malaria distribution, prevalence, drug resistance and control in Indonesia. Adv Parasitol, 74 (C), pp. 41-175. | Show Abstract | Read more

Approximately 230 million people live in Indonesia. The country is also home to over 20 anopheline vectors of malaria which transmit all four of the species of Plasmodium that routinely infect humans. A complex mosaic of risk of infection across this 5000-km-long archipelago of thousands of islands and distinctive habitats seriously challenges efforts to control malaria. Social, economic and political dimensions contribute to these complexities. This chapter examines malaria and its control in Indonesia, from the earliest efforts by malariologists of the colonial Netherlands East Indies, through the Global Malaria Eradication Campaign of the 1950s, the tumult following the coup d'état of 1965, the global resurgence of malaria through the 1980s and 1990s and finally through to the decentralization of government authority following the fall of the authoritarian Soeharto regime in 1998. We detail important methods of control and their impact in the context of the political systems that supported them. We examine prospects for malaria control in contemporary decentralized and democratized Indonesia with multidrug-resistant malaria and greatly diminished capacities for integrated malaria control management programs.

Asih PB, Syafruddin D, Leake J, Sorontou Y, Sadikin M, Sauerwein RW, Vinetz J, Baird JK. 2011. Phenotyping clinical resistance to chloroquine in Plasmodium vivax in northeastern Papua, Indonesia. Int J Parasitol Drugs Drug Resist, 1 (1), pp. 28-32. | Show Abstract | Read more

Chloroquine (CQ)-resistant Plasmodium vivax was first documented in 1989 and threatens much of eastern Indonesia, with > 50% of therapeutic failure rates. We screened 2236 subjects for malaria infection through active case detection and identified 232 infected cases with 100 subjects carried P. vivax mono infection. We prospectively evaluated therapeutic responses to CQ in 73 subjects infected by P. vivax in northeastern Papua, Indonesia. We phenotyped these infections as susceptible or resistant to CQ using a 28-day in vivo test format. Eighteen subjects (25%) had persistent or recurrent parasitemia during the test and were provisionally classified as resistant. Among the remainder, 46 (63%) subjects had no persistent or recurrent parasitemia and were classified as having infections sensitive to CQ, 4 were lost to follow up, and 5 dropped out. Among the 18 provisionally resistant cases, 1 subject (6%) had persistent parasitemia at Day 3 and was considered as a direct treatment failure, 2 subjects (11%) had recurrent parasitemia by Day 7 and were considered early treatment failures, and 7 (39%) and 8 (44%) had recurrent parasitemia by Days 14 and 28, respectively. Analysis of blood for CQ+N-desethylchloroquine (DCQ) levels on day of recurrence from 15 of the 18 with treatment failures showed 11 subjects having CQ+DCQ blood levels ⩾ 100 ng/ml and 2 with CQ+DCQ blood levels < 100 ng/ml. The 28-day cumulative incidence of therapeutic failure likely due to parasite resistance was 17.5%. These findings affirm P. vivax resistance to CQ in eastern Indonesia, albeit at lower levels than reported elsewhere. This simple means of phenotyping P. vivax infections could be implemented in other malaria endemic areas of Indonesia.

Cited:

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Kim S, Nguon C, Guillard B, Duong S, Chy S, Sum S, Nhem S, Bouchier C, Tichit M, Christophel E et al. 2011. Performance of the carestart™ G6PD deficiency screening test, a point-of-care diagnostic for primaquine therapy screening PLoS ONE, 6 (12), | Show Abstract | Read more

Development of reliable, easy-to-use, rapid diagnostic tests (RDTs) to detect glucose-6-phosphate dehydrogenase (G6PD) deficiency at point of care is essential to deploying primaquine therapies as part of malaria elimination strategies. We assessed a kit under research and development called CareStart™ G6PD deficiency screening test (Access Bio, New Jersey, USA) by comparing its performance to quantitative G6PD enzyme activity using a standardized spectrophotometric method ('gold standard'). Blood samples (n = 903) were collected from Cambodian adults living in Pailin province, western Cambodia. G6PD enzyme activities ranged from 0 to 20.5 U/g Hb (median 12.0 U/g Hg). Based on a normal haemoglobin concentration and wild-type G6PD gene, the normal values of G6PD enzymatic activity for this population was 3.6 to 20.5 U/g Hg (95 th percentiles from 5.5 to 17.2 U/g Hg). Ninety-seven subjects (10.7%) had & 3.6 U/g Hg and were classified as G6PD deficient. Prevalence of deficiency was 15.0% (64/425) among men and 6.9% (33/478) among women. Genotype was analyzed in 66 G6PD-deficient subjects and 63 of these exhibited findings consistent with Viangchang genotype. The sensitivity and specificity of the CareStart™ G6PD deficiency screening test was 0.68 and 1.0, respectively. Its detection threshold was < 2.7 U/g Hg, well within the range of moderate and severe enzyme deficiencies. Thirteen subjects (1.4%, 12 males and 1 female) with G6PD enzyme activities < 2 U/g Hg were falsely classified as "normal" by RDT. This experimental RDT test here evaluated outside of the laboratory for the first time shows real promise, but safe application of it will require lower rates of falsely "normal" results. © 2011 Kim et al.

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44

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Baird JK, Surjadjaja C. 2011. Consideration of ethics in primaquine therapy against malaria transmission Trends in Parasitology, 27 (1), pp. 11-16. | Show Abstract | Read more

Millions of people receive primaquine against sexual plasmodia responsible for malaria transmission. These gametocytes cause no symptoms and do not threaten the host, but they infect mosquitoes and threaten the community. Primaquine causes hemolysis in the small minority of patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Clinical studies in the 1950s demonstrated gametocytocidal primaquine to be safe without G6PDd screening. However, the evaluated G6PDd variant, African A-, represents mild sensitivity to primaquine. The view of primaquine as a safe gametocytocide thus rests largely upon observations from a G6PDd variant that is unlikely to challenge safety. The early clinical work does not seem to afford an adequate assessment of safety in G6PDd patients. Potential risk of harm without clinical benefit to the patient raises ethical questions that should be examined. © 2010 Elsevier Ltd.

Baird JK. 2010. Eliminating malaria--all of them. Lancet, 376 (9756), pp. 1883-1885. | Read more

Baird JK, Surjadjaja C. 2011. Consideration of ethics in primaquine therapy against malaria transmission. Trends Parasitol, 27 (1), pp. 11-16. | Show Abstract | Read more

Millions of people receive primaquine against sexual plasmodia responsible for malaria transmission. These gametocytes cause no symptoms and do not threaten the host, but they infect mosquitoes and threaten the community. Primaquine causes hemolysis in the small minority of patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Clinical studies in the 1950s demonstrated gametocytocidal primaquine to be safe without G6PDd screening. However, the evaluated G6PDd variant, African A-, represents mild sensitivity to primaquine. The view of primaquine as a safe gametocytocide thus rests largely upon observations from a G6PDd variant that is unlikely to challenge safety. The early clinical work does not seem to afford an adequate assessment of safety in G6PDd patients. Potential risk of harm without clinical benefit to the patient raises ethical questions that should be examined.

Soepandi PZ, Burhan E, Mangunnegoro H, Nawas A, Aditama TY, Partakusuma L, Isbaniah F, Ikhsan M, Swidarmoko B, Sutiyoso A et al. 2010. Clinical course of avian influenza A(H5N1) in patients at the Persahabatan Hospital, Jakarta, Indonesia, 2005-2008. Chest, 138 (3), pp. 665-673. | Show Abstract | Read more

BACKGROUND: Limited understanding of the presentation and course of influenza A(H5N1) infection in humans hinders evidence-based management. METHODS: We reviewed the case records of patients admitted to the Persahabatan Hospital (RSP), Jakarta, Indonesia, with influenza A(H5N1) confirmed by real-time polymerase chain reaction. RESULTS: Twenty-two previously well patients, aged 3 to 47 years (median 24.5 years), were identified. All attended a clinic or hospital after a median of 2 days of illness (range 0-7). Times to first dose of oseltamivir (three died before receiving oseltamivir) were 2 to 12 days (median 7 days), administered mostly (n = 15) at RSP. Nineteen patients required mechanical ventilation. Deaths numbered 18 (case fatality = 82%) occurring within hours to 6 days of RSP admission, corresponding to 6 to 16 days of illness. Admission hyperglycemia ( >or= 140 mg/dL), unrelated to steroids or known underlying diabetes mellitus, and elevated D-dimer levels (0.81-5.2 mg/L, upper limit of normal < 0.5 mg/L) were present in 14/21 (67%) and 20/21 (95%) patients, respectively. Fibrinogen concentrations were mostly low/normal at 129.9 to 517.9 mg/dL (median 241.1, normal 200-400 mg/dL), whereas C-reactive protein (9/11) and ferritin (6/8) levels were increased. Risk factors for death (univariate analysis) included: (1) increased D-dimers, (2) hyperglycema, (3) increased urea, (4) more extensive chest radiograph shadowing, and (5) lower admission oxygen saturation. CONCLUSIONS: Early diagnosis and effective treatment of human influenza A(H5N1) infection remains challenging. Most patients were referred late with advanced disease. Oseltamivir had limited clinical impact. Elevated D-dimer levels, consistent with fibrinolysis, and hyperglycemia warrant more research to determine their underlying mechanisms and optimal treatment.

Guerra CA, Howes RE, Patil AP, Gething PW, Van Boeckel TP, Temperley WH, Kabaria CW, Tatem AJ, Manh BH, Elyazar IR et al. 2010. The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis, 4 (8), pp. e774. | Show Abstract | Read more

BACKGROUND: A research priority for Plasmodium vivax malaria is to improve our understanding of the spatial distribution of risk and its relationship with the burden of P. vivax disease in human populations. The aim of the research outlined in this article is to provide a contemporary evidence-based map of the global spatial extent of P. vivax malaria, together with estimates of the human population at risk (PAR) of any level of transmission in 2009. METHODOLOGY: The most recent P. vivax case-reporting data that could be obtained for all malaria endemic countries were used to classify risk into three classes: malaria free, unstable (<0.1 case per 1,000 people per annum (p.a.)) and stable (> or =0.1 case per 1,000 p.a.) P. vivax malaria transmission. Risk areas were further constrained using temperature and aridity data based upon their relationship with parasite and vector bionomics. Medical intelligence was used to refine the spatial extent of risk in specific areas where transmission was reported to be absent (e.g., large urban areas and malaria-free islands). The PAR under each level of transmission was then derived by combining the categorical risk map with a high resolution population surface adjusted to 2009. The exclusion of large Duffy negative populations in Africa from the PAR totals was achieved using independent modelling of the gene frequency of this genetic trait. It was estimated that 2.85 billion people were exposed to some risk of P. vivax transmission in 2009, with 57.1% of them living in areas of unstable transmission. The vast majority (2.59 billion, 91.0%) were located in Central and South East (CSE) Asia, whilst the remainder were located in America (0.16 billion, 5.5%) and in the Africa+ region (0.10 billion, 3.5%). Despite evidence of ubiquitous risk of P. vivax infection in Africa, the very high prevalence of Duffy negativity throughout Central and West Africa reduced the PAR estimates substantially. CONCLUSIONS: After more than a century of development and control, P. vivax remains more widely distributed than P. falciparum and is a potential cause of morbidity and mortality amongst the 2.85 billion people living at risk of infection, the majority of whom are in the tropical belt of CSE Asia. The probability of infection is reduced massively across Africa by the frequency of the Duffy negative trait, but transmission does occur on the continent and is a concern for Duffy positive locals and travellers. The final map provides the spatial limits on which the endemicity of P. vivax transmission can be mapped to support future cartographic-based burden estimations.

Maguire JD, Baird JK. 2010. The 'non-falciparum' malarias: the roles of epidemiology, parasite biology, clinical syndromes, complications and diagnostic rigour in guiding therapeutic strategies. Ann Trop Med Parasitol, 104 (4), pp. 283-301. | Show Abstract | Read more

Plasmodium vivax, P. ovale, P. malariae and P. falciparum routinely infect humans. The infections caused by these parasites are loosely referred to as vivax (or benign tertian), ovale, malariae (or quartan) and falciparum (or malignant tertian) malaria, respectively. Recently, P. knowlesi, a parasite of macaque monkeys in South-east Asia, has been identified as the cause of uncomplicated and severe human malaria in Malaysian Borneo. The prescription of appropriate therapies for reliably diagnosed malaria requires a grasp of the epidemiology of the 'non-falciparum' malarias, the biology of the parasites involved, the chemotherapeutic strategies that are available and the problems of emerging drug resistance and changing clinical syndromes. This review is intended to increase clinicians' understanding of how these factors relate to the selection of the antimalarial drugs to be given to a case of 'non-falciparum' malaria, with the aims of improving outcomes and preventing relapses and recrudescences.

Wells TN, Burrows JN, Baird JK. 2010. Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. Trends Parasitol, 26 (3), pp. 145-151. | Show Abstract | Read more

Plasmodium vivax is the major species of malaria parasite outside Africa. It is especially problematic in that the infection can relapse in the absence of mosquitoes by activation of dormant hypnozoites in the liver. Medicines that target the erythrocytic stages of Plasmodium falciparum are also active against P. vivax, except where these have been compromised by resistance. However, the only clinical therapy against relapse of vivax malaria is the 8-aminoquinoline, primaquine. This molecule has the drawback of causing haemolysis in genetically sensitive patients and requires 14 days of treatment. New, safer and more-easily administered drugs are urgently needed, and this is a crucial gap in the broader malaria-elimination agenda. New developments in cell biology are starting to open ways to the next generation of drugs against hypnozoites. This search is urgent, given the time needed to develop a new medication.

Sutanto I, Endawati D, Ling LH, Laihad F, Setiabudy R, Baird JK. 2010. Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia. Malar J, 9 (1), pp. 52. | Show Abstract | Read more

BACKGROUND: Chloroquine was used as first-line treatment for Plasmodium falciparum or Plasmodium vivax in Indonesia before the initial launch of artemisinin combination therapy in 2004. A study to evaluate efficacies of chloroquine against P. falciparum and P. vivax was undertaken at Lampung in southern Sumatra, western Indonesia in 2002. METHODS: Patients infected by P. falciparum or P. vivax were treated with 25 mg/kg chloroquine base in three daily doses over 48 hr. Finger prick blood was collected on Days 0, 2, 3, 7, 14, 21 and 28 after starting drug administration. Whole blood chloroquine and its desethyl metabolite were measured on Days-0, -3 and -28, or on the day of recurrent parasitaemia. RESULTS: 42 patients infected by P. falciparum were enrolled, and 38 fullfilled criteria for per protocol analysis. Only six of 38 (16%) showed a response consistent with senstivity to chloroquine. 25 of 32 failures were confirmed resistant by demonstrating chloroquine levels on day of recurrence exceeding the minimally effective concentration (200 ng/mL whole blood). The 28-day cumulative incidence of resistance in P. falciparum was 68% (95% CI: 0.5260 - 0.8306). Thirty one patients infected by P. vivax were enrolled, and 23 were evaluable for per protocol analysis. 15 out of 23 (65%) subjects had persistent or recurrent parasitaemia. Measurement of chloroquine levels confirmed all treatment failures prior to Day-15 as resistant. Beyond Day-15, 4 of 7 recurrences also had drug levels above 100 ng/mL and were classified as resistant. The 28-day cumulative incidence of chloroquine resistance in P. vivax was 43% (95% CI: 0.2715 - 0.6384). CONCLUSION: These findings confirm persistantly high levels of resistance to chloroquine by P. falciparum in southern Sumatra, and suggest that high-grade and frequent resistance to chloroquine by P. vivax may be spreading westward in the Indonesia archipelago.

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Baird JK. 2010. Eliminating malaria - All of them The Lancet, 376 (9756), pp. 1883-1885. | Read more

Baird JK. 2009. Severe and fatal vivax malaria challenges 'benign tertian malaria' dogma. Ann Trop Paediatr, 29 (4), pp. 251-252. | Read more

Valecha N, Pinto RG, Turner GD, Kumar A, Rodrigues S, Dubhashi NG, Rodrigues E, Banaulikar SS, Singh R, Dash AP, Baird JK. 2009. Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria. Am J Trop Med Hyg, 81 (5), pp. 758-762. | Show Abstract | Read more

An otherwise healthy 20-year-old woman in Goa, India, received antibiotics after a diagnosis of upper respiratory tract infection. One week later, vivax malaria was diagnosed at a health center, but the patient developed respiratory distress and lost consciousness. She arrived at emergency department in shock, breathless, and comatose. She died within minutes. Two independent laboratories later confirmed Plasmodium vivax by microscopy (140,000/microL) and by nested and real-time polymerase chain reaction methods. Post-mortem examination showed congestion of alveolar capillaries by heavy monocytic infiltrates, along with diffuse damage to alveolar membranes consistent with acute respiratory distress syndrome. Parasites seen in lung tissue were roughly proportionate to both peripheral hyperparasitemia and those seen in other organs without lesions. In this patient, vivax malaria caused a rapidly fatal respiratory distress.

Baird JK. 2009. Malaria zoonoses. Travel Med Infect Dis, 7 (5), pp. 269-277. | Show Abstract | Read more

The genus Plasmodium includes many species that naturally cause malaria among apes and monkeys. The 2004 discovery of people infected by Plasmodium knowlesi in Malaysian Borneo alerted to the potential for non-human species of plasmodia to cause human morbidity and mortality. Subsequent work revealed what appears to be a surprisingly high risk of infection and relatively severe disease, including among travelers to Southeast Asia. The biology and medicine of this zoonosis is reviewed here, along with an examination of the spectrum of Plasmodium species that may cause infection of humans.

Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso PL, del Portillo HA. 2009. Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite. Lancet Infect Dis, 9 (9), pp. 555-566. | Show Abstract | Read more

Plasmodium vivax is geographically the most widely distributed cause of malaria in people, with up to 2.5 billion people at risk and an estimated 80 million to 300 million clinical cases every year--including severe disease and death. Despite this large burden of disease, P vivax is overlooked and left in the shadow of the enormous problem caused by Plasmodium falciparum in sub-Saharan Africa. The technological advances enabling the sequencing of the P vivax genome and a recent call for worldwide malaria eradication have together placed new emphasis on the importance of addressing P vivax as a major public health problem. However, because of this parasite's biology, it is especially difficult to interrupt the transmission of P vivax, and experts agree that the available methods for preventing and treating infections with P vivax are inadequate. It is thus imperative that the development of new methods and strategies become a priority. Advancing the development of such methods needs renewed emphasis on understanding the biology, pathogenesis, and epidemiology of P vivax. This Review critically examines what is known about P vivax, focusing on identifying the crucial gaps that create obstacles to the elimination of this parasite in human populations.

Sutanto I, Suprijanto S, Nurhayati, Manoempil P, Baird JK. 2009. Resistance to chloroquine by Plasmodium vivax at Alor in the Lesser Sundas Archipelago in eastern Indonesia. Am J Trop Med Hyg, 81 (2), pp. 338-342. | Show Abstract

The therapeutic response to standard chloroquine therapy against Plasmodium vivax was evaluated in 36 subjects living at Alor in the Lesser Sundas Archipelago of eastern Indonesia. Chloroquine level were measured on 32 individuals, and showed evidence of adequate absorption of standard chloroquine therapy. Three subjects failed treatment by Day 2 or 3, with evidence of rising asexual parasitemia, and two others had stable parasitemia to Day 7. Ten more subjects had recurrent parasitemia by Day 14, two by Day 21, and another one by Day 28. Three subjects had recurrent parasitemia on Days 14 and 28, but with chloroquine < 100 ng/mL. Eleven subjects cleared parasitemia by Day 3 and had no recurrences up to Day 28. In summary, 28-day cumulative incidence of confirmed resistance to chloroquine was 56% of infections evaluated. Chloroquine should not be considered adequate for treatment of acute vivax malaria acquired in this region.

Baird JK. 2009. Resistance to therapies for infection by Plasmodium vivax. Clin Microbiol Rev, 22 (3), pp. 508-534. | Show Abstract | Read more

The gravity of the threat posed by vivax malaria to public health has been poorly appreciated. The widely held misperception of Plasmodium vivax as being relatively infrequent, benign, and easily treated explains its nearly complete neglect across the range of biological and clinical research. Recent evidence suggests a far higher and more-severe disease burden imposed by increasingly drug-resistant parasites. The two frontline therapies against vivax malaria, chloroquine and primaquine, may be failing. Despite 60 years of nearly continuous use of these drugs, their respective mechanisms of activity, resistance, and toxicity remain unknown. Although standardized means of assessing therapeutic efficacy against blood and liver stages have not been developed, this review examines the provisional in vivo, ex vivo, and animal model systems for doing so. The rationale, design, and interpretation of clinical trials of therapies for vivax malaria are discussed in the context of the nuance and ambiguity imposed by the hypnozoite. Fielding new drug therapies against real-world vivax malaria may require a reworking of the strategic framework of drug development, namely, the conception, testing, and evaluation of sets of drugs designed for the cure of both blood and liver asexual stages as well as the sexual blood stages within a single therapeutic regimen.

Doolan DL, Dobaño C, Baird JK. 2009. Acquired immunity to malaria. Clin Microbiol Rev, 22 (1), pp. 13-36. | Show Abstract | Read more

Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection; much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum. The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.

Baird JK. 2008. Real-world therapies and the problem of vivax malaria. N Engl J Med, 359 (24), pp. 2601-2603. | Read more

Murhandarwati EE, Black CG, Wang L, Weisman S, Koning-Ward TF, Baird JK, Tjitra E, Richie TL, Crabb BS, Coppel RL. 2008. Acquisition of invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein 1 in a transmigrant population requires multiple infections. J Infect Dis, 198 (8), pp. 1212-1218. | Show Abstract | Read more

Antibodies against the 19 kDa C-terminal fragment of merozoite surface protein 1 (MSP1(19)) are a major component of the invasion-inhibitory response in individuals immune to malaria. We report here the acquisition of MSP1(19)-specific invasion-inhibitory antibodies in a group of transmigrants who experienced their sequential malaria infections during settlement in an area of Indonesia where malaria is highly endemic. We used 2 transgenic Plasmodium falciparum parasite lines that expressed either endogenous MSP1(19) or the homologous region from P. chabaudi to measure the MSP1(19)-specific invasion-inhibitory antibodies. The results revealed that the acquisition of MSP1(19)-specific invasion-inhibitory antibodies required 2 or more P. falciparum infections. In contrast, enzyme-linked immunosorbent assays on the same serum samples showed that MSP1(19)-specific antibodies are present after the first malaria infection. This delay in the acquisition of functional antibodies by residents of areas where malaria is endemic is consistent with the observation that multiple malaria infections are required before clinical immunity is acquired.

Mehlotra RK, Mattera G, Bockarie MJ, Maguire JD, Baird JK, Sharma YD, Alifrangis M, Dorsey G, Rosenthal PJ, Fryauff DJ et al. 2008. Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother, 52 (6), pp. 2212-2222. | Show Abstract | Read more

Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also modulate CQR. To compare patterns of genetic variation at Pfcrt and Pfmdr1 loci, we investigated 460 blood samples from P. falciparum-infected patients from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking Pfcrt (five loci [approximately 40 kb]) and Pfmdr1 (either two loci [approximately 5 kb] or four loci [approximately 10 kb]). CQR Pfmdr1 allele-associated MS haplotypes showed considerably higher genetic diversity and higher levels of subdivision than CQR Pfcrt allele-associated MS haplotypes in both Asian and African parasite populations. However, both Pfcrt and Pfmdr1 MS haplotypes showed similar levels of low diversity in South American parasite populations. Median-joining network analyses showed that the Pfcrt MS haplotypes correlated well with geography and CQR Pfcrt alleles, whereas there was no distinct Pfmdr1 MS haplotype that correlated with geography and/or CQR Pfmdr1 alleles. Furthermore, multiple independent origins of CQR Pfmdr1 alleles in Asia and Africa were inferred. These results suggest that variation at Pfcrt and Pfmdr1 loci in both Asian and African parasite populations is generated and/or maintained via substantially different mechanisms. Since Pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time.

Krudsood S, Tangpukdee N, Wilairatana P, Phophak N, Baird JK, Brittenham GM, Looareesuwan S. 2008. High-dose primaquine regimens against relapse of Plasmodium vivax malaria. Am J Trop Med Hyg, 78 (5), pp. 736-740. | Show Abstract

Plasmodium vivax causes debilitating but usually non-lethal malaria in most of Asia and South America. Prevention of relapse after otherwise effective therapy for the acute attack requires a standard daily dose of primaquine administered over 14 days. This regimen has < 90% efficacy in Thailand, and is widely regarded as ineffective because of poor compliance over the relatively long duration of dosing. We evaluated the efficacy, safety, and tolerability of alternative primaquine dosing regimens combined with artesunate among 399 Thai patients with acute, symptomatic P. vivax malaria. Patients were randomly assigned to one of six treatment groups: all patients received artesunate, 100 mg once a day for 5 days. Groups 1-5 then received primaquine, 30 mg a day for 5, 7, 9, 11, and 14 days, respectively. Group 6 received primaquine, 30 mg twice a day for 7 days. The 28-day cure rates were 85%, 89%, 94%, 100%, and 96%, respectively. Treatment of P. vivax malaria with artesunate for 5 days followed by high-dose primaquine, 30 mg twice a day for 7 days, was highly effective, well-tolerated, and equivalent or superior to the standard regimen of primaquine therapy.

Baird JK. 2007. Neglect of Plasmodium vivax malaria. Trends Parasitol, 23 (11), pp. 533-539. | Show Abstract | Read more

Plasmodium vivax infects 130-435 million of the 2.6 billion people living at risk of infection. Recent studies suggest that vivax malaria can become lethal in a similar way to severe falciparum malaria. First-line therapies remain unchanged after 50 years. Despite evidence of failing chloroquine efficacy, little work has assessed the problem or explored alternative therapies. Primaquine treatment, the only therapeutic option against relapse, might also be failing. No licensed primary chemoprophylactic agent protects travelers from relapse. Misdiagnosis of species now affects clinical decisions resulting in inadequate therapy for P. falciparum and P. vivax. All of these factors demonstrate the lack of research on P. vivax.

Barcus MJ, Basri H, Picarima H, Manyakori C, Sekartuti, Elyazar I, Bangs MJ, Maguire JD, Baird JK. 2007. Demographic risk factors for severe and fatal vivax and falciparum malaria among hospital admissions in northeastern Indonesian Papua. Am J Trop Med Hyg, 77 (5), pp. 984-991. | Show Abstract

Between January 1998 and December 2000, the Jayapura Provincial Public Hospital in northeastern Indonesian New Guinea (Papua) admitted 5,936 patients with a diagnosis of malaria. The microscopic diagnosis at admission was Plasmodium falciparum (3,976, 67%), Plasmodium vivax (1,135, 19%), Plasmodium malariae (8, < 1%), and mixed species infections (817, 14%). Approximately 9% (367) of patients were classified as having severe malaria (277 P. falciparum, 36 P. vivax, 53 mixed infections, and 1 P. malariae) and 88 died (79 P. falciparum/mixed infections and 9 P. vivax). Risk of fatal outcomes among severe malaria patients was indistinguishable between those with falciparum versus vivax malaria (OR = 0.89; P = 0.771). Compared with non-pregnant women, pregnant women showed no higher risk of severe malaria (P = 0.643) or death caused by severe malaria (P = 0.748). This study compares admissions per population (based on census data), parasitemia, morbidity, and mortality among children versus adults, pregnant versus non-pregnant women, and urban/suburban versus rural residents.

Price RN, Dorsey G, Ashley EA, Barnes KI, Baird JK, d'Alessandro U, Guerin PJ, Laufer MK, Naidoo I, Nosten F et al. 2007. World Antimalarial Resistance Network I: clinical efficacy of antimalarial drugs. Malar J, 6 (1), pp. 119. | Show Abstract | Read more

The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.

Baird JK, Snow RW. 2007. Acquired immunity in a holoendemic setting of Plasmodium falciparum and p. Vivax malaria. Am J Trop Med Hyg, 76 (6), pp. 995-996.

Fryauff DJ, Owusu-Agyei S, Utz G, Baird JK, Koram KA, Binka F, Nkrumah F, Hoffman SL. 2007. Mefloquine treatment for uncomplicated falciparum malaria in young children 6-24 months of age in northern Ghana. Am J Trop Med Hyg, 76 (2), pp. 224-231. | Show Abstract

Mefloquine (MQ) single dose 20 mg/kg treatment of falciparum malaria was evaluated in 186 children of 6-24 months of age in northern Ghana. There were 15 RII/RIII-type parasitologic failures, all with Day 2 MQ blood levels significantly lower than children whose parasitemias cleared before Day 7 and remained clear through 28 days. Predictors of RII/RIII parasitologic response were vomiting after MQ dosing, Day 2 MQ levels < 500 ng/mL, and undetectable Day 2 levels of the carboxymefloquine metabolite. There were 50 cases of delayed RI parasitologic failure, but 71% of these cases had undetectable Day 28 blood levels of MQ and drug levels in the remaining 29% ranged below the 620 ng/mL level that suppresses MQ sensitive strains of P. falciparum. Drug levels among infants that tolerated MQ well were not associated with age, weight, hemoglobin, parasitemia, and pre-existing symptoms of vomiting or diarrhea. An observed recurrent parasitemia of 34,400 trophozoites/microL against a MQ blood concentration of 550 ng/mL was taken as indication of tolerance to suppressive levels of the drug at this location.

Baird JK. 2007. A rare glimpse at the efficacy of primaquine. Am J Trop Med Hyg, 76 (2), pp. 201-202.

Baird JK, Schwartz E, Hoffman SL. 2007. Prevention and treatment of vivax malaria. Curr Infect Dis Rep, 9 (1), pp. 39-46. | Show Abstract | Read more

Plasmodium vivax is a significant public health threat throughout most of the tropics and to travelers to these regions. The infection causes a debilitating febrile syndrome that often recurs and in rare cases ends in death. The complex life cycle of the parasite compounds the difficulty of prevention and treatment, principally due to the phenomenon of relapse. Most commonly used drugs for preventing malaria fail to prevent late relapses by this parasite. Treatment requires dealing with both blood and liver stages. Since 1950, primaquine has been the only drug available for treatment of liver stages, and important clinical questions surround its appropriate use (ie, dosing, efficacy, safety, and tolerability). Likewise, chloroquine has been first-line therapy for vivax malaria since 1946, and the emergence of resistance to the drug further complicates therapeutic management decisions.

Sanjana P, Barcus MJ, Bangs MJ, Ompusunggu S, Elyazar I, Marwoto H, Tuti S, Sururi M, Tjokrosonto S, Baird JK. 2006. Survey of community knowledge, attitudes, and practices during a malaria epidemic in central Java, Indonesia. Am J Trop Med Hyg, 75 (5), pp. 783-789. | Show Abstract

We surveyed adults in a randomly selected sample of 1,000 households in 50 villages in nine malarial sub-districts in Purworejo, central Java, Indonesia from May to July 2001. The survey assessed malaria knowledge, attitudes, and practices in communities experiencing epidemic malaria to begin exploring broad strategies for controlling the disease in the region. A pre-tested survey instrument consisting of 93 questions addressed demographic characteristics, socioeconomic factors, knowledge and perceptions of malaria, burden and severity of disease, treatment-seeking behavior, malaria prevention practices, and perceptions of government malaria control efforts. The survey was taken by in-person interview of all subjects. Most (97%) subjects were aware of malaria and more than two-thirds correctly identified mosquitoes as the vector. Forty-one percent of households in both forest/hilly and agricultural/urban areas reported malaria illness in the past year. Thirty-six percent (357 households) owned at least one bed net, 92% of these had been purchased by the owners. However, only 36% of households with bed nets affirmed their use as a means of preventing malaria. Nearly all respondents reported a willingness to accept spraying of residual insecticides for malaria prevention, yet less than 5% were willing to pay a nominal fee (US $3) for this service. Fifty-two percent of respondents reported self-treatment of malaria illness without visiting a health facility. This assessment of knowledge, attitudes, and practices showed a broad awareness of malaria and its consequences among residents of malarial areas in the Menoreh Hills of Central Java.

Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ. 2006. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg, 75 (3), pp. 402-415. | Show Abstract

Primaquine phosphate has been used for preventing relapse of Plasmodium vivax and P. ovale malaria since the early 1950s, based on its ability to kill latent (hypnozoite) and developing liver stages of these parasites. There are three uses for primaquine in malaria: radical cure of established infection with P. vivax or P. ovale malaria; presumptive anti-relapse therapy (PART; terminal prophylaxis) in persons with extensive exposure to these parasites; and primary prophylaxis against all malaria species. All persons for whom primaquine is being considered must have a glucose-6-phosphate dehydrogenase (G6PD) enzyme level checked before use, and persons who have a deficiency of G6PD must not take primaquine for prophylaxis or PART. The recommended adult dose for PART based on clinical trials and expert opinion is 30 mg base daily for 14 days, started on return from a malarious region and overlapping with a blood schizonticide. The adult dose for primary prophylaxis is 30 mg daily begun 1 day before travel and continued for 7 days after return. This review will examine the evidence for these recommendations.

Maguire JD, Krisin, Marwoto H, Richie TL, Fryauff DJ, Baird JK. 2006. Mefloquine is highly efficacious against chloroquine-resistant Plasmodium vivax malaria and Plasmodium falciparum malaria in Papua, Indonesia. Clin Infect Dis, 42 (8), pp. 1067-1072. | Show Abstract | Read more

BACKGROUND: During the period of 1996-1999, we prospectively monitored 243 Javanese adults and children after arriving in Papua, Indonesia, and microscopically documented each new case of malaria by active surveillance. METHODS: In a randomized, open-label, comparative malaria treatment trial, 72 adults and 50 children received chloroquine for each incident case of malaria, and 74 adults and 47 children received mefloquine. RESULTS: Among 975 primary treatment courses, the cumulative 28-day curative efficacies were 26% and 82% for chloroquine against Plasmodium falciparum malaria and Plasmodium vivax malaria, respectively. Mefloquine cure rates were far superior (96% against P. falciparum malaria and 99.6% against P. vivax malaria). CONCLUSIONS: Mefloquine is a useful alternative treatment for P. vivax malaria and P. falciparum malaria in areas such as Papua, where chloroquine is still recommended as the first-line therapeutic agent.

Bousema JT, Roeffen W, van der Kolk M, de Vlas SJ, van de Vegte-Bolmer M, Bangs MJ, Teelen K, Kurniawan L, Maguire JD, Baird JK, Sauerwein RW. 2006. Rapid onset of transmission-reducing antibodies in javanese migrants exposed to malaria in papua, indonesia. Am J Trop Med Hyg, 74 (3), pp. 425-431. | Show Abstract

Transmission of Plasmodium falciparum malaria is initiated by sexual stages in the mosquito. Anti-Pfs48/45 and anti-Pfs230 sexual stage antibodies that are ingested together with parasites can reduce parasite development and subsequently malaria transmission. Acquisition of sexual stage immunity was studied in a cohort of 102 non-immune Javanese individuals migrating to hyperendemic Papua Indonesia. Seroprevalence of antibodies against Pfs48/45 and Pfs230 and functional transmission-reducing activity (TRA) were measured upon arrival and at 6, 12, and 24 months. Asexual parasitemia and gametocytemia were assessed every two weeks. The TRA and seroreactivity increased with the number of P. falciparum infections. The longitudinally sustained association between TRA and antibodies against Pfs48/45 (odds ratio [OR] = 3.74, 95% confidence interval [CI] = 1.51-9.29) and Pfs230 (OR = 3.72, 95% CI = 1.36-10.17) suggests that functional transmission reducing immunity is acquired after limited exposure to infection.

Maguire JD, Lederman ER, Barcus MJ, O'Meara WA, Jordon RG, Duong S, Muth S, Sismadi P, Bangs MJ, Prescott WR et al. 2006. Production and validation of durable, high quality standardized malaria microscopy slides for teaching, testing and quality assurance during an era of declining diagnostic proficiency. Malar J, 5 pp. 92. | Show Abstract | Read more

BACKGROUND: Sets of Giemsa-stained, blood smear slides with systematically verified composite diagnoses would contribute substantially to development of externally validated quality assurance systems for the microscopic diagnosis of malaria. METHODS: whole blood from Plasmodium-positive donors in Cambodia and Indonesia and individuals with no history of risk for malaria was collected. Using standard operating procedures, technicians prepared Giemsa-stained thick and thin smears from each donor. One slide from each of the first 35 donations was distributed to each of 28 individuals acknowledged by reputation as having expertise in the microscopic diagnosis of malaria. These reference readers recorded presence or absence of Plasmodium species and parasite density. A composite diagnosis for each donation was determined based on microscopic findings and species-specific small subunit ribosomal RNA (ssrRNA) DNA polymerase chain reaction (PCR) amplification. RESULTS: More than 12,000 slides were generated from 124 donations. Reference readers correctly identified presence of parasites on 85% of slides with densities <100 parasites/microl, which improved to 100% for densities >350 parasites/microl. Percentages of agreement with composite diagnoses were highest for Plasmodium falciparum (99%), followed by Plasmodium vivax (86%). CONCLUSION: Herein, a standardized method for producing large numbers of consistently high quality, durable Giemsa-stained blood smears and validating composite diagnoses for the purpose of creating a malaria slide repository in support of initiatives to improve training and competency assessment amidst a background of variability in diagnosis is described.

Lederman ER, Maguire JD, Sumawinata IW, Chand K, Elyazar I, Estiana L, Sismadi P, Bangs MJ, Baird JK. 2006. Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia. Malar J, 5 pp. 108. | Show Abstract | Read more

BACKGROUND: Chloroquine (CQ) or sulfadoxine-pyrimethamine (SP) monotherapy for Plasmodium falciparum often leads to therapeutic failure in Indonesia. Combining CQ with other drugs, like SP, may provide an affordable, available and effective option where artemisinin-combined therapies (ACT) are not licensed or are unavailable. METHODS: This study compared CQ (n = 29 subjects) versus CQ + SP (with or without primaquine; n = 88) for clinical and parasitological cure of uncomplicated falciparum malaria in the Menoreh Hills region of southern Central Java, Indonesia. Gametocyte clearance rates were measured with (n = 56 subjects) and without (n = 61) a single 45 mg dose of primaquine (PQ). RESULTS: After 28 days, 58% of subjects receiving CQ had cleared parasitaemia and remained aparasitaemic, compared to 94% receiving CQ combined with SP (p < 0.001). Msp-2 genotyping permitted reinfection-adjusted cure rates for CQ and CQ combined with SP, 70% and 99%, respectively (p = 0.0006). CONCLUSION: Primaquine exerted no apparent affect on cure of asexual stage parasitaemia, but clearly accelerated clearance of gametocytes. CQ combined with SP was safe and well-tolerated with superior efficacy over CQ for P. falciparum parasitaemia in this study.

Baird JK. 2005. Effectiveness of antimalarial drugs. N Engl J Med, 352 (15), pp. 1565-1577. | Read more

Sá JM, Nomura T, Neves JD, Baird JK, Wellems TE, del Portillo HA. 2005. Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains. Exp Parasitol, 109 (4), pp. 256-259. | Show Abstract | Read more

We describe here the sequence of the Plasmodium vivax mdr1 gene from 10 different isolates differing in chloroquine sensitivity. The deduced amino acid sequence of PvMDR1 shares more than 70% similarity with other malarial MDR proteins and it displays consensus motifs of an ABC family transporter including two transmembrane domains and two ATP binding cassettes. Similarity and dendrogram analyses revealed that sequences could be grouped according to their geographical origin. Within each geographical group however, no correlation was found between chloroquine resistance and specific mutations.

Hastings MD, Maguire JD, Bangs MJ, Zimmerman PA, Reeder JC, Baird JK, Sibley CH. 2005. Novel Plasmodium vivax dhfr alleles from the Indonesian Archipelago and Papua New Guinea: association with pyrimethamine resistance determined by a Saccharomyces cerevisiae expression system. Antimicrob Agents Chemother, 49 (2), pp. 733-740. | Show Abstract | Read more

In plasmodia, the dihydrofolate reductase (DHFR) enzyme is the target of the pyrimethamine component of sulfadoxine-pyrimethamine (S/P). Plasmodium vivax infections are not treated intentionally with antifolates. However, outside Africa, coinfections with Plasmodium falciparum and P. vivax are common, and P. vivax infections are often exposed to S/P. Cloning of the P. vivax dhfr gene has allowed molecular comparisons of dhfr alleles from different regions. Examination of the dhfr locus from a few locations has identified a very diverse set of alleles and showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia where S/P has been used extensively. We have surveyed patient isolates from six locations in Indonesia and two locations in Papua New Guinea. We sequenced P. vivax dhfr alleles from 114 patient samples and identified 24 different alleles that differed from the wild type by synonymous and nonsynonymous point mutations, insertions, or deletions. Most importantly, five alleles that carried four or more nonsynonymous mutations were identified. Only one of these highly mutant alleles had been previously observed, and all carried the 57L and 117T mutations. P. vivax cannot be cultured continuously, so we used a yeast assay system to determine in vitro sensitivity to pyrimethamine for a subset of the alleles. Alleles with four nonsynonymous mutations conferred very high levels of resistance to pyrimethamine. This study expands significantly the total number of novel dhfr alleles now identified from P. vivax and provides a foundation for understanding how antifolate resistance arises and spreads in natural P. vivax populations.

Syafruddin D, Asih PB, Casey GJ, Maguire J, Baird JK, Nagesha HS, Cowman AF, Reeder JC. 2005. Molecular epidemiology of Plasmodium falciparum resistance to antimalarial drugs in Indonesia. Am J Trop Med Hyg, 72 (2), pp. 174-181. | Show Abstract

The extent of gene polymorphisms associated with resistance to chloroquine and sulfadoxine-pyrimethamine was examined in field isolates of Plasmodium falciparum from Indonesia. Eight malaria-endemic areas, representing a broad region of the western and eastern Indonesian Archipelago were surveyed. Blood from 20-50 patients was collected at each site, DNA was isolated, and the sequences of four different genes (dihydrofolate reductase [dhfr], dihydropteroate synthase [dhps], P. falciparum multidrug resistance 1 [pfmdr1], and P. falciparum chloroquine resistance transporter [pfcrt]) were analyzed using polymerase chain reaction and restriction fragment length polymorphisms to detect polymorphisms previously shown to be associated with resistance. This analysis identified polymorphisms in dhfr at 108-Asn/Thr, 16-Val, and 59-Arg. Polymorphisms in dhps were found less frequently, either 437-Gly alone or paired with 540-Glu. The pfcrt 76-Thr polymorphism was fixed in all parasite populations and pfmdr1 86-Tyr polymorphisms in all populations except in the most eastern regions. The pfmdr1 1042-Asp polymorphism occurred less frequently. These findings indicate that polymorphisms in genes associated with drug resistance in P. falciparum are found across a broad region of Indonesia.

Baird JK, Hoffman SL. 2004. Primaquine therapy for malaria. Clin Infect Dis, 39 (9), pp. 1336-1345. | Show Abstract | Read more

Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines the wide range of clinical applications of primaquine described in the medical literature between 1946 and 2004. The risk of relapse of Plasmodium vivax malaria without primaquine therapy ranged from 5% to 80% or more, depending largely upon geographic location. Supervision of therapy profoundly impacts the risk of relapse, and almost all reports of malaria resistant to primaquine are associated with lack of such supervision. We nonetheless suspect that there is widespread resistance to the standard course of primaquine therapy, which is 15 mg primaquine base daily for 14 days. Clinical evidence confirms that a course of 15 mg daily for just 5 days, a regimen widely used in areas where malaria is endemic, has no discernible efficacy. This review supports a recommendation for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.

Baird JK. 2004. Chloroquine resistance in Plasmodium vivax. Antimicrob Agents Chemother, 48 (11), pp. 4075-4083. | Read more

Belizario VY, de Leon WU, Bersabe MJ, Purnomo, Baird JK, Bangs MJ. 2004. A focus of human infection by Haplorchis taichui (Trematoda: Heterophyidae) in the southern Philippines. J Parasitol, 90 (5), pp. 1165-1169. | Show Abstract | Read more

We report an exceptionally high rate of infection by Haplorchis taichui (Nishigori, 1924) in human populations on Mindanao Island, southern Philippines. This intestinal fluke is seldom encountered, and this is the first report of high prevalence of infection (36%) in humans by H. taichui in the Philippines. The likely source of haplorchine infection has been linked to consumption of raw or undercooked freshwater fish containing infective metacercariae. The most common clinical symptoms appeared as upper abdominal discomfort or pain and borborygmi. Praziquantel (75 mg/kg divided in 3 doses in 1 day) was a well-tolerated and effective treatment for infection by H. taichui.

Hastings MD, Porter KM, Maguire JD, Susanti I, Kania W, Bangs MJ, Sibley CH, Baird JK. 2004. Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine. J Infect Dis, 189 (4), pp. 744-750. | Show Abstract | Read more

BACKGROUND: The target enzyme of pyrimethamine is dihydrofolate reductase (DHFR), but little is known about allelic variants of dhfr in Plasmodium vivax populations. Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P. vivax in vivo. METHODS: We studied P. vivax dhfr mutations in 24 patients who received S/P therapy in Papua or Central Java, Indonesia, and we measured the resistance of the alleles in vitro in a dhfr yeast expression assay. RESULTS: Fourteen (58%) of 24 patients had an inadequate therapeutic response. Two of 6 alleles that were identified were novel. One allele that expressed 4 point mutations (57L+58R+61M+117T) correlated with a high risk of therapeutic failure. The 9 patients infected by P. vivax carrying this allele proved 23 times more likely to experience early therapeutic failure, compared with patients infected by P. vivax carrying other alleles (P=.003; 95% confidence interval, 2-450). This allele also conferred high levels of pyrimethamine resistance in vitro. The experimental antifolate WR99210 inhibited the allele in this system. CONCLUSIONS: The present study identified a strong correlation between specific mutations in P. vivax dhfr and S/P treatment failure. Our results suggest that WR99210 could provide effective therapy for S/P-resistant P. vivax.

Baird JK, Fryauff DJ, Hoffman SL. 2003. Primaquine for prevention of malaria in travelers. Clin Infect Dis, 37 (12), pp. 1659-1667. | Show Abstract | Read more

An expanding risk and range of endemic malaria threatens travelers. Primaquine is an old drug recently demonstrated to offer effective prophylaxis. Clinical trials conducted in Indonesia, Kenya, and Colombia showed that a primaquine base (30 mg per day) had protective efficacy against Plasmodium falciparum and Plasmodium vivax of 85%-93%. Among 339 children (age, >8 years) and adults taking this regimen for 12-52 weeks, there was no greater risk of adverse symptomatic events among primaquine users than among recipients of placebo in double-blind studies. Among 151 subjects evaluated after 20 or 52 weeks of daily primaquine therapy, methemoglobinemia was found to be mild (<13%; typically <6%) and transient (duration, <2 weeks). We consider primaquine base (0.5 mg/kg per day consumed with food) to be safe, well-tolerated, and effective prophylaxis against malaria for nonpregnant persons and those with normal glucose-6-phosphate dehydrogenase levels. Primaquine's major advantage over most drugs for chemoprophylaxis is that it does not have to be taken before entering or beyond 3 days after leaving a malarious area.

Doan HN, Taylor WR, Nguyen DT, Tran TU, Fryauff DJ, Susanti I, Gómez-Saladín E, Le DC, Baird JK. 2003. Short report: in vivo sensitivity of Plasmodium falciparum to halofantrine in southern central Vietnam. Am J Trop Med Hyg, 69 (5), pp. 553-554. | Show Abstract

Drug-resistant Plasmodium falciparum is present in Vietnam. We assessed the in vivo sensitivity of P. falciparum to halofantrine in two villages in the southern part of central Vietnam. Halofantrine (8 mg/kg x 3 doses) was administered to 37 patients with either P. falciparum (n = 32) or mixed P. falciparum/P. vivax malaria (n = 5). End points were parasite sensitivity or resistance (RI/RII/RIII) determined by parasite clearance, persistence, or recurrence during 28 days of follow-up. By day 28, 31 (93.9%) of 33 (95% confidence interval = 79.8-99.2%) patients were sensitive. Two patients had recurrent P. falciparum parasitemia on days 14 and 21. Halofantrine effectively treated uncomplicated P. falciparum malaria in these Vietnamese patients.

Gomez JC, McNamara DT, Bockarie MJ, Baird JK, Carlton JM, Zimmerman PA. 2003. Identification of a polymorphic Plasmodium vivax microsatellite marker. Am J Trop Med Hyg, 69 (4), pp. 377-379. | Show Abstract

Microsatellite markers derived from simple sequence repeats have been useful in studying a number of human pathogens, including the human malaria parasite Plasmodium falciparum. Genetic markers for P. vivax would likewise help elucidate the genetics and population characteristics of this other important human malaria parasite. We have identified a locus in a P. vivax telomeric clone that contains simple sequence repeats. Primers were designed to amplify this region using a two-step semi-nested polymerase chain reaction protocol. The primers did not amplify template obtained from non-infected individuals, nor DNA from primates infected with the other human malaria parasites (P. ovale, P. malariae, or P. falciparum). The marker was polymorphic in P. vivax-infected field isolates obtained from Papua New Guinea, Indonesia and Guyana. This microsatellite marker may be useful in genetic and epidemiologic studies of P. vivax malaria.

Baird JK, Krisin, Barcus MJ, Elyazar IR, Bangs MJ, Maguire JD, Fryauff DJ, Richie TL, Sekartuti, Kalalo W. 2003. Onset of clinical immunity to Plasmodium falciparum among Javanese migrants to Indonesian Papua. Ann Trop Med Parasitol, 97 (6), pp. 557-564. | Show Abstract | Read more

Onset of clinical immunity to Plasmodium falciparum occurred among Javanese migrants to Indonesian Papua. Surveillance of the 243 migrants investigated began on the day of their arrival in Indonesian Papua and continued for 33 months. Asexual parasitaemia without fever constituted objective evidence of clinical immunity. Compared with first infection, the odds ratio (OR) for not having fever at the fourth infection within 24 months was 3.2 [95% confidence interval (CI)=1.03-10.2; P=0.02]. The corresponding OR with fewer infections within 24 months was not distinguishable from 1.0. The level of the fourth parasitaemia within 24 months (N=58) was classified as 'high' or 'low' in relation to the median count at first infection (840 parasites/microl; N=187). Fourth parasitaemias that were low-but not those that were high (OR=1.8; CI=0.6-5.4; P=0.35)-were associated with dramatic protection from fever (OR=31; CI=3.5-1348; P=0.0001). Among the adult subjects, the risk of fever with low parasitaemia was significantly higher at the first infection than at the fourth (OR=12.6; CI=1.7-530; P=0.005), indicating the development of clinical immunity. A similar but less marked pattern appeared among the children investigated (OR=6.5; CI=0.8-285; P=0.06).

Barcus MJ, Krisin, Elyazar IR, Marwoto H, Richie TL, Basri H, Wiady I, Fryauff DJ, Maguire JD, Bangs MJ, Baird JK. 2003. Primary infection by Plasmodium falciparum or P. vivax in a cohort of Javanese migrants to Indonesian Papua. Ann Trop Med Parasitol, 97 (6), pp. 565-574. | Show Abstract | Read more

The clinical and parasitological characteristics of the first naturally acquired malarial infection have rarely been documented in humans. When 243 migrants from non-endemic Java were followed from the day of their arrival in Indonesian Papua, 217 (89%) were found to become infected with Plasmodium falciparum and/or P. vivax before they were lost to follow-up. The incidence of malarial infection in the children investigated (who were aged 6-10 years) was indistinguishable from that in the adults (aged >20 years), with 1.10 and 1.14 P. falciparum infections/person-year (relative risk=0.97; 95% confidence interval=0.72-1.29) and 1.47 and 1.49 P. vivax infections/person-year (relative risk=0.99; 95% confidence interval=0.72-1.29), respectively. During their first infections, the children had higher P. falciparum parasitaemias than the adults (with geometric means of 1318 and 759 parasites/microl, respectively; P=0.04) but similar P. vivax parasitaemias (with geometric means of 355 and 331 parasites/microl, respectively; P=0.76). At first infection, 56% of the subjects were febrile and 90% complained of symptoms. There were no differences between children and adults with respect to these two parameters, either for P. falciparum or P. vivax. These findings indicate that, with promptly diagnosed and treated uncomplicated malaria, migrant children and adults in north-eastern Indonesian Papua have an equal risk of malarial infection and of disease following their first infections with P. falciparum and P. vivax.

Krisin, Basri H, Fryauff DJ, Barcus MJ, Bangs MJ, Ayomi E, Marwoto H, Elyazar IR, Richie TL, Baird JK. 2003. Malaria in a cohort of Javanese migrants to Indonesian Papua. Ann Trop Med Parasitol, 97 (6), pp. 543-556. | Show Abstract | Read more

The epidemiology of infection by Plasmodium falciparum and P. vivax was investigated among Javanese migrants to an endemic region of Papua, Indonesia. A cohort of 243 migrants from Java was followed for malaria in a new settlement village in the endemic Armopa area of north-eastern Papua, beginning on the day each migrant arrived in the village. The subjects were monitored during home visits (three/week) and by the twice-monthly production of bloodsmears that were checked for malarial parasites. At the end of 33 months, 159 (65%) of the subjects remained under follow-up. The prevalence of parasitaemia in the village declined from 16% among those already living there when the study began in August 1996, to 5% when the study finished in June 1999. Over this period, 596 infections by P. falciparum and 723 by P. vivax occurred in the cohort, 22 and 27 of the subjects each experiencing at least six infections by P. falciparum and P. vivax, respectively. The incidence of malarial infection was higher during the first and second years post-migration (3.2 and 2.7 infections/person-year) than during the third (1.2 infections/person-year). Although the geometric mean parasite counts for P. falciparum increased over time (1209, 1478, and 1830 parasites/microl in the first, second and third years, respectively), the corresponding values for P. vivax (497, 535 and 490 parasites/microl) showed no such trend. Only one of the nine subjects who developed severe malaria (requiring intravenous quinine therapy) was a child, giving an odds ratio for a case of severe malaria being in an adult of 6.1 (P=0.08).

Baird JK. 2003. The American Society of Tropical Medicine and Hygiene should keep its name. Am J Trop Med Hyg, 69 (3), pp. 234-235.

Baird JK, Basri H, Weina P, MaGuire JD, Barcus MJ, Picarema H, Elyazar IR, Ayomi E, Sekartuti. 2003. Adult Javanese migrants to Indonesian Papua at high risk of severe disease caused by malaria. Epidemiol Infect, 131 (1), pp. 791-797. | Show Abstract | Read more

Migrants from Java arrive in hyperendemic Papua, Indonesia lacking exposure to endemic malaria. We evaluated records of evacuation to hospital with a diagnosis of severe malaria from a transmigration village in northeastern Papua. During the first 30 months, 198 residents with severe disease were evacuated (7.5 evacuations/100 person-years). During this period the risk of evacuation for adults (> 15 years of age) was 2.8. (95% CI = 2.1-3.8; P < 0.0001) relative to children, despite apparently equal exposure to risk of infection. Relative risk (RR) for adults was greatest during the first 6 months (RR > 16; 95% CI > or = 2.0-129; P = 0.0009), and diminished during the second 6 months (RR = 9.4; 95% CI = 2.7-32.8; P < 0.0001) and the third 6 months (RR = 3.7; 95% CI = 1.7-7.9; P = 0.0004). During the next two 6-month intervals, the RR for adults was 1.6 and 1.5 (95 % CI range 0.8-2.6; P < 0.18). Adults lacking chronic exposure were far more likely to progress to severe disease compared to children during initial exposure, but not after chronic exposure to infection.

Hudson Keenihan SN, Ratiwayanto S, Soebianto S, Krisin, Marwoto H, Krishnegowda G, Gowda DC, Bangs MJ, Fryauff DJ, Richie TL et al. 2003. Age-dependent impairment of IgG responses to glycosylphosphatidylinositol with equal exposure to Plasmodium falciparum among Javanese migrants to Papua, Indonesia. Am J Trop Med Hyg, 69 (1), pp. 36-41. | Show Abstract

Immune responses directed at glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum may offer protection against symptomatic malaria. To independently explore the effect of age on generation of the anti-GPI IgG response, we measured serum anti-GPI IgGs in a longitudinal cohort of migrant Javanese children (6-12 years old) and adults (> or = 20 years old) with equivalent numbers of exposures to P. falciparum in Papua, Indonesia. While the peak response in adults was achieved after a single infection, comparable responses in children required > or = 3-4 infections. Significantly fewer children (16%) than adults (41%) showed a high (optical density > 0.44) anti-GPI IgG response (odds ratio [OR] = 3.8, 95% confidence interval [CI] = 2.3-6.3, P < 0.0001), and adults were more likely to show a persistently high response (OR = 5.5, 95% CI = 1.0-56.8, P = 0.03). However, the minority of children showing a strong response were significantly less likely to experience symptoms with subsequent parasitemia compared with those with a weak response (OR = 4.0, 95% CI = 1.1-13.8, P = 0.02). This effect was not seen among high- and low-responding adults (OR = 1.2, 95% CI = 0.5-2.8, P = 0.60). Host age, independent of cumulative exposure, apparently represents a key determinant of the quantitative and qualitative nature of the IgG response to P. falciparum GPI.

Sumawinata IW, Bernadeta, Leksana B, Sutamihardja A, Purnomo, Subianto B, Sekartuti, Fryauff DJ, Baird JK. 2003. Very high risk of therapeutic failure with chloroquine for uncomplicated Plasmodium falciparum and P. vivax malaria in Indonesian Papua. Am J Trop Med Hyg, 68 (4), pp. 416-420. | Show Abstract

Chloroquine remains the first-line therapy for uncomplicated malaria in Indonesia. Among a series of trials of chloroquine for malaria on this archipelago conducted since 1990, we now report the highest risk of therapeutic failure yet observed. A clinical trial of standard chloroquine therapy for uncomplicated malaria at Arso PIR V in northeastern Indonesian Papua was conducted during 1995. We enrolled 104 non-immune subjects infected with Plasmodium falciparum (n = 55), P. vivax (n = 29), or P. falciparum plus P. vivax (n = 20) and administered supervised standard chloroquine therapy (10 + 10 + 5 mg/kg at 24-hour intervals). The 28-day cumulative incidence of therapeutic failure was 95% for P. falciparum, 84% for P. vivax, and 100% for mixed infections. Only one subject each for P. falciparum and P. vivax remained free of parasites at day 28. All recurrent parasitemias occurred with whole blood levels of chloroquine plus desethylchloroquine exceeding 100 ng/ml. These findings document almost complete failure of chloroquine against P. falciparum or P. vivax near the northeastern coast of Indonesian Papua.

Nagesha HS, Casey GJ, Rieckmann KH, Fryauff DJ, Laksana BS, Reeder JC, Maguire JD, Baird JK. 2003. New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine-resistant parasite isolates. Am J Trop Med Hyg, 68 (4), pp. 398-402. | Show Abstract

Mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene were examined to assess their associations with chloroquine resistance in clinical samples from Armopa (Papua) and Papua New Guinea. In Papua, two of the five pfcrt haplotypes found were new: SVIET from Armopa and CVIKT from an isolate in Timika. There was also a strong association (P < 0.0001) between the pfcrt 76T allele and chloroquine resistance in 50 samples. In Papua New Guinea, mutations in the pfcrt gene were observed in 15 isolates with chloroquine minimum inhibitory concentrations (MICs) of 16-64 pmol, while the remaining six isolates, which had a wild-type pfcrt gene at codon 76, had MICs of 2-8 pmol. These observations confirm that mutations at codon 76 in the pfcrt gene are present in both in vivo and in vitro cases of chloroquine resistance, and that detection of the pfcrt 76T allele could predict potential chloroquine treatment failures.

Baird JK, Rieckmann KH. 2003. Can primaquine therapy for vivax malaria be improved? Trends Parasitol, 19 (3), pp. 115-120. | Show Abstract | Read more

The incidence and range of endemic malaria caused by Plasmodium vivax has expanded during the past 30 years. This parasite forms hypnozoites in the liver, creating a persistent reservoir of infection. Primaquine (PQ), introduced 50 years ago, is the only drug available to eliminate hypnozoites. However, lengthy treatment courses and follow-up periods are not conducive to assessing the effectiveness of this drug in preventing relapses. Resistance to standard therapy could be widespread. Studies are urgently needed to gauge this problem and to determine the safety, tolerability and efficacy of shorter courses and higher doses of PQ.

Hale BR, Owusu-Agyei S, Fryauff DJ, Koram KA, Adjuik M, Oduro AR, Prescott WR, Baird JK, Nkrumah F, Ritchie TL et al. 2003. A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum. Clin Infect Dis, 36 (5), pp. 541-549. | Show Abstract | Read more

Tafenoquine is a promising new 8-aminoquinoline drug that may be useful for malaria prophylaxis in nonpregnant persons with normal glucose-6-phosphate dehydrogenase (G6PD) function. A randomized, double-blind, placebo-controlled chemoprophylaxis trial was conducted with adult residents of northern Ghana to determine the minimum effective weekly dose of tafenoquine for the prevention of infection by Plasmodium falciparum. The primary end point was a positive malaria blood smear result during the 13 weeks of study drug coverage. Relative to the placebo, all 4 tafenoquine dosages demonstrated significant protection against P. falciparum infection: for 25 mg/week, protective efficacy was 32% (95% confidence interval [CI], 20%-43%); for 50 mg/week, 84% (95% CI, 75%-91%); for 100 mg/week, 87% (95% CI, 78%-93%); and for 200 mg/week, 86% (95% CI, 76%-92%). The mefloquine dosage of 250 mg/week also demonstrated significant protection against P. falciparum infection (protective efficacy, 86%; 95% CI, 72%-93%). There was little difference between study groups in the adverse events reported, and there was no evidence of a relationship between tafenoquine dosage and reports of physical complaints or the occurrence of abnormal laboratory parameters. Tafenoquine dosages of 50, 100, and 200 mg/week were safe, well tolerated, and effective against P. falciparum infection in this study population.

Lacy MD, Maguire JD, Barcus MJ, Ling J, Bangs MJ, Gramzinski R, Basri H, Sismadi P, Miller GB, Chulay JD et al. 2002. Atovaquone/proguanil therapy for Plasmodium falciparum and Plasmodium vivax malaria in Indonesians who lack clinical immunity. Clin Infect Dis, 35 (9), pp. e92-e95. | Show Abstract | Read more

Thirty-eight of 295 subjects participating in a randomized, double-blind, placebo-controlled trial of the efficacy of daily administration of atovaquone/proguanil for malaria prevention developed malaria at some time during the 20-week prophylaxis period. These subjects (3 atovaquone/proguanil recipients and 35 placebo recipients) were treated with 4 tablets of atovaquone/proguanil per day for 3 days. Atovaquone/proguanil provided safe, well-tolerated, and effective therapy for uncomplicated malaria in nonimmune Indonesians.

Ling J, Baird JK, Fryauff DJ, Sismadi P, Bangs MJ, Lacy M, Barcus MJ, Gramzinski R, Maguire JD, Kumusumangsih M et al. 2002. Randomized, placebo-controlled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin Infect Dis, 35 (7), pp. 825-833. | Show Abstract | Read more

The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis. Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been >95% effective in preventing Plasmodium falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who migrated to Papua (where malaria is endemic) < or =26 months before the study period. Subjects received prophylaxis with 1 Malarone tablet (250 mg of atovaquone and 100 mg of proguanil hydrochloride; n=148) or placebo (n=149) per day for 20 weeks. Hematologic and clinical chemistry values did not change significantly. The protective efficacy of atovaquone/proguanil was 84% (95% confidence interval [CI], 44%-95%) for P. vivax malaria, 96% (95% CI, 72%-99%) for P. falciparum malaria, and 93% (95% CI, 77%-98%) overall. Atovaquone/proguanil was well tolerated, safe, and effective for the prevention of drug-resistant P. vivax and P. falciparum malaria in individuals without prior malaria exposure who migrated to Papua, Indonesia.

Maguire JD, Lacy MD, Sururi, Sismadi P, Krisin, Wiady I, Laksana B, Bangs MJ, Masbar S, Susanti I et al. 2002. Chloroquine or sulfadoxine-pyrimethamine for the treatment of uncomplicated, Plasmodium falciparum malaria during an epidemic in Central Java, Indonesia. Ann Trop Med Parasitol, 96 (7), pp. 655-668. | Show Abstract | Read more

A recent malaria epidemic in the Menoreh Hills of Central Java has increased concern about the re-emergence of endemic malaria on Java, which threatens the island's 120 million residents. A 28-day, in-vivo test of the efficacy of treatment of malaria with antimalarial drugs was conducted among 167 villagers in the Menoreh Hills. The treatments investigated, chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), constitute, respectively, the first- and second-line treatments for uncomplicated malaria in Indonesia. The prevalence of malaria among 1389 residents screened prior to enrollment was 33%. Treatment outcomes were assessed by microscopical diagnoses, PCR-based confirmation of the diagnoses, measurement of the whole-blood concentrations of CQ and desethylchloroquine (DCQ), and identification of the Plasmodium falciparum genotypes. The 28-day cumulative incidences of therapeutic failure for CQ and SP were, respectively, 47% (N = 36) and 22% (N = 50) in the treatment of P. falciparum, and 18% (N = 77) and 67% (N = 6) in the treatment of P. vivax. Chloroquine was thus an ineffective therapy for P. falciparum malaria, and the presence of CQ-resistant P. vivax and SP-resistant P. falciparum will further compromise efforts to control resurgent malaria on Java.

Maguire JD, Sumawinata IW, Masbar S, Laksana B, Prodjodipuro P, Susanti I, Sismadi P, Mahmud N, Bangs MJ, Baird JK. 2002. Chloroquine-resistant Plasmodium malariae in south Sumatra, Indonesia. Lancet, 360 (9326), pp. 58-60. | Show Abstract | Read more

Oral chloroquine is the treatment of choice for uncomplicated Plasmodium malariae infections worldwide. We did a prospective 28-day in-vivo assessment of the efficacy of chloroquine for treatment of P malariae on Legundi Island in Lampung Bay, Sumatra, Indonesia. Of 28 patients, one had recurrent parasitaemia on day 28, and two had persistent parasitaemia to day 8. Whole-blood chloroquine and desethylchloroquine concentrations were at ordinarily effective levels (> or = 100 microg/L) on day 8 in both cases of persistent parasitaemia. These findings suggest that clinical resistance to chloroquine by P malariae occurs in the Indonesian archipelago of southeast Asia.

Fryauff DJ, Leksana B, Masbar S, Wiady I, Sismadi P, Susanti AI, Nagesha HS, Syafruddin, Atmosoedjono S, Bangs MJ, Baird JK. 2002. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia. Ann Trop Med Parasitol, 96 (5), pp. 447-462. | Show Abstract | Read more

Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene. Night-biting mosquitoes were surveyed by human landing collections and tested for sporozoite infection. Among the five species of human-biting anophelines collected, Anopheles sundaicus was dominant (68%) and the only species found to be infective--two (1.2%) of 167 females being found carrying P. vivax sporozoites. The risk of malarial infection for humans on Nias was considered high because of the abundance of asymptomatic carriers, the reduced effectiveness of the available antimalarial drugs, and the biting and infection 'rates' of the local An. sundaicus.

Baird JK, Tiwari T, Martin GJ, Tamminga CL, Prout TM, Tjaden J, Bravet PP, Rawlins S, Ferrel M, Carucci D, Hoffman SL. 2002. Chloroquine for the treatment of uncomplicated malaria in Guyana. Ann Trop Med Parasitol, 96 (4), pp. 339-348. | Show Abstract | Read more

At a public hospital in Georgetown, Guyana, 44 patients seeking treatment for symptomatic, slide-confirmed malaria were given standard chloroquine (CQ) therapy and followed for 28 days. The patients apparently had pure infections with Plasmodium falciparum (14), P. vivax (13) or P. malariae (one), or mixed infections either of P. falciparum and P. vivax (17) or of P. falciparum, P. malariae and P. vivax (two). Each received supervised treatment with 10 mg CQ base/kg on each of days 0 and 1, and 5 mg/kg on day 2. On the day of enrollment (day 0), the patients complained of fever (100%), headache (100%), malaise (94%), myalgia (79%), nausea (67%), vertigo (49%) and vomiting (33%). Many (39%) were ill enough to confine themselves to bed. On day 4, fewer of the subjects complained of fever (15%), headache (15%), malaise (6%), myalgia (21%), nausea (6%), vertigo (24%) or vomiting (0%) despite the relatively high (>48%) risk of therapeutic failure. The cumulative incidence of parasitological failure against P. falciparum was 15% at day 4, 33% at day 7 and 48% at day 14. All of the P. vivax and P. malariae infections cleared before day 4 and none recurred by day 7. Two infections with P. vivax recurred later (on day 14 or 28) but in the presence of less than adequate, whole-blood concentrations of CQ plus desethyl-chloroquine (i.e. <100 ng/ml). Taken together, the results indicate a high risk of therapeutic failure of CQ against P. falciparum but also indicate that resistance to CQ in P. vivax occurs infrequently in Guyana.

Baird JK, Wiady I, Sutanihardja A, Suradi, Purnomo, Basri H, Sekartuti, Ayomi E, Fryauff DJ, Hoffman SL. 2002. Short report: therapeutic efficacy of chloroquine combined with primaquine against Plasmodium falciparum in northeastern Papua, Indonesia. Am J Trop Med Hyg, 66 (6), pp. 659-660. | Show Abstract | Read more

Chloroquine combined with primaquine was evaluated for therapy of uncomplicated malaria caused by Plasmodium falciparum in nonimmune Javanese migrants to northeastern Papua, Indonesia. Subjects were randomized to treatment with standard chloroquine therapy (25 mg/kg in 3 doses over the course of 48 hours) with 30 mg primaquine administered daily for 28 days (n = 25) or a placebo of primaquine (n = 28). The 14-day cumulative incidence of therapeutic failure was 56% with primaquine and 79% with placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.1-1.3; P = 0.08). Primaquine administered daily created a marginally significant improvement in therapeutic efficacy at day 14, but not at day 7 (20% versus 36%; OR, 0.2; 95% CI, 0.1-1.8; P = 0.2) or day 28 (82% versus 93%; OR, 0.31; 95% Cl, 0.04-2.1; P = 0.23). This report corroborates studies suggesting that therapeutic doses of primaquine exert no discernible effect on parasitemia by P. falciparum.

Baird JK, Owusu Agyei S, Utz GC, Koram K, Barcus MJ, Jones TR, Fryauff DJ, Binka FN, Hoffman SL, Nkrumah FN. 2002. Seasonal malaria attack rates in infants and young children in northern Ghana. Am J Trop Med Hyg, 66 (3), pp. 280-286. | Show Abstract | Read more

The incidence density of infection and disease caused by Plasmodium falciparum in children aged six to 24 months living in the holoendemic Sahel of northern Ghana was measured during the wet and dry seasons of 1996 and 1997. At the beginning of each season, a cohort composed of 259 and 277 randomly selected children received supervised curative therapy with quinine and Fansidar and primaquine for those with normal glucose-6-phosphate dehydrogenase activity. The 20 weeks of post-therapy follow-up consisted of three home visits weekly and examination of Giemsa-stained blood films once every two weeks. Blood films were also taken from children brought to clinic with illness. The incidence density of parasitemia after radical cure was 4.7 infections/person-year during the dry season and 7.1 during the wet season (relative risk = 1.51, 95% confidence interval [CI] = 1.25-1.81; P = 0.00001). Although the mean parasitemia count at time of reinfection in the dry season (3,310/microl) roughly equaled that in the wet season (3,056/microl; P = 0.737), the risk ratio for parasitemia > 20,000/microl during the wet season was 1.71 (95% CI = 1.2-2.4; P = 0.0025). The risk ratio for parasitemia > 20,000/microl with fever during the wet season was 2.45 (95% CI = 1.5-4.1; P = 0.0002). The risk ratio for anemia (hemoglobin < 8 g/dl) at first post-radical cure parasitemia showed no difference between seasons (1.0; 95% CI = 0.73-1.4; P = 0.9915). We did not see seasonal differences in anemia known to exist in this region, probably because the longitudinal cohort design using first parasitemia as an end point prevented the subjects from developing the repeated or chronic infections required for anemia induction. These findings bear upon the design of malaria drug and vaccine trials in holoendemic areas.

Barcus MJ, Laihad F, Sururi M, Sismadi P, Marwoto H, Bangs MJ, Baird JK. 2002. Epidemic malaria in the Menoreh Hills of Central Java. Am J Trop Med Hyg, 66 (3), pp. 287-292. | Show Abstract | Read more

After more than 50 years of effective management, resurgent malaria threatens residents in the Menoreh Hills and the foothills of the Dieng Plateau of Central Java, Indonesia. The Dieng Plateau dominates the highland center of Central Java. The steep Menoreh Hills, surrounded by rice paddy habitats, cover approximately 500 km2 with no peaks greater than 1,000 m. We studied epidemic malaria in Purworejo district, one of the three districts containing the Menoreh Hills. Between 1986 and 1995, the annual parasite incidence (API) in Purworejo ranged from 2 to 11 cases per 1,000 residents per year and was typically approximately 5 per 1,000. In 2000 the API was 44.5. This sharp increase was confined to subdistricts in and around the Menoreh Hills and Dieng Plateau foothills. The primary vectors of malaria, those favoring steep, forested hillsides on Java, were Anopheles maculatus and Anopheles balabacensis. Deterioration of vector control activity, followed by a severe economic downturn in 1997, may explain the epidemic. Malaria in the Menoreh Hills and lower Dieng Plateau threatens surrounding areas of rice paddy inhabited by Anopheles aconitus as well as a nearby coastal habitat where the even more efficient vector Anopheles sundaicus occurs in abundance. Most of the 130 million people living on Java never experienced the hyper- and holoendemic malaria that occurred throughout most of the island before the effective DDT spraying and chloroquine treatment campaigns of the 1950s. Reintroduced endemic malaria threatens the island of Java.

Baird JK, Bangs MJ, Maguire JD, Barcus MJ. 2002. Epidemiological measures of risk of malaria. Methods Mol Med, 72 pp. 13-22. | Read more

Baird JK, Lacy MD, Basri H, Barcus MJ, Maguire JD, Bangs MJ, Gramzinski R, Sismadi P, Krisin, Ling J et al. 2001. Randomized, parallel placebo-controlled trial of primaquine for malaria prophylaxis in Papua, Indonesia. Clin Infect Dis, 33 (12), pp. 1990-1997. | Show Abstract | Read more

Malaria causes illness or death in unprotected travelers. Primaquine prevents malaria by attacking liver-stage parasites, a property distinguishing it from most chemoprophylactics and obviating 4-week postexposure dosing. A daily adult regimen of 30 mg primaquine prevented malaria caused by Plasmodium falciparum and P. vivax for 20 weeks in 95 of 97 glucose-6-phosphate dehydrogenase (G6PD)-normal Javanese transmigrants in Papua, Indonesia. In comparison, 37 of 149 subjects taking placebo in a parallel trial became parasitemic. The protective efficacy of primaquine against malaria was 93% (95% confidence interval [CI] 71%-98%); against P. falciparum it was 88% (95% CI 48%-97%), and >92% for P. vivax (95% CI >37%-99%). Primaquine was as well tolerated as placebo. Mild methemoglobinemia (mean of 3.4%) returned to normal within 2 weeks. Blood chemistry and hematological parameters revealed no evidence of toxicity. Good safety, tolerance, and efficacy, along with key advantages in dosing requirements, make primaquine an excellent drug for preventing malaria in nonpregnant, G6PD-normal travelers.

Rogers WO, Baird JK, Kumar A, Tine JA, Weiss W, Aguiar JC, Gowda K, Gwadz R, Kumar S, Gold M, Hoffman SL. 2001. Multistage multiantigen heterologous prime boost vaccine for Plasmodium knowlesi malaria provides partial protection in rhesus macaques. Infect Immun, 69 (9), pp. 5565-5572. | Show Abstract | Read more

A nonhuman primate model for malaria vaccine development allowing reliable, stringent sporozoite challenge and evaluation of both cellular and antibody responses is needed. We therefore constructed a multicomponent, multistage DNA vaccine for the simian malaria species Plasmodium knowlesi including two preerythrocytic-stage antigens, the circumsporozoite protein (PkCSP) and sporozoite surface protein 2 (PkSSP2), and two blood stage antigens, apical merozoite antigen 1 (PkAMA1) and merozoite surface protein 1 (PkMSP1p42), as well as recombinant canarypox viruses encoding the four antigens (ALVAC-4). The DNA vaccine plasmids expressed the corresponding antigens in vitro and induced antiparasite antibodies in mice. Groups of four rhesus monkeys received three doses of a mixture of the four DNA vaccine plasmids and a plasmid encoding rhesus granulocyte-monocyte colony-stimulating factor, followed by boosting with a single dose of ALVAC-4. Three groups received the priming DNA doses by different routes, either by intramuscular needle injection, by intramuscular injection with a needleless injection device, the Biojector, or by a combination of intramuscular and intradermal routes by Biojector. Animals immunized by any route developed antibody responses against sporozoites and infected erythrocytes and against a recombinant PkCSP protein, as well as gamma interferon-secreting T-cell responses against peptides from PkCSP. Following challenge with 100 P. knowlesi sporozoites, 1 of 12 experimental monkeys was completely protected and the mean parasitemia in the remaining monkeys was significantly lower than that in 4 control monkeys. This model will be important in preclinical vaccine development.

Owusu-Agyei S, Koram KA, Baird JK, Utz GC, Binka FN, Nkrumah FK, Fryauff DJ, Hoffman SL. 2001. Incidence of symptomatic and asymptomatic Plasmodium falciparum infection following curative therapy in adult residents of northern Ghana. Am J Trop Med Hyg, 65 (3), pp. 197-203. | Show Abstract | Read more

Adult residents of holoendemic malaria regions in Africa have a naturally acquired immunity (NAI) to malaria that renders them more resistant to new infections, limits parasitemia, and reduces the frequency and severity of illness. Given such attributes, it is not clear how one might evaluate drug or vaccine efficacy in adults without serious confounding. To determine symptomatic and asymptomatic malaria attack rates in adults of northern Ghana, 197 men and women underwent curative therapy for any pre-existing malaria infections at the start of the high transmission (wet) season. They were monitored for first parasitemia and first clinical episode of infection by Plasmodium falciparum over a 20-week period (May-October 1996). The cumulative incidence of primary infection by P. falciparum was 0.98 and incidence density of infection was calculated to be 7.0 cases/person-year. Symptoms were reported by 19.5% of the individuals at the time of first recurrent parasitemia. Incidence of infection, parasite density, and the frequency of symptoms were comparable in males and females. The results suggest that NAI did not provide these adults with significant defense against rapid re-infection and suggest that this population-infection design could serve to demonstrate the efficacy of a drug or vaccine in preventing parasitemia.

Maguire JD, Susanti AI, Krisin, Sismadi P, Fryauff DJ, Baird JK. 2001. The T76 mutation in the pfcrt gene of Plasmodium falciparum and clinical chloroquine resistance phenotypes in Papua, Indonesia. Ann Trop Med Parasitol, 95 (6), pp. 559-572. | Show Abstract | Read more

The T76 mutation in the pfcrt gene has been linked to chloroquine (CQ) resistance in Plasmodium falciparum. PCR-based analysis of pfcrt alleles was performed on pre-treatment samples from 107 individuals who had P. falciparum infections and lived in Papua, Indonesia. The results of a 28-day, in-vivo test revealed clinical resistance to CQ in 79 (74%) of the samples. The crude sensitivity of the pfcrt T76 assay for detecting the CQ-resistant infections in the samples was 96% and the crude specificity 52%. Discordance between pfcrt genotype and in-vivo phenotype was analysed either by genotyping of the merozoite surface protein-2 (to distinguish re-infection from recrudescence) or by amplification of the P. falciparum-specific small-subunit ribosomal RNA (ssrRNA) gene, using nested PCR (to detect any sub-patent but resistant parasites in infections misclassified as sensitive by the in-vivo test). When adjusting for the results of these analyses, the sensitivity and specificity of the pfcrt T76 assay for detecting the CQ-resistant infections became 93% and 82%, respectively. Overall, the present results indicate that the pfcrt T76 assay may be used to forecast therapeutic failure caused by CQ resistance. Validation requires exploration of the phenotype classifications based on the results of in-vivo tests, using genetic analyses that distinguish re-infection from recrudescence and detect microscopically subpatent parasitaemias.

McKenzie FE, Ferreira MU, Baird JK, Snounou G, Bossert WH. 2001. Meiotic recombination, cross-reactivity, and persistence in Plasmodium falciparum. Evolution, 55 (7), pp. 1299-1307. | Show Abstract | Read more

We incorporate a representation of Plasmodium falciparum recombination within a discrete-event model of malaria transmission. We simulate the introduction of a new parasite genotype into a human population in which another genotype has reached equilibrium prevalence and compare the emergence and persistence of the novel recombinant forms under differing cross-reactivity relationships between the genotypes. Cross-reactivity between the parental (initial and introduced) genotypes reduces the frequency of appearance of recombinants within three years of introduction from 100% to 14%, and delays their appearance by more than a year, on average. Cross-reactivity between parental and recombinant genotypes reduces the frequency of appearance to 36% and increases the probability of recombinant extinction following appearance from 0% to 83%. When a recombinant is cross-reactive with its parental types, its probability of extinction is influenced by cross-reactivity between the parental types in the opposite manner; that is, its probability of extinction after appearance decreases. Frequencies of P. falciparum outcrossing are mediated by frequencies of mixed-genotype infections in the host population, which are in turn mediated by the structure of cross-reactivity between parasite genotypes. The three leading hypotheses about how meiosis relates to oocyst production lead to quantitative, but no qualitative, differences in these results.

Nomura T, Carlton JM, Baird JK, del Portillo HA, Fryauff DJ, Rathore D, Fidock DA, Su X, Collins WE, McCutchan TF et al. 2001. Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria. J Infect Dis, 183 (11), pp. 1653-1661. | Show Abstract | Read more

Chloroquine (CQ)-resistant Plasmodium vivax malaria was first reported 12 years ago, nearly 30 years after the recognition of CQ-resistant P. falciparum. Loss of CQ efficacy now poses a severe problem for the prevention and treatment of both diseases. Mutations in a digestive vacuole protein encoded by a 13-exon gene, pfcrt, were shown recently to have a central role in the CQ resistance (CQR) of P. falciparum. Whether mutations in pfcrt orthologues of other Plasmodium species are involved in CQR remains an open question. This report describes pfcrt homologues from P. vivax, P. knowlesi, P. berghei, and Dictyostelium discoideum. Synteny between the P. falciparum and P. vivax genes is demonstrated. However, a survey of patient isolates and monkey-adapted lines has shown no association between in vivo CQR and codon mutations in the P. vivax gene. This is evidence that the molecular events underlying P. vivax CQR differ from those in P. falciparum.

Taylor WR, Doan HN, Nguyen DT, Tran TU, Fryauff DJ, Gómez-Saladín E, Kain KC, Le DC, Baird JK. 2000. Assessing drug sensitivity of Plasmodium vivax to halofantrine or choroquine in southern, central Vietnam using an extended 28-day in vivo test and polymerase chain reaction genotyping. Am J Trop Med Hyg, 62 (6), pp. 693-697. | Show Abstract | Read more

Chloroquine-resistant Plasmodium vivax malaria is emerging in Oceania, Asia, and Latin America. We assessed the drug sensitivity of P. vivax to chloroquine or halofantrine in two villages in southern, central Vietnam. This area has chloroquine-resistant Plasmodium falciparum but no documented chloroquine-resistant P. vivax. Standard dose chloroquine (25 mg/kg, over 48 hours) or halofantrine (8 mg/kg, 3 doses) was administered to 29 and 25 patients, respectively. End points were parasite sensitivity or resistance determined at 28 days. Of the evaluable patients, 23/23 100% (95% confidence interval [CI] 85.1-100) chloroquine and 21/24 (87.5%) (95% CI 67.6-97.3) halofantrine-treated patients were sensitive. Three halofantrine recipients had initial clearance but subsequent recurrence of their parasitemias. Genotyping of the recurrent and Day 0 parasitemias differed, suggesting either new infections or relapses of liver hypnozoites from antecedent infections. Among these Vietnamese patients, P. vivax was sensitive to chloroquine and halofantrine. Genotyping was useful for differentiating the recurrent vivax parasitemias.

Baird JK. 2000. Resurgent malaria at the millennium: control strategies in crisis. Drugs, 59 (4), pp. 719-743. | Show Abstract | Read more

Completion of the Panama Canal in 1914 marked the beginning of an era of vector control that achieved conspicuous success against malaria. In 1955 the World Health Organization (WHO) adopted the controversial Global Eradication Campaign emphasising DDT (dichlorodiphenyltrichloroethane) spraying in homes. The incidence of malaria fell sharply where the programme was implemented, but the strategy was not applied in holoendemic Africa. This, along with the failure to achieve eradication in larger tropical regions, contributed to disillusionment with the policy. The World Health Assembly abandoned the eradication strategy in 1969. A resurgence of malaria began at about that time and today reaches into areas where eradication or control had been achieved. A global malaria crisis looms. In 1993 the WHO adopted a Global Malaria Control Strategy that placed priority in control of disease rather than infection. This formalises a policy that emphasises diagnosis and treatment in a primary healthcare setting, while de-emphasising spraying of residual insecticides. The new policy explicitly stresses malaria in Africa, but expresses the intent to bring control programmes around the world into line with the strategy. This review raises the argument that a global control strategy conceived to address the extraordinary malaria situation in Africa may not be suitable elsewhere. The basis of argument lies in the accomplishments of the Global Eradication Campaign viewed in an historical and geographical context. Resurgent malaria accompanying declining vector control activities in Asia and the Americas suggests that the abandonment of residual spraying may be premature given the tools now at hand. The inadequacy of vector control as the primary instrument of malaria control in holoendemic Africa does not preclude its utility in Asia and the Americas.

Baird JK, Hoffman SL. 1999. Prevention of malaria in travelers. Med Clin North Am, 83 (4), pp. 923-vi. | Show Abstract

Malaria occurs throughout the tropics and represents a serious health threat to people exposed to risk of infection. Health care providers may be the only link between information for their traveling patients and that threat. The likelihood of infection can be reduced drastically by deliberate measures that minimize exposure to biting mosquitoes. However, personal protective measures alone rarely suffice where exposure to anopheline mosquitoes and infected human beings is appreciable.

Baird JK. 1998. Primaquine as anti-relapse therapy for Plasmodium vivax. Trans R Soc Trop Med Hyg, 92 (6), pp. 687. | Read more

Baird JK, Masbar S, Basri H, Tirtokusumo S, Subianto B, Hoffman SL. 1998. Age-dependent susceptibility to severe disease with primary exposure to Plasmodium falciparum. J Infect Dis, 178 (2), pp. 592-595. | Show Abstract | Read more

This study investigated the incidence of severe disease following primary exposure to Plasmodium falciparum by nonimmune children and adults in Irian Jaya, Indonesia. Four months after arrival, the cross-sectional prevalence of P. falciparum was 72%, and the monthly cumulative incidence of clinical diagnoses of malaria was 81%. Delirium or unconsciousness prompted evacuation to the hospital. Records of emergency evacuation of persons with a clinical diagnosis of malaria revealed an incidence density among adults (>15 years) of 1.34 events/person-year in the third month, whereas the rate in children remained stable at approximately 0.25 events/person-year (relative risk = 4.51, 95% confidence interval [CI] = 1.94-11). Through the first 6 months of exposure, 23.2% of adults were evacuated to the hospital with a diagnosis of malaria compared with 8.6% of children (relative risk = 2.7, 95% CI = 1.9-3.8). In this population with relatively few infants or people of advanced age, the risk of severe disease following primary exposure to P. falciparum increased with age.

Baird JK. 1998. Age-dependent characteristics of protection v. susceptibility to Plasmodium falciparum. Ann Trop Med Parasitol, 92 (4), pp. 367-390. | Show Abstract | Read more

Naturally acquired immunity to Plasmodium falciparum may be linked to key features of the immune system that change during normal development and ageing. Evidence of this was seen in non-immune Javanese transmigrants taking up residence in hyperendemic Irian Jaya, Indonesia. After 1-2 years of residence, the adult migrants had less frequent and less intense parasitaemias than their children. Splenomegaly and malaria-like symptoms were also less common in the adults. These age-dependent patterns of relative resistance to P. falciparum mirrored those in lifelong residents. The Javanese adults acquired protective immunity against chronic exposure to infection relatively quickly compared with their children. However, during the initial exposure to infection, the incidence of emergency medical evacuation to hospital with a clinical diagnosis of malaria was 7-fold higher among the adults than in their children. The exaggerated susceptibility of adults to severe morbidity and mortality has been reported in other populations during initial exposure to infection. Thus, whereas adults acquired protection against chronic exposure more rapidly than the children, they were initially more susceptible to severe disease. One possible explanation for these findings is the changes in the immune system that normally occur during ageing. Such changes may establish differences between children and adults that profoundly affect the course of infection by P. falciparum. The ratio of naive to memory T cells gradually diminishes during ageing, as a result of the cumulative effect of exposure to the myriad antigens encountered throughout the normal course of life. Moreover, the gradual involution of the thymus progressively limits the production of naive T cells. The likelihood of stimulating memory T cells with cross-reactive antigens may increase with age and this may bias the immune response to the relative benefits of the host under chronic exposure, or to the detriment of the host under acute exposure. Intrinsic features of the immune system that change with age may determine key characteristics of the immune response to infection by P. falciparum, and whether that response is relatively harmful or beneficial may depend upon the conditions of exposure (i.e. acute or chronic).

Fryauff DJ, Soekartono, Tuti S, Leksana B, Suradi, Tandayu S, Baird JK. 1998. Survey of resistance in vivo to chloroquine of Plasmodium falciparum and P. vivax in North Sulawesi, Indonesia. Trans R Soc Trop Med Hyg, 92 (1), pp. 82-83. | Read more

Baird JK, Hoffman SL. 1997. Iron supplementation in prevention of severe anaemia and malaria. Lancet, 350 (9094), pp. 1855. | Read more

Baird JK, Leksana B, Masbar S, Suradi, Sutanihardja MA, Fryauff DJ, Subianto B. 1997. Whole blood chloroquine concentrations with Plasmodium vivax infection in Irian Jaya, Indonesia. Am J Trop Med Hyg, 56 (6), pp. 618-620. | Show Abstract | Read more

Whole blood concentrations of self-administered chloroquine (CQ) and its metabolite desethylchloroquine (DCQ) were measured in 168 patients with microscopically confirmed infection by Plasmodium vivax in northeastern Irian Jaya, Indonesia. The study consisted of both survey and passive case detection in four separate villages between 1992 and 1994. The subjects were Javanese people 4-51 years old who had lived in the Arso region for up to two years. The sum of CQ and DCQ ranged from 0 to 8,342 ng/ml of whole blood, and 122 subjects (73%) had > or = 100 ng/ml of CQ plus DCQ, the estimated minimally effective concentration (MEC) in whole blood against chloroquine-sensitive P. vivax. Among 56 subjects reporting to a clinic with symptoms of malaria, 53 (95%) had ordinarily effective levels of chloroquine in blood. Among 109 largely asymptomatic malaria patients found by survey case detection, 69 (63%) had chloroquine blood levels greater than the MEC. Virtually all clinical and most subclinical vivax malaria in this region occurs despite ordinarily effective levels of chloroquine in blood.

Baird JK, Wiady I, Fryauff DJ, Sutanihardja MA, Leksana B, Widjaya H, Kysdarmanto, Subianto B. 1997. In vivo resistance to chloroquine by Plasmodium vivax and Plasmodium falciparum at Nabire, Irian Jaya, Indonesia. Am J Trop Med Hyg, 56 (6), pp. 627-631. | Show Abstract | Read more

A survey of resistance to chloroquine by Plasmodium vivax and P. falciparum was conducted during May 1995 at three mesoendemic villages 30 km southeast of Nabire, near the central northern coast of Irian Jaya, Indonesia. The prevalence of malaria at Urusumu (n = 157), Margajaya (n = 573), and Topo (n = 199) was 18%. 9%, and 9%, respectively, with spleen rates among children of 79%, 10%, and 27%. Infected patients among those screened formed a study population of 64 subjects eligible for a 28-day in vivo test of resistance to chloroquine. Sixty-three patients successfully completed the test; 45 males and 18 females 1-60 years of age, of whom 29 were Javanese transmigrants of five years residence in Irian Jaya and 34 were native to Irian Jaya. The seven-day day cumulative incidence of therapeutic failure for P. vivax and P. falciparum was 15% (n = 34) and 30% (n = 37). The 14- and 28-day estimates of cumulative incidence were 45% and 64% for P. vivax and 58% and 89% for P. falciparum. Almost all recurrences appeared in the face of ordinarily effective levels of chloroquine and its major metabolite, desethylchloroquine, in whole blood (> or = 100 ng/ml). Four infections by P. malariae in subjects enrolled in this study cleared by day 2 and none reappeared within 28 days. Chloroquine no longer provides effective therapy for falciparum or vivax malaria along the northern coast of Irian Jaya, Indonesia.

Baird JK, Leksana B, Masbar S, Fryauff DJ, Sutanihardja MA, Suradi, Wignall FS, Hoffman SL. 1997. Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels. Am J Trop Med Hyg, 56 (6), pp. 621-626. | Show Abstract | Read more

To develop criteria for the diagnosis of resistance to chloroquine using an in vivo test, we examined published records of early clinical trials of quinine and chloroquine against Plasmodium vivax. These data established the timing of relapse by tropical P. vivax relative to therapy by these drugs. The first relapse occurred 17 days after initiating and three days after terminating quinine therapy. The median day of relapse was day 23, and 59% of the patients had relapsed by day 30 (n = 333). In contrast, no relapse occurred until day 36 following chloroquine treatment (n = 256). Data from our laboratory may help explain this difference; among 91 Indonesian patients with malaria, the mean whole blood levels of chloroquine (CQ) and desethylchloroquine (DCQ) were 141 ng/ml (95% confidence interval = 115-167) on day 28 after initiating standard therapy (25 mg base/kg in three doses over a 48-hr period). This exceeds the estimated minimal effective concentration of chloroquine (100 ng/ml of whole blood). Thus, chloroquine lingering in the blood for at least 28 days after starting standard therapy was sufficient to eliminate or at least suppress chloroquine-sensitive tropical P. vivax. We conclude that a parasitemia by P. vivax recurring in the 28 days after full compliance to standard chloroquine therapy demonstrates resistance. If the recurrence appears before day 16, it is almost certainly a recrudescence and between days 17 and 28 it may be either a recrudescence or a relapse by chloroquine-resistant parasites. Recurrences beyond day 28 could be relapse by chloroquine-sensitive P. vivax.

Reeder JC, Davern KM, Baird JK, Rogerson SJ, Brown GV. 1997. The age-specific prevalence of Plasmodium falciparum in migrants to Irian Jaya is not attributable to agglutinating antibody repertoire. Acta Trop, 65 (3), pp. 163-173. | Show Abstract | Read more

Previous observations have shown that individuals migrating from a malaria free area to a malaria endemic region in North Eastern Irian Jaya quickly acquire anti-parasite immunity, in an age-dependent manner. Sera from migrants and long-term residents in this area were examined for their ability to agglutinate a range of Plasmodium falciparum isolates and to disrupt erythrocyte rosettes. Antibody responses to merozoite surface protein 2 (MSP2) and ring-infected erythrocyte surface antigen (RESA) were also determined. The range of isolates agglutinated by sera from the migrants approached that seen in long-term residents. No difference was found between migrant adults and children in the range of agglutinating antibody, size of agglutinates, nor disruption of rosettes. Anti-MSP2 and anti-RESA antibodies were the only factors examined which showed a correlation with age. We conclude that although antibody to parasite neoantigens expressed on the surface of infected erythrocytes may play a role in the acquisition of immunity, the humoral response to other P. falciparum antigens is more likely to account for the age-dependent prevalence of parasitaemia observed.

Fryauff DJ, Baird JK, Candradikusuma D, Masbar S, Sutamihardja MA, Leksana B, Tuti S, Marwoto H, Richie T, Romzan A. 1997. Survey of in vivo sensitivity to chloroquine by Plasmodium falciparum and P. vivax in Lombok, Indonesia. Am J Trop Med Hyg, 56 (2), pp. 241-244. | Show Abstract | Read more

A malariometric survey was conducted in 14 villages of Sekotong district, in Lombok, Indonesia during October 1994. Point prevalence of malaria ranged from 0% to 15% in the surveyed villages, averaging 6% overall, and Plasmodium falciparum accounted for 63% of the infections. Forty-nine patients with uncomplicated malaria and parasite counts ranging from 40 to 10,800 asexual forms/microliter were enrolled in a 28-day in vivo test of chloroquine sensitivity. All subjects received a supervised therapeutic regimen of chloroquine (25 mg base/kg over a 48-hr period) and parasitemia and symptoms were closely monitored for 28 days. Asexual parasites were eliminated within four days in the 29 P. falciparum and 20 P. vivax study patients enrolled. The cumulative incidence of therapeutic failure (recurrent symptomatic parasitemia) among P. falciparum cases at days 7, 14, and 28 was 7%, 10%, and 14% (4 of 29), respectively. However in all four cases, parasitemias recurred against chloroquine blood levels below the minimally effective concentration (MEC) of 200 ng/ml and do not confirm chloroquine resistance. All 20 P. vivax parasitemias were sensitive to chloroquine and the blood remained clear, with the exception of one case in which an asymptomatic parasitemia appeared on day 28. Parasitemias by P. falciparum and P. vivax that were observed before supervised therapy, but in the presence of whole blood chloroquine above normally suppressive MEC levels, suggest resistance to suppressive or prophylactic regimens of chloroquine.

Fryauff DJ, Baird JK, Purnomo, Awalludin M, Jones T, Subianto B, Richie TL, Tjitra E, Wignall FS, Hoffman SL. 1997. Malaria in a nonimmune population after extended chloroquine or primaquine prophylaxis. Am J Trop Med Hyg, 56 (2), pp. 137-140. | Show Abstract | Read more

Extended chemoprophylaxis against endemic malaria raises concern with regard to susceptibility after ceasing use of the drug. In this study, we measured attack rates of malaria among adult men for 28 weeks after they ended one year of prophylaxis using either weekly chloroquine (5 mg base/kg, n = 20), daily primaquine (0.5 mg base/kg, n = 30), or a placebo of primaquine (n = 41). The 28-week incidence densities, times to parasitemia, parasite densities, and symptoms of primary post-prophylaxis infections were not significantly different among the former primaquine, chloroquine, and placebo groups. However, the incidence of Plasmodium falciparum infection in the post-chloroquine group was significantly greater than in the post-primaquine group during the first (P = 0.03) and second (P = 0.02) months post-prophylaxis. Six of 10 primary P. falciparum and three of 10 P. vivax infections occurred in the former chloroquine group within one month after ending prophylaxis and the mean time to infection was 30-35 days. In contrast, only one P. falciparum and no P. vivax infections occurred during the first month after ending primaquine prophylaxis. The mean time to first parasitemia by either species of malaria parasite in this group was 72-77 days. There was no indication that daily use of primaquine for one year placed subjects at greater risk of malaria infection or to more severe clinical symptoms of malaria than subjects who had taken placebo or chloroquine, despite the potential for some degree of immunity to have been acquired in these latter two groups during the year-long prophylaxis period. The results do suggest that chloroquine suppressed P.falciparum infections until drug levels decreased, and that primaquine had effectively prevented the establishment of liver-stage parasites.

Fryauff DJ, Baird JK, Basri H, Wiady I, Purnomo, Bangs MJ, Subianto B, Harjosuwarno S, Tjitra E, Richie TL, Hoffman SL. 1997. Halofantrine and primaquine for radical cure of malaria in Irian Jaya, Indonesia. Ann Trop Med Parasitol, 91 (1), pp. 7-16. | Show Abstract | Read more

The combination of halofantrine and primaquine therapies was calculated as a regimen for achieving radical curve of falciparum or vivax malaria in Irian Jaya, Indonesia, and compared with combined chloroquine and primaquine therapies. The patients who volunteered for the study [adult, male, Indonesian immigrants with no previous exposure to endemic malaria, normal glucose-6-phosphate dehydrogenase (G6PD) activity, uncomplicated malaria illness, no prior use of antimalarials, and parasitaemias of 0.001%-1.1%] were randomized to receive either halofantrine (24 mg base/kg bodyweight, in three equal doses over 12 h) or chloroquine (25 mg base/kg bodyweight over 48 h, in doses of 10, 10 and 5 mg base/kg at 24-h intervals). Each patient also received concurrent daily primaquine (0.5 mg base/kg bodyweight) for 14 days followed by the same dose on alternate days to day 28. A recurrent parasitaemia during the 28 days of follow-up constituted drug failure. Of the 40 cases of falciparum malaria and 26 cases of vivax malaria treated with halofantrine-primaquine, none had a recurrent parasitaemia (100% efficacy). In contrast, 20 of 30 patients with falciparum malaria and three of 27 with vivax malaria had recurrent parasitaemias after chloroquine-primaquine, giving efficacies of 33% and 89%, respectively. Halofantrine-primaquine was significantly more effective than chloroquine-primaquine against falciparum malaria (P < 0.001) but was similarly efficacious against vivax malaria (P = 0.23). On average, fever associated with falciparum or vivax malaria cleared 17 h faster with halofantrine-primaquine (P < 0.01) although there were no significant differences (P > 0.4) in parasite-clearance times between the two regimens. The halofantrine-primaquine regimen was also associated with a more rapid and significant decline in malaria-related physical complaints.

Fryauff DJ, Richards AL, Baird JK, Richie TL, Mouzin E, Tjitra E, Sutamihardja MA, Ratiwayanto S, Hadiputranto H, Larasati RP et al. 1996. Lymphocyte proliferative response and subset profiles during extended periods of chloroquine or primaquine prophylaxis. Antimicrob Agents Chemother, 40 (12), pp. 2737-2742. | Show Abstract

Immune suppression and disturbances of normal leukocyte populations are side effects attributed to many antimalarial drugs and were concerns during a recent year-long placebo-controlled trial that compared daily primaquine (0.5 mg of base per kg of body weight per day) with weekly chloroquine (300 mg of base one time per week) for malaria prophylaxis. The study took place in Irian Jaya, Indonesia, from July 1994 to August 1995 and enrolled 129 Javanese men with normal glucose-6-phosphate dehydrogenase function. Tests for lymphocyte function and subset composition were conducted blindly on a cross-section of subjects during weeks 10 (n = 42) and 48 (n = 72) of supervised prophylaxis. Lymphocyte function, measured as the proliferative response of peripheral blood mononuclear cells to a panel of mitogens (pokeweed mitogen, phytohemagglutinin, and concanavalin A) and antigens (purified protein derivative of Mycobacterium tuberculosis and Clostridium tetani toxoid) and expressed as a stimulation index, allowed for statistical comparison between groups and sampling times. The lymphocyte subset composition for each group and time point was based on flow cytometry profiling, and the results were expressed as the mean percentages of CD3 (total T cells), CD19 (total B cells), CD4+ (T-helper and inducer cells), and CD8+ (T suppressor and cytotoxic cells), CD3/CD16+ CD56 (natural killer cells), CD3/anti-HLA-DR (activated T cells) cells and the CD4+/CD8+ ratios. Lymphocyte stimulation indices were statistically comparable among the placebo, primaquine, and chloroquine groups at both time points, although the primaquine group was distinguished by having repeatedly greater proportions of subjects with high ( > 3.0) stimulation indices. The lymphocyte subset profiles of these groups at both time points were also similar and undistorted relative to those of healthy reference populations matched for age, sex, and ethnicity. The results provide quantitative support for the safety of daily primaquine prophylaxis.

Baird JK, Hoffman SL. 1996. Progress in prevention and treatment of malaria CURRENT OPINION IN INFECTIOUS DISEASES, 9 (5), pp. 319-329. | Read more

Baird JK, Caneta-Miguel E, Masbar S, Bustos DG, Abrenica JA, Layawen AV, Calulut JM, Leksana B, Wignall FS. 1996. Survey of resistance to chloroquine of falciparum and vivax malaria in Palawan, The Philippines. Trans R Soc Trop Med Hyg, 90 (4), pp. 413-414. | Read more

Baird JK, Sustriayu Nalim MF, Basri H, Masbar S, Leksana B, Tjitra E, Dewi RM, Khairani M, Wignall FS. 1996. Survey of resistance to chloroquine by Plasmodium vivax in Indonesia. Trans R Soc Trop Med Hyg, 90 (4), pp. 409-411. | Show Abstract | Read more

In February 1995 we surveyed to chloroquine among patients with Plasmodium vivax malaria at Nias Island, in the Indian Ocean near north-western Sumatra, Indonesa. The subjects, 21 indigenous males and females (6-50 years old) infected with > 40 asexual blood stage parasites of P. vivax per microliter of blood, had mild symptoms or none at all. Seven of these patients had > 100 ng/mL whole blood chloroquine levels before the first supervised dose of chloroquine (3 doses of 10 mg/kg, 10 mg/kg, 5 mg/kg of base given at 24 h intervals). Whole blood chloroquine levels on the last day of dosing confirmed normal absorption (range 413-3248, mean 1141, SD 616 ng/mL). Blood films were examined on days 0, 2, 4, 7, 11, 14, 18, 21 and 28 after initiating therapy. Three patients had recurrent asexual P. vivax parasitaemias between days 14 and 18, despite effective levels of chloroquine in whole blood (> or = 100 ng/mL) at the time of recurrence. Resistance to standard chloroquine therapy by P. vivax appeared in 14% of infections among residents of Nias.

Baird JK, Sismadi P, Masbar S, Leksana B, Sekartuti, Ramzan A, Tjitra E. 1996. Chloroquine sensitive Plasmodium falciparum and P. vivax in central Java, Indonesia. Trans R Soc Trop Med Hyg, 90 (4), pp. 412-413. | Read more

Baird JK, Sismadi P, Masbar S, Ramzan A, Purnomo BW, Sekartuti, Tjitra E, Rumoko BW, Arbani PR. 1996. A focus of endemic malaria in central Java. Am J Trop Med Hyg, 54 (1), pp. 98-104. | Show Abstract | Read more

This report describes one of the few remaining foci of endemic malaria on the island of Java, the Kokap subdistrict, near the Southcentral coast. Kokap was hypoendemic in June 1994 with prevalence of parasitemia at 0.98% (n = 10,606 of 40,246 residents). Plasmodium vivax comprised 63% of infections and P. falciparum all others. The incidence of indigenous infection during 1993 was 48 cases/1,000 person-years (p-yr), and it was relatively uniform among age groups (38 to 53/1,000 p-yr). Nine deaths due to malaria had been recorded in the past three years (8.3 deaths per 100,000 p-yr); the case fatality rate was 0.17%. Subdistricts adjoining Kokap to the north, east, and south reported incidence rates of < 2 cases/1,000 p-yr. To the west, Purworejo District had a high case incidence (11 cases/1,000 p-yr) but other districts to the west did not (< 1.2 cases/1,000 p-yr). The highest case incidence village area within Kokap (169 cases/1,000 p-yr) bordered the district of Purworejo to the west. Endemic malaria in Kokap and Purworejo coincided with where steep hills and narrow valleys dominated the terrain.

Fryauff DJ, Baird JK, Basri H, Sumawinata I, Purnomo, Richie TL, Ohrt CK, Mouzin E, Church CJ, Richards AL. 1995. Randomised placebo-controlled trial of primaquine for prophylaxis of falciparum and vivax malaria. Lancet, 346 (8984), pp. 1190-1193. | Show Abstract | Read more

Drug resistance has made malaria prevention difficult and the new agents are too expensive for widespread use. Primaquine, an established drug for treatment, is potentially useful for prevention. Malaria prophylaxis with primaquine was evaluated in Irian Jaya during one year in Javanese men who were not deficient in glucose-6-phosphate dehydrogenase (G-6-PD). 126 volunteers were randomised to receive 0.5 mg/kg primaquine base or placebo daily (double-blinded), or 300 mg chloroquine base weekly (open). The protective efficacy of primaquine relative to placebo was 94.5% (95% confidence interval 57-99) for Plasmodium falciparum and 90.4% (95% CI 58-98) for P vivax. Attack rates for either parasite did not differ significantly between the chloroquine and placebo groups. Incidence density of physical complaints not associated with parasitaemia was low (17-18 complaints/person-year) and was about the same in all groups except for cough, which was increased in the primaquine group. Complete blood counts were normal and no evidence of hepatic or renal dysfunction was found with primaquine. However, at 50 weeks the primaquine group had a mean methaemoglobin of 5.8% (range 1.4-13%), which declined by half within 7 days of ending prophylaxis. When used daily for one year by men with normal G-6-PD activity, primaquine was well tolerated and effective for prevention of malaria.

Baird JK, Basri H, Subianto B, Fryauff DJ, McElroy PD, Leksana B, Richie TL, Masbar S, Wignall FS, Hoffman SL. 1995. Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine. J Infect Dis, 171 (6), pp. 1678-1682. | Show Abstract | Read more

Optimal therapy for infection by chloroquine-resistant Plasmodium vivax has not been established. From 1992 to 1994 during three separate studies, 147 Javanese residents of Irian Jaya infected by P. vivax were treated with either chloroquine (25 mg of base/kg during 3 days or 10 mg of base/kg in one dose) plus primaquine (10 mg/kg during 28 days or 2.5 mg/kg during 3 days) (n = 78), chloroquine plus placebo (n = 50), or halofantrine (24 mg base/kg in 12 h; n = 19). There was no difference in tolerance to or side effects of any of the regimens. Within 14 days of starting therapy, therapeutic failure among these patients was 44% for chloroquine, 5% for chloroquine plus primaquine (P < .001), and 0 for halofantrine (P < .001). After 28 days, therapeutic failure was 78%, 15%, and 6%, respectively. Thus, chloroquine plus primaquine in combination and halofantrine alone are effective therapies for chloroquine-resistant P. vivax.

Baird JK, Fryauff DJ, Basri H, Bangs MJ, Subianto B, Wiady I, Purnomo, Leksana B, Masbar S, Richie TL. 1995. Primaquine for prophylaxis against malaria among nonimmune transmigrants in Irian Jaya, Indonesia. Am J Trop Med Hyg, 52 (6), pp. 479-484. | Show Abstract | Read more

A comparison of primaquine versus chloroquine for prophylaxis among nonimmune transmigrants from Java and Bali in the hyperendemic Arso region of Irian Jaya, Indonesia was conducted. Forty-five subjects received 0.5 mg of primaquine base/kg of body weight every other day, and 54 people in the same village received weekly 5 mg of chloroquine base/kg for 16-19 weeks beginning in December 1992. Plasmodium falciparum accounted for 18 of 30 infections with chloroquine, and four of five infections among subjects receiving primaquine. Plasmodium vivax was found in 12 people taking chloroquine but in just one person taking primaquine. The risk of malaria among people taking chloroquine relative to that among subjects taking primaquine was 3.96 (P = 0.014) for P. falciparum and 10.56 (P = 0.012) for P. vivax. Primaquine was better tolerated than chloroquine. The minimal protective efficacy for primaquine prophylaxis was 74% against P. falciparum and 90% against P. vivax among nonimmune children and adults living in Irian Jaya. These findings require confirmation with randomized, double-blinded, and placebo-controlled trials.

Baird JK. 1995. Host age as a determinant of naturally acquired immunity to Plasmodium falciparum. Parasitol Today, 11 (3), pp. 105-111. | Show Abstract | Read more

The usual course of infection by Plasmodium falciparum among adults who lack a history of exposure to endemic malaria is fulminant. The infection in adults living with hyper- to holoendemic malaria is chronic and benign. Naturally acquired immunity to falciparum malaria is the basis of this difference. Confusion surrounds an essential question regarding this process: What is its rate of onset? Opinions vary because of disagreement over the relationships between exposure to infection, antigenic polymorphism and naturally acquired immunity. In this review, Kevin Baird discusses these relationships against a backdrop of host age as a determinant of naturally acquired immunity to falciparum malaria.

Baird JK. 1994. Age and 'strain-transcending' immunity to Plasmodium falciparum. Parasitol Today, 10 (8), pp. 302. | Read more

Jones TR, Baird JK, Bangs MJ, Annis BA, Purnomo, Basri H, Gunawan S, Harjosuwarno S, McElroy PD, Hoffman SL. 1994. Malaria vaccine study site in Irian Jaya, Indonesia: Plasmodium falciparum incidence measurements and epidemiologic considerations in sample size estimation. Am J Trop Med Hyg, 50 (2), pp. 210-218. | Show Abstract | Read more

Malaria epidemiologic and entomologic studies were performed during both the high transmission and low transmission seasons to characterize the Plasmodium falciparum malaria transmission at a proposed malaria vaccine trial site in Irian Jaya, Indonesia. The study population consisted of two subsets: native Irianese men with lifelong exposure to malaria and transmigrants who arrived from a nonmalarious area 2.5 years before the start of the study. All subjects received a radical cure for malaria and were then monitored weekly by blood film. Both P. falciparum malaria attack rates and incidence densities were calculated; transmigrants had a significantly higher rate (P = 0.003) than the Irianese during the low transmission season study (20-weeks long) but not during the high transmission season study (12-weeks long). Lack of exposure-induced immunity left the transmigrants at a minimum 17-25% greater relative risk of becoming parasitemic compared with the Irianese during the low transmission season study. During the high transmission season study, 50% of the transmigrants were P. falciparum positive by week 6 and 50% of the Irianese by week 9. During the low transmission season, 50% of the transmigrants were positive by week 10 and 43% of the Irianese were positive by week 17. Entomologic studies showed that Anopheles koliensis was the predominant vector (> 98% of anopheline catch). Entomologic inoculation rates for P. falciparum were 0.018 and 0.39 infective bites/person/night for the low and high transmission seasons, respectively. New P. vivax cases represented between 16% and 42% of all initial malaria cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Baird JK, Purnomo, Basri H, Bangs MJ, Andersen EM, Jones TR, Masbar S, Harjosuwarno S, Subianto B, Arbani PR. 1993. Age-specific prevalence of Plasmodium falciparum among six populations with limited histories of exposure to endemic malaria. Am J Trop Med Hyg, 49 (6), pp. 707-719. | Show Abstract | Read more

The age-specific prevalence of Plasmodium falciparum parasitemia among residents of six villages in northeastern Irian Jaya, Indonesia, has been measured for a period of five years. All study subjects were transmigrants from Java living in Irian Jaya for three weeks to 72 months, depending upon the village and point of measurement. Fifteen separate estimates of prevalence were obtained from 4,554 Giemsa-stained thick blood films from 91 to 701 people (mean sample size = 304) among the six villages. The prevalence of parasitemia among people who had lived in Irian Jaya for less than one year did not decrease as a function of age, except in one village at eight months. In contrast, after 16 months to two years or more of residence, the prevalence of parasitemia decreased markedly with increasing age beyond 6-10 or 11-15 years. Social, behavioral, or entomologic characteristics of these populations did not explain the decreasing prevalence of parasitemia with age. An age-dependent naturally acquired protective immunity appeared to develop in all of these villages after 1-2 years of exposure to hyperendemic malaria.

Ware LA, Kain KC, Lee Sim BK, Haynes JD, Baird JK, Lanar DE. 1993. Two alleles of the 175-kilodalton Plasmodium falciparum erythrocyte binding antigen. Mol Biochem Parasitol, 60 (1), pp. 105-109. | Show Abstract | Read more

EBA-175, erythrocyte binding antigen 175, is a 175-kDa antigen of Plasmodium falciparum which has been shown to be involved in the recognition of erythrocytes by merozoites and may be involved in the process of erythrocyte invasion. Invasion of erythrocytes by Camp strain merozoites is inhibited by pre-treatment of red blood cells by EBA-175 from the heterologous strain, FCR-3. The sequence of the Camp strain has been published and we report here the sequence of the FCR-3 strain. The sequences are nearly identical except for a 423-bp segment in the FCR-3 strain, F-segment, that is not found in the Camp strain and a 342-bp segment, C-segment, present in the Camp strain but not in the FCR-3 strain. The locations of these two segments are different in Camp and FCR-3 EBA-175 genes and there is little DNA or amino acid sequence homology between them. The essentially dimorphic alleles, F-segment and C-segment, are conserved in all isolates examined to date. Evidence of genetic cross-over between the FCR-3 and the Camp EBA-175 genes was not observed in the analysis of a limited number of wild isolates. The continued study of the biological relevance of these sequence divergences in EBA-175 may further elucidate the sequence of events resulting in merozoite invasion of erythrocytes.

Baird JK, Jones TR, Bangs MJ, Richie TL, Hoffman SL. 1993. Malaria field studies at NAMRU-2, Indonesia. Navy Med, 84 (2), pp. 14-20.

Baird JK, Purnomo, Jones TR. 1992. Diagnosis of malaria in the field by fluorescence microscopy of QBC capillary tubes. Trans R Soc Trop Med Hyg, 86 (1), pp. 3-5. | Show Abstract | Read more

The diagnostic performance of commercial capillary tubes containing acridine orange dye (QBC) was compared with the standard diagnosis of malaria by microscopical examination of Giemsa-stained thick blood films (GTS) in remote field conditions. The comparison was conducted among 165 volunteers living in northeastern Irian Jaya, Indonesia, an area having hyperendemic malaria transmission. By GTS, 65 volunteers were positive for malaria, but only 49 were judged positive by QBC. Among the 100 blood films found negative by GTS, 5 were considered positive by QBC. Thus, relative to a GTS standard, the sensitivity and specificity of the QBC was 75% and 95%, respectively. The mean limit of detection for the QBC was approximately 60 parasites per microliter blood, whereas the limit of detection for GTS was 20 parasites per microliter blood. Also, a number of practical difficulties were encountered using the QBC at the field site. The QBC approach to diagnosis of malaria was less sensitive and more inconvenient than GTS under the conditions in remote Irian Jaya.

Baird JK, Jones TR, Danudirgo EW, Annis BA, Bangs MJ, Basri H, Purnomo, Masbar S. 1991. Age-dependent acquired protection against Plasmodium falciparum in people having two years exposure to hyperendemic malaria. Am J Trop Med Hyg, 45 (1), pp. 65-76. | Show Abstract | Read more

An epidemiologic study of susceptibility to frequent and high-grade parasitemia by Plasmodium falciparum revealed that age-dependent acquired protection developed within a two-year period of exposure to hyperendemic infection pressure. The study was conducted in a single village in northeastern Irian Jaya, Indonesia, where half the residents were native to the province and the other half were transmigrants from areas of Java, where there is little or no malaria transmission. Five separate measures of susceptibility to the asexual parasitemia of falciparum malaria were derived from results of four months of biweekly surveillance of 240 volunteers. Increasing protection as a function of age among the Javanese was a consistent pattern among the five estimates of susceptibility. These age-dependent functions of protection were quantitatively parallel to those among life-long residents of Irian Jaya. When humoral immune responsiveness to ring-infected erythrocyte surface antigen (RESA) was measured by ELISA, a similar pattern emerged; the relative level of antibody to RESA increased as parallel functions of age among the two subpopulations. Acquired protective immunity against P. falciparum was not the cumulative product of many years of heavy exposure to antigen. Instead, the full benefit of protection appeared to develop quickly. The degree of protection was governed by recent exposure and age, independent of history of chronic heavy exposure.

Baird JK, Basri H, Jones TR, Purnomo, Bangs MJ, Ritonga A. 1991. Resistance to antimalarials by Plasmodium falciparum in Arso PIR, Irian Jaya, Indonesia. Am J Trop Med Hyg, 44 (6), pp. 640-644. | Show Abstract | Read more

Between 1987 and 1990, susceptibility of Plasmodium falciparum to chloroquine and to Fansidar was measured in vivo in 151 volunteers using the standard 7-day test. All volunteers lived in Arso PIR, Irian Jaya. A 25 mg/kg dose of chloroquine base was administered over a three-day period to 92 volunteers positive for P. falciparum rings (greater than 10 rings/200 white blood cells). Fifty volunteers (54%) showed results consistent with resistance. Twenty-nine were classified RII, and 21 RIII. In November 1989, a single curative dose of Fansidar was administered to 59 volunteers divided among three groups with 18 months, four years, and life-long exposure to endemic malaria. The proportion of volunteers in each group still positive for P. falciparum on day 7 of followup was 54%, 0%, and 14%, respectively. Thus, immune status profoundly effected clinically response to Fansidar. Standard in vitro microtests were also performed on parasites from 11 volunteers against chloroquine, amodiaquine, quinine, pyrimethamine/sulfadoxine, and and mefloquine. Nine of ten isolates showed in vitro growth consistent with resistance to chloroquine. Tests with other drugs showed few isolates with results considered indicative of susceptibility. Arso PIR has a severe drug resistance problem.

Baird JK, Basri H, Purnomo, Bangs MJ, Subianto B, Patchen LC, Hoffman SL. 1991. Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia. Am J Trop Med Hyg, 44 (5), pp. 547-552. | Show Abstract | Read more

Evidence of emerging resistance to chloroquine by Plasmodium vivax is described from Irian Jaya (Indonesian New Guinea). Sixteen of 24 residents in the village of Arso PIR II taking supervised weekly chloroquine prophylaxis (5 mg base/kg) had asexual parasitemia with P. vivax at least once during eight weeks of surveillance. An American working in the same village developed symptomatic P. vivax parasitemia despite chloroquine prophylaxis. Five days after therapy with 600 mg chloroquine base, the asexual parasitemia in the American increased 40-fold, but cleared after treatment with 1,500 mg chloroquine base. Serum samples were not available from many of the cases, but six local residents and the American had serum levels of chloroquine in excess of the ordinarily suppressive 15 ng/ml at the time of their asexual parasitemias (16-70 ng/ml). The weekly 300 mg base tablet of chloroquine, which has been the standard for prophylaxis against malaria for more than 40 years, was not effective against P. vivax in Arso PIR, Irian Jaya.

Baird JK, Jones TR, Purnomo, Masbar S, Ratiwayanto S, Leksana B. 1991. Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya. Am J Trop Med Hyg, 44 (2), pp. 183-190. | Show Abstract | Read more

An epidemiologic study of hyperendemic malaria in Arso PIR, a village in northeastern Irian Jaya (Indonesian New Guinea), revealed evidence suggesting suppression of gametocytemia independent of immune control of the asexual parasitemia. A total of 240 people, representing ages between 2 and 60 years, were followed by biweekly blood film examination for 16 weeks beginning in November 1987. Two distinct subpopulations were represented--1) life-long residents of Irian Jaya, and 2) transmigrants from Java who arrived in Irian Jaya 20 months before the surveillance effort began. Twenty-five percent of blood films from natives and 31% from Javanese were positive for falciparum malaria; of these, the rate of gametocytemia was 21% for natives, and 42% for the Javanese transmigrants (P less than 0.001). This difference could not be explained by differences in the frequency or grade of parasitemia, illness, or by known patterns of antimalarial consumption. Similarly, in Wor, a village near Arso PIR, the gametocyte rate for P. falciparum diminished from 83% to 25% in transmigrants from Java between their eleventh and twenty-fifth month of residence in Irian Jaya, a period during which the falciparum malaria rate remained stable between 30% and 50%. An immunofluorescent antibody test using whole, acetone-fixed gametocytes as substrate revealed correlation between antibody titer and protection from gametocytemia among the semi-immune natives of Arso PIR, but not among the Javanese. Specific immune suppression of gametocytes, independent of immune control of asexual parasites, can explain all of these observations.

Baird JK, Riberu W, Masbar S, Purnomo. 1991. Ivermectin inhibits molting of Wuchereria bancrofti third stage larvae in vitro. J Parasitol, 77 (1), pp. 162-163. | Show Abstract | Read more

The effect of ivermectin or diethylcarbamazine (DEC) on Wuchereria bancrofti molting from the third to the fourth larval stage (L3 to L4) was evaluated in vitro. L3 larvae were harvested from laboratory-reared Aedes togoi 2 wk after feeding upon a microfilaremic human volunteer. The larvae were kept in an artificial medium (Franke's NI medium) with 10% human serum under an atmosphere of 5% CO2 for 20 days. Experimental tubes also contained ivermectin (0.1-1,000 ng/ml) or DEC (0.1-10,000 ng/ml). An estimated concentration of 50 ng/ml ivermectin inhibited molting in 50% of the larvae expected to molt. For DEC, this value was roughly 1,000 ng/ml. In this in vitro culture system, ivermectin inhibited the L3 to L4 molt of W. bancrofti and was roughly 20-fold more potent in this activity than DEC.

Jones TR, Baird JK, Basri H, Purnomo, Danudirgo EW. 1991. Prevalence of malaria in native and transmigrant populations. Effects of age and history of exposure. Trop Geogr Med, 43 (1-2), pp. 1-6. | Show Abstract

A malaria prevalence study was performed in a village in Irian Jaya, Indonesia, that contains a population of people who have been exposed lifelong to hyperendemic malaria and another population of people who had arrived 18 months previously from areas of very low endemicity. Mean spleen sizes correlated positively with prevalence of malaria, not resistance to it. Prevalence of sexual and asexual blood stage parasites was higher in transmigrants than in the natives. The data also show that clinical resistance to malaria in this part of the world includes resistance to Plasmodium falciparum gametocytemia and that this is not the passive byproduct of a reduction in asexual parasites. This indicates that the introduction of native people into a populated malarious area will increase the percent of gametocyte carriers and may, thereby, increase the entomologic inoculation rate.

Baird JK, Purnomo, Masbar S. 1990. Plasmodium ovale in Indonesia. Southeast Asian J Trop Med Public Health, 21 (4), pp. 541-544. | Show Abstract

We report 34 infections by Plasmodium ovale found among 15,806 blood film examinations taken between 1973 and 1989 from several sites in Indonesia. Twenty five of the P. ovale infections occurred in a single sample of 514 people living in Owi, Irian Jaya. We detected five additional infections at 3 other sites in Irian Jaya. Other infections by P. ovale occurred at two sites in West Flores. Another infection has already been reported from East Timor. Despite relatively frequent sampling of populations on Sumatra, Kalimantan, Java and Sulawesi, P. ovale has not been found on those islands. It appears that this parasite occurs only on the easternmost islands of the Indonesian archipelago where it is nonetheless a rare finding.

Riberu WA, Atmosoedjono S, Purnomo, Tirtokusumo S, Bangs MJ, Baird JK. 1990. Cultivation of sexually mature Brugia malayi in vitro. Am J Trop Med Hyg, 43 (1), pp. 3-5. | Show Abstract | Read more

Sexually mature male and female Brugia malayi were developed from third stage larvae after 60 days in the in vitro culture system described by Franke and others in 1987 (Am J Trop Med Hyg 37: 370-375). Between 75 and 100 days in culture, many worms produced living microfilariae. Each gravid female produced 200-1,500 microfilariae/day.

Baird JK, Baird CR, Sabrosky CW. 1989. North American cuterebrid myiasis. Report of seventeen new infections of human beings and review of the disease. J Am Acad Dermatol, 21 (4 Pt 1), pp. 763-772. | Show Abstract | Read more

Human infection with botfly larvae (Cuterebra species) are reported, and 54 cases are reviewed. Biologic, epidemiologic, clinical, histopathologic, and diagnostic features of North American cuterebrid myiasis are described. A cuterebrid maggot generally causes a single furuncular nodule. Most cases occur in children in the northeastern United States or the Pacific Northwest; however, exceptions are common. Most lesions of North American cuterebrid myiasis are caused by second or third instar Cuterebra maggots that appear in late August, September, and October. First instar maggots are unusual and occur in the vitreous humor or in the upper respiratory tract of patients in late spring and early summer.

Baird JK, Neafie RC, Connor DH. 1988. Nodules in the conjunctiva, bung-eye, and bulge-eye in Africa caused by Mansonella perstans. Am J Trop Med Hyg, 38 (3), pp. 553-557. | Show Abstract | Read more

Eight patients from Uganda, Sudan, Nigeria, and Zaire presented with swelling of the eyelids, proptosis, or conjunctival granulomas. In 5 patients the cause was Mansonella perstans; in 1, it was a Wuchereria bancrofti-like worm; and in 2, an unidentifiable worm. The morphologic features and histopathologic changes in the conjunctiva and periorbital fat are described and illustrated.

Baird JK, Kassebaum LJ, Ludwig GK. 1988. Hepatic granuloma in a man from North America caused by a nymph of Linguatula serrata. Pathology, 20 (2), pp. 198-199. | Show Abstract | Read more

A calcified nodule on the liver of a 62-year-old man from North Carolina, USA, contained a degenerated nymph of Linguatula serrata. The nodule was incidentally discovered at laparotomy for malignant lymphoma and cholelithiasis. The cuticle was all that remained of the parasite, but sclerotized openings and large spines on the cuticle proved the parasite was L. serrata, a pentastomid arthropod. Anatomic location and size of the parasite indicated that it was consistent with the nymphal stage of L. serrata. This is the fifth confirmed infection of humans from North America by a pentastomid parasite.

Baird JK, Neafie RC, Lanoie L, Connor DH. 1987. Adult Mansonella perstans in the abdominal cavity in nine Africans. Am J Trop Med Hyg, 37 (3), pp. 578-584. | Show Abstract | Read more

Adult Mansonella perstans infected the abdominal cavity of nine patients seen at Karawa Hospital in the Ubangi territory of Zaire. In four patients the worms were removed at laparotomy, and in the other five they were removed at autopsy. Twelve adult worms were identified in the nine patients. None of the worms caused symptoms or contributed to the patient's death. Worms were in the hernial sac in three patients, and one each was in connective tissue beside a reactive mesenteric lymph node, in peripancreatic connective tissue, in perirenal connective tissue, in hepatic portal connective tissue, on the serosal surface of the small intestine, and in connective tissue adjacent to rectum. The diameter of male worms was 45 microns to 60 microns and of female worms, 80 microns to 125 microns. One female worm was removed intact. It was 6 cm long and had a bifurcated tail characteristic of M. perstans.

Baird JK, Neafie RC, Connor DH. 1987. Filariasis in Trinidad. Trop Geogr Med, 39 (4), pp. 388-389.

Baird JK. 1987. False parasites in tissue sections. Parasitol Today, 3 (9), pp. 273-276. | Read more

Baird JK, Neafie RC, Lanoie L, Connor DH. 1987. Abdominal angiostrongylosis in an African man: case study. Am J Trop Med Hyg, 37 (2), pp. 353-356. | Show Abstract | Read more

A nodule removed from the cecum of a 25-year-old Zairian man contained a degenerated adult nematode. The surrounding tissue contained larvae and eggs in various stages of cleavage. Eggs and larvae were indistinguishable from those of Angiostrongylus costaricensis. These morphological features are described. The diameter and cuticle, and the anatomic location of the adult worm is consistent with A. costaricensis. The tissue reaction was chronic with granulomatous inflammation and numerous eosinophils. This is the first report of abdominal angiostrongylosis of a human in Africa.

Baird JK, Wear DJ. 1987. Cercarial dermatitis: the swimmer's itch. Clin Dermatol, 5 (3), pp. 88-91. | Read more

Baird JK, De Vinatea ML, Macher AM, Sierra JA, Lasala G. 1987. AIDS. Case for diagnosis series, 1987. Mil Med, 152 (4), pp. M17-M24.

Tuur SM, Macher AM, De Vinatea ML, Baird JK, Neafle R, McGivney RK, McKee EM. 1987. AIDS. Case for diagnosis, 1987. Mil Med, 152 (3), pp. M9-16.

Baird JK, Macher AM, De Vinatea ML, Connor DH, Kollwitz F, Teitelbaum S. 1987. Case for diagnosis. AIDS. Mil Med, 152 (1), pp. M89-M96.

NELSON A, MACHER A, NEAFIE R, BAIRD J. 1986. AIDS - CASE FOR DIAGNOSIS, 1986 - MILITARY MEDICINE MILITARY MEDICINE, 151 (12), pp. M81-M88.

Baird JK, Alpert LI, Friedman R, Schraft WC, Connor DH. 1986. North American brugian filariasis: report of nine infections of humans. Am J Trop Med Hyg, 35 (6), pp. 1205-1209. | Show Abstract | Read more

Nine people living in Rhode Island, New York, Pennsylvania, Florida, or California acquired autochthonous brugian filariasis. Each patient had an enlarged lymph node containing a single worm or, in one patient, a pair of worms. Most worms were in lymphatic vessels within the node, but two worms were in the substance of the node. Ten worms were studied, seven female and three male. Female worms contained paired uteri that occupied most of the body cavity of the worm, and male worms contained a single reproductive tract. No worms were gravid. The diameter of the worms was small, 30 micron to 75 micron. The usual diameter of female worms was 65 micron to 75 micron, and 45 micron to 50 micron for male worms. The morphologic features of these worms, their anatomical location, and their geographic distribution are all characteristic of infection with a North American Brugia species.

Baird JK, Davidson DE, Decker-Jackson JE. 1986. Oxidative activity of hydroxylated primaquine analogs. Non-toxicity to glucose-6-phosphate dehydrogenase-deficient human red blood cells in vitro. Biochem Pharmacol, 35 (7), pp. 1091-1098. | Show Abstract | Read more

The individual effects of two putative metabolites of primaquine (5,6-dihydroxyprimaquine and 5,6-dihydroxy-8-aminoquinoline) on the hexose monophosphate shunt (HMS) and on the ATP-dependent proteolytic system which rapidly degrades oxidized erythrocyte protein were measured in intact red blood cells in vitro from two blood donors. In red cells treated with nitrite (1-40 mM) or phenylhydrazine (0.01-10 mM), proteolytic activity was detected only with concentrations (7.5 mM NaNO2 and 0.25 mM phenylhydrazine) causing greater than 15-fold elevation of HMS activity, and glucose-6-phosphate dehydrogenase (G6PD)-deficient (25% of normal activity) red cell suspensions thus treated showed approximately 30% greater proteolysis. G6PD-normal and deficient red cells treated with the primaquine analogs, however, did not experience proteolysis with concentrations (0.25 mM) in excess of those causing 17-fold elevation of HMS activity. Stimulation of the HMS by the primaquine analogs thus appears unrelated to an erythrotoxic oxidative stress. Methylene blue is known to cause an elevation of HMS activity through direct and diaphorase II-dependent oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) which is independent of injurious oxidative stress. It was found that the putative primaquine metabolites also caused direct and diaphorase II-dependent oxidation of NADPH in dilute hemolysate, thus suggesting that the putative primaquine metabolites have a methylene blue-like redox disposition in red blood cells. Results obtained in this study suggest that the hemolytic toxicity of primaquine may be unrelated to processes which lead to oxidative deterioration of red cell protein.

Baird JK, McCormick GJ, Canfield CJ. 1986. Effects of nine synthetic putative metabolites of primaquine on activity of the hexose monophosphate shunt in intact human red blood cells in vitro. Biochem Pharmacol, 35 (7), pp. 1099-1106. | Show Abstract | Read more

Suspensions of washed human red blood cells were treated with nine synthetic putative metabolic derivatives of primaquine (PQ'), and their individual effects on activity of the hexose monophosphate shunt (HMS) were quantitated by radiometric analysis of 14CO2 from [14C] glucose. The most potent HMS stimulant was 5-hydroxy-6-methoxy-8-aminoquinoline (5H6MQ), which caused 10-fold elevation of HMS activity at an estimated concentration of 0.004 mM. Ten millimolar primaquine (PQ) was required to achieve the same effect. Thus, 5H6MQ was approximately 2500-fold more reactive with the HMS than PQ. Other analogs achieved less than 0.4- to 154-fold increases in HMS reactivity. Patterns of effects on HMS activity indicated that 5-hydroxylation and/or N-dealkylation of PQ strongly enhanced HMS reactivity. In contrast, none of the putative metabolites of PQ activated the proteolytic system known to degrade oxidized protein in red cells, indicating that stimulation of the HMS by the PQ analogs was not related to an injurious oxidative stress. Red cells pretreated with 1.0 mM N-ethylmaleimide (NEM) or with 1.0% (w/v) sodium nitrite to cause glutathione sulfhydryl blockage and conversion of red cell hemoglobin to methemoglobin (metHb), respectively, also showed elevation of HMS activity when exposed to 5H6MQ. These observations suggested that 5H6MQ-induced elevation of HMS activity was at least partially independent of glutathione redox reactions, hydrogen peroxide accumulation and reaction with oxyhemoglobin. The relevance of these observations to proposed mechanisms of hemolytic toxicity of PQ is discussed.

George GH, Baird JK, Thorpe RG, Connor DH. 1986. Non-ulcerative amebiasis of rectum. Acta Trop, 43 (1), pp. 93-95.

Baird JK, Decker-Jackson JE, Davidson DE. 1984. An in vitro micro-volume procedure for rapid measurement of erythrocytic hexose monophosphate shunt activity. Int J Biochem, 16 (10), pp. 1049-1052. | Show Abstract | Read more

A radiometric micro-volume procedure for measurement of erythrocytic hexose monophosphate shunt (HMS) activity in intact cells in vitro is described. The procedure is rapid, allowing 200 individual HMS determinations in a single experiment of 5 hr duration. The procedure is reproducible, yielding HMS activity means insignificantly different (P greater than 0.05) between replicate experiments. A profile of sodium nitrite-induced HMS stimulation is reported: HMS was elevated 2-fold (P less than 0.001) between zero and 2.5 mM NaNO2; HMS elevation was more distinct (7-fold) between 2.5 and 5.0 mM NaNO2; maximum activity (22-fold) was observed between 10 and 20 mM NaNO2; greater than 20 mM NaNO2 caused significant (P less than 0.001) diminution of HMS; glucose carbon recycling through the HMS occurred only with greater than 2.5 mM NaNO2 where this process contributed less than or equal to 16% to total HMS activity.

Baird JK. 1984. Methylene blue-mediated hexose monophosphate shunt stimulation in human red blood cells in vitro: independence from intracellular oxidative injury. Int J Biochem, 16 (10), pp. 1053-1058. | Show Abstract | Read more

The red blood cell hexose monophosphate shunt (HMS) and proteolytic responses to several concentrations of Methylene Blue or sodium nitrite were measured. The results suggested two distinct mechanisms for activation of the HMS: (1) nitrite treatment increased HMS activity in response to oxidative challenge to red cell protein; (2) Methylene Blue treatment activated HMS without injurious oxidative challenge. Nitrite-treated cells actively degraded protein, whereas Methylene Blue-treated red cells did not activate proteolytic systems that degrade oxidized red cell protein. These observations are relevant to proposed in vitro systems for evaluation of drug hemolytic toxicity potential on the basis of HMS stimulation capacity.

Baird JK, Lambros C. 1984. Effect of membrane filtration of antimalarial drug solutions on in vitro activity against Plasmodium falciparum. Bull World Health Organ, 62 (3), pp. 439-444. | Show Abstract

Antimalarial activities of chloroquine, mefloquine, amodiaquine, and quinine in vitro against Plasmodium falciparum were diminished as a consequence of membrane filtration. Filtered drug solutions gave ID(50) values up to 25-fold greater than those of non-filtered (ethanol-sterilized) drug solutions. Loss of activity by filtration was overcome by increasing the drug concentration prior to filtration. Water solutions filtered through Millex-GS filter units consistently showed an absorbance maximum at 277 nm, accompanied by a lesser peak at 225 nm. Water filtrates from Nucleopore and Millex-GV filters showed no absorbance at 277 nm and only slight absorbance was evident for the Gelman filter unit. Activity losses were attributed to extractable contaminating moieties in the membrane filters and/or drug binding to the membrane filters.

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RICE S, BUTLER P, PILLING M, BAIRD J. 1979. SOLUTION OF THE DEBYE-SMOLUCHOWSKI EQUATION FOR THE RATE OF REACTION OF IONS IN DILUTE-SOLUTION JOURNAL OF CHEMICAL PHYSICS, 70 (9), pp. 4001-4007. | Read more

Yuan L, Wang Y, Parker DM, Gupta B, Yang Z, Liu H, Fan Q, Cao Y, Xiao Y, Lee MC et al. 2015. Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar. Antimicrob Agents Chemother, 59 (2), pp. 1230-1235. | Show Abstract | Read more

Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating.

Syafruddin D, Bangs MJ, Sidik D, Elyazar I, Asih PB, Chan K, Nurleila S, Nixon C, Hendarto J, Wahid I et al. 2014. Impact of a spatial repellent on malaria incidence in two villages in Sumba, Indonesia. Am J Trop Med Hyg, 91 (6), pp. 1079-1087. | Show Abstract | Read more

A randomized, double-blinded, placebo-controlled study was conducted to examine the effect of spatial repellent (SR) in households at risk of malaria in Indonesia. Following presumptive radical cure for malaria in 180 adult men representing sentinels of new infection in four clusters within two villages, all households were given either metofluthrin or placebo mosquito coils. Weekly blood smear screening and human-landing mosquito catches were done throughout the 6 months intervention. Malaria infections occurred in 61 subjects living in placebo households and 31 subjects living in SR coil households, suggesting a 52% protective effect of SR. Likewise, anopheles indoor human landing rates were 32% lower in homes receiving SR coils. Differences in the malaria attack rate between SR- and placebo-treated homes was significant when not accounting for the effects of clustering. When the analysis was adjusted for intra-cluster correlation, the differences between SR- and placebo-treated homes were not statistically significant. The findings provide evidence of SR public health benefit and support a larger trial statistically powered to detect those effects.

Baird JK, Dewi M, Subekti D, Elyazar I, Satyagraha AW. 2015. Noninferiority of glucose-6-phosphate dehydrogenase deficiency diagnosis by a point-of-care rapid test vs the laboratory fluorescent spot test demonstrated by copper inhibition in normal human red blood cells. Transl Res, 165 (6), pp. 677-688. | Show Abstract | Read more

Tens of millions of patients diagnosed with vivax malaria cannot safely receive primaquine therapy against repeated attacks caused by activation of dormant liver stages called hypnozoites. Most of these patients lack access to screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency, a highly prevalent disorder causing serious acute hemolytic anemia with primaquine therapy. We optimized CuCl inhibition of G6PD in normal red blood cells (RBCs) to assess G6PD diagnostic technologies suited to point of care in the impoverished rural tropics. The most widely applied technology for G6PD screening-the fluorescent spot test (FST)-is impractical in that setting. We evaluated a new point-of-care G6PD screening kit (CareStart G6PD, CSG) against FST using graded CuCl treatments to simulate variable hemizygous states, and varying proportions of CuCl-treated RBC suspensions to simulate variable heterozygous states of G6PD deficiency. In experiments double-blinded to CuCl treatment, technicians reading FST and CSG test (n = 269) classified results as positive or negative for deficiency. At G6PD activity ≤40% of normal (n = 112), CSG test was not inferior to FST in detecting G6PD deficiency (P = 0.003), with 96% vs 90% (P = 0.19) sensitivity and 75% and 87% (P = 0.01) specificity, respectively. The CSG test costs less, requires no specialized equipment, laboratory skills, or cold chain for successful application, and performs as well as the FST standard of care for G6PD screening. Such a device may vastly expand access to primaquine therapy and aid in mitigating the very substantial burden of morbidity and mortality imposed by the hypnozoite reservoir of vivax malaria.

Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. 2014. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis, 14 (10), pp. 982-991. | Show Abstract | Read more

BACKGROUND: Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. METHODS: We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. FINDINGS: We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. INTERPRETATION: Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. FUNDING: Wellcome Trust (UK).

Battle KE, Karhunen MS, Bhatt S, Gething PW, Howes RE, Golding N, Van Boeckel TP, Messina JP, Shanks GD, Smith DL et al. 2014. Geographical variation in Plasmodium vivax relapse. Malar J, 13 (1), pp. 144. | Show Abstract | Read more

BACKGROUND: Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission. METHODS: A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse. RESULTS: Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas. CONCLUSIONS: The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.

Nixon CP, Nixon CE, Arsyad DS, Chand K, Yudhaputri FA, Sumarto W, Wangsamuda S, Asih PB, Marantina SS, Wahid I et al. 2014. Distance to Anopheles sundaicus larval habitats dominant among risk factors for parasitemia in meso-endemic Southwest Sumba, Indonesia. Pathog Glob Health, 108 (8), pp. 369-380. | Show Abstract | Read more

BACKGROUND: The decline in intensity of malaria transmission in many areas now emphasizes greater importance of understanding the epidemiology of low to moderate transmission settings. Marked heterogeneity in infection risk within these populations creates opportunities to understand transmission and guide resource allocation to greater impact. METHODS: In this study, we examined spatial patterns of malaria transmission in a hypo- to meso-endemic area of eastern Indonesia using malaria prevalence data collected from a cross-sectional socio-demographic and parasitological survey conducted from August to November 2010. An entomological survey performed in parallel, identified, mapped, and monitored local anopheline larval habitats. RESULTS: A single spatial cluster of higher malaria prevalence was detected during the study period (relative risk=2.13; log likelihood ratio=20.7; P<0.001). In hierarchical multivariate regression models, risk of parasitemia was inversely correlated with distance to five Anopheles sundaicus known larval habitats [odds ratio (OR)=0.21; 95% confidence interval (CI)=0.14-0.32; P<0.001], which were located in a geographically restricted band adjacent to the coastline. Increasing distance from these sites predicted increased hemoglobin level across age strata after adjusting for confounders (OR=1.6; 95% CI=1.30-1.98; P<0.001). CONCLUSION: Significant clustering of malaria parasitemia in close proximity to very specific and relatively few An. sundaicus larval habitats has direct implications for local control strategy, policy, and practice. These findings suggest that larval source management could achieve profound if not complete impact in this region.

Ingram RJ, Crenna-Darusallam C, Soebianto S, Noviyanti R, Baird JK. 2014. The clinical and public health problem of relapse despite primaquine therapy: case review of repeated relapses of Plasmodium vivax acquired in Papua New Guinea. Malar J, 13 (1), pp. 488. | Show Abstract | Read more

BACKGROUND: Primaquine is the only drug available for preventing relapse following a primary attack by Plasmodium vivax malaria. This drug imposes several important problems: daily dosing over two weeks; toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; partner blood schizontocides possibly impacting primaquine safety and efficacy; cytochrome P-450 abnormalities impairing metabolism and therapeutic activity; and some strains of parasite may be tolerant or resistant to primaquine. There are many possible causes of repeated relapses in a patient treated with primaquine. CASE DESCRIPTION: A 56-year-old Caucasian woman from New Zealand traveled to New Ireland, Papua New Guinea for two months in 2012. One month after returning home she stopped daily doxycycline prophylaxis against malaria, and one week later she became acutely ill and hospitalized with a diagnosis of Plasmodium vivax malaria. Over the ensuing year she suffered four more attacks of vivax malaria at approximately two-months intervals despite consuming primaquine daily for 14 days after each of those attacks, except the last. Genotype of the patient's cytochrome P-450 2D6 alleles (*5/*41) corresponded with an intermediate metabolizer phenotype of predicted low activity. DISCUSSION: Multiple relapses in patients taking primaquine as prescribed present a serious clinical problem, and understanding the basis of repeated therapeutic failure is a challenging technical problem. This case highlights these issues in a single traveler, but these problems will also arise as endemic nations approach elimination of malaria transmission.

Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, Sakuntabhai A, Satyagraha AW, Williams TN, Baird JK, Hay SI. 2013. Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malar J, 12 (1), pp. 418. | Show Abstract | Read more

BACKGROUND: Primaquine is essential for malaria control and elimination since it is the only available drug preventing multiple clinical attacks by relapses of Plasmodium vivax. It is also the only therapy against the sexual stages of Plasmodium falciparum infectious to mosquitoes, and is thus useful in preventing malaria transmission. However, the difficulties of diagnosing glucose-6-phosphate dehydrogenase deficiency (G6PDd) greatly hinder primaquine's widespread use, as this common genetic disorder makes patients susceptible to potentially severe and fatal primaquine-induced haemolysis. The risk of such an outcome varies widely among G6PD gene variants. METHODS: A literature review was conducted to identify surveys of G6PD variant frequencies among representative population groups. Informative surveys were assembled into two map series: (1) those showing the relative proportions of the different variants among G6PDd individuals; and (2) those showing allele frequencies of G6PD variants based on population surveys without prior G6PDd screening. RESULTS: Variants showed conspicuous geographic patterns. A limited repertoire of variants was tested for across sub-Saharan Africa, which nevertheless indicated low genetic heterogeneity predominated by the G6PD A(-202A) mutation, though other mutations were common in western Africa. The severe G6PD Mediterranean variant was widespread across western Asia. Further east, a sharp shift in variants was identified, with high variant heterogeneity in the populations of China and the Asia-Pacific where no single variant dominated. CONCLUSIONS: G6PD variants exhibited distinctive region-specific distributions with important primaquine policy implications. Relative homogeneity in the Americas, Africa, and western Asia contrasted sharply with the heterogeneity of variants in China, Southeast Asia and Oceania. These findings will inform rational risk assessments for primaquine in developing public health strategies for malaria control and elimination, and support the future development of regionally targeted policies. The major knowledge gaps highlighted here strongly advocate for further investigation of G6PD variant diversity and their primaquine-sensitivity phenotypes.

Elyazar IR, Sinka ME, Gething PW, Tarmidzi SN, Surya A, Kusriastuti R, Winarno, Baird JK, Hay SI, Bangs MJ. 2013. The distribution and bionomics of anopheles malaria vector mosquitoes in Indonesia. Adv Parasitol, 83 pp. 173-266. | Show Abstract | Read more

Malaria remains one of the greatest human health burdens in Indonesia. Although Indonesia has a long and renowned history in the early research and discoveries of malaria and subsequently in the successful use of environmental control methods to combat the vector, much remains unknown about many of these mosquito species. There are also significant gaps in the existing knowledge on the transmission epidemiology of malaria, most notably in the highly malarious eastern half of the archipelago. These compound the difficulty of developing targeted and effective control measures. The sheer complexity and number of malaria vectors in the country are daunting. The difficult task of summarizing the available information for each species and/or species complex is compounded by the patchiness of the data: while relatively plentiful in one area or region, it can also be completely lacking in others. Compared to many other countries in the Oriental and Australasian biogeographical regions, only scant information on vector bionomics and response to chemical measures is available in Indonesia. That information is often either decades old, geographically patchy or completely lacking. Additionally, a large number of information sources are published in Dutch or Indonesian language and therefore less accessible. This review aims to present an updated overview of the known distribution and bionomics of the 20 confirmed malaria vector species or species complexes regarded as either primary or secondary (incidental) malaria vectors within Indonesia. This chapter is not an exhaustive review of each of these species. No attempt is made to specifically discuss or resolve the taxonomic record of listed species in this document, while recognizing the ever evolving revisions in the systematics of species groups and complexes. A review of past and current status of insecticide susceptibility of eight vector species of malaria is also provided.

Sutanto I, Tjahjono B, Basri H, Taylor WR, Putri FA, Meilia RA, Setiabudy R, Nurleila S, Ekawati LL, Elyazar I et al. 2013. Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia. Antimicrob Agents Chemother, 57 (3), pp. 1128-1135. | Show Abstract | Read more

Radical cure of Plasmodium vivax infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by P. vivax acquired in Papua, Indonesia.

Howes RE, Battle KE, Satyagraha AW, Baird JK, Hay SI. 2013. G6PD Deficiency. Global Distribution, Genetic Variants and Primaquine Therapy Advances in Parasitology, 81 pp. 135-201. | Show Abstract | Read more

Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and. primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination. © 2013 Elsevier Ltd.

Baird JK. 2013. Evidence and implications of mortality associated with acute Plasmodium vivax malaria. Clin Microbiol Rev, 26 (1), pp. 36-57. | Show Abstract | Read more

Vivax malaria threatens patients despite relatively low-grade parasitemias in peripheral blood. The tenet of death as a rare outcome, derived from antiquated and flawed clinical classifications, disregarded key clinical evidence, including (i) high rates of mortality in neurosyphilis patients treated with vivax malaria; (ii) significant mortality from zones of endemicity; and (iii) the physiological threat inherent in repeated, very severe paroxysms in any patient, healthy or otherwise. The very well-documented course of this infection, with the exception of parasitemia, carries all of the attributes of "perniciousness" historically linked to falciparum malaria, including severe disease and fatal outcomes. A systematic analysis of the parasite biomass in severely ill patients that includes blood, marrow, and spleen may ultimately explain this historic misunderstanding. Regardless of how this parasite is pernicious, recent data demonstrate that the infection comes with a significant burden of morbidity and associated mortality. The extraordinary burden of malaria is not heavily weighted upon any single continent by a single species of parasite-it is a complex problem for the entire endemic world, and both species are of fundamental importance. Humanity must rally substantial resources, intellect, and energy to counter this daunting but profound threat.

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