Transmission Blocking Activity of Low-dose Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine. METHODS: Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters. RESULTS: Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22-98) of mosquitoes positive for oocysts and 57% (range, 4-92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified. CONCLUSIONS: Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect.

Plasmodium vivax Relapse Rates in Allied Soldiers during the Second World War: Importance of Hypnozoite Burden.

Allied soldiers suffered repeated relapses of Plasmodium vivax malaria during and immediately after the Second World War. This surprised many military medical officers who had underestimated the huge casualties produced by P. vivax malaria. Tropical (Philippines) strains of P. vivax were known to relapse more frequently than those from temperate regions (the United States). Intense exposure to mosquito infection likely increased the absolute number of hypnozoites in soldiers' livers. Both quinine and quinacrine were used as chemosuppressive agents, but their inconsistent use until at least 1943 promoted intermittent parasitological failures. Fear of hemolytic reactions after a mass casualty event in 1943 engendered fear and avoidance of the only 8-aminoquinoline pamaquine then available to cure relapses. Variable chemosuppression likely prevented acquisition of effective parasitological immunity. Unexpectedly high relapse rates in soldiers were likely an indirect measure of the high hypnozoite burden and suggest how difficult it will be to eliminate P. vivax malaria from endemic areas.

Drug-free holidays: pre-travel versus during travel malaria chemoprophylaxis.

Although efficacious forms of malaria chemoprophylaxis currently exist, many travelers to malaria-endemic areas fail to use them effectively. We suggest that taking antimalarial medications prior to travel may prevent more malaria by improving compliance. Treatment regimens of antimalarial drugs taken prior to travel could protect persons for up to one month of exposure. We urge additional testing of pre-travel malaria chemoprophylaxis regimens.

Historical review: Does falciparum malaria destroy isolated tribal populations?

Many isolated populations of tribal peoples were nearly destroyed when they first contacted infectious diseases particularly respiratory pathogens such as measles and smallpox. Surviving groups have often been found to have declining populations in the face of multiple social and infectious threats. Malaria, especially Plasmodium falciparum, was thought to be a major cause of depopulation in some tribal peoples isolated in tropical jungles. The dynamics of such host parasite interactions is unclear especially since most such populations would have had long histories of exposure to malaria. Three groups are individually reviewed: Meruts of Borneo, Yanomami of Amazonia, Jarawas of the Andaman Islands. The purpose of this review is to examine the role of falciparum malaria in the depopulation of some isolated tribal groups in order to understand what measures, if any, would be likely to prevent such losses.

Historical Review: Problematic Malaria Prophylaxis with Quinine.

Quinine, a bitter-tasting, short-acting alkaloid drug extracted from cinchona bark, was the first drug used widely for malaria chemoprophylaxis from the 19th century. Compliance was difficult to enforce even in organized groups such as the military, and its prophylaxis potential was often questioned. Severe adverse events such as blackwater fever occurred rarely, but its relationship to quinine remains uncertain. Quinine prophylaxis was often counterproductive from a public health viewpoint as it left large numbers of persons with suppressed infections producing gametocytes infective for mosquitoes. Quinine was supplied by the first global pharmaceutical cartel which discouraged competition resulting in a near monopoly of cinchona plantations on the island of Java which were closed to Allied use when the Japanese Imperial Army captured Indonesia in 1942. The problems with quinine as a chemoprophylactic drug illustrate the difficulties with medications used for prevention and the acute need for improved compounds.

Protection of Military Personnel Against Vector-Borne Diseases: A Review of Collaborative Work of the Australian and US Military Over the Last 30 Years.

Australian and US military medical services have collaborated since World War II to minimize vector-borne diseases such as malaria, dengue, and scrub typhus. In this review, collaboration over the last 30 years is discussed. The collaborative projects and exchange scientist programs have resulted in mutually beneficial outcomes in the fields of drug development and personal protection measures against vector-borne diseases.

Review of mass drug administration for malaria and its operational challenges.

Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings.

Evaluation of the safety and tolerability of a short higher-dose primaquine regimen for presumptive anti-relapse therapy in healthy subjects.

The safety and tolerability of primaquine (PQ) administered as a short higher-dose (30mg twice daily for 7 days) regimen in 203 Australian Defence Force personnel was evaluated in an open-label presumptive anti-relapse therapy study. No clinically significant differences were measured in the subjects' haematological and biochemical indices before and after PQ treatment. The most common adverse events were nausea, abdominal pain, headache and insomnia, many of which were mild in severity (30%; 60/203) and transient; 19% of subjects (39/203) experienced moderate (with some interference with daily duties requiring no or minimal medical therapy) adverse events. Two subjects (1%) had severe gastrointestinal adverse events requiring cessation of medication, but neither was seriously ill. Ten subjects (5%) had peripheral cyanosis (blueness of the lips), but none reported any respiratory compromise. These findings suggest that the short higher-dose PQ regimen is safe and well tolerated, which could improve PQ compliance and effectiveness.