The role of chemoprophylaxis in eliminating forest malaria and preventing simian malaria in humans

Abstract

The regional elimination and eventual eradication of human malaria will require addressing the most difficult, persistent, and stubborn pockets of transmission.1Feachem RGA Chen I Akbari O et al.Malaria eradication within a generation: ambitious, achievable, and necessary.Lancet. 2019; 394: 1056-1112Summary Full Text Full Text PDF PubMed Scopus (151) Google Scholar In recent years, southeast Asia has made tremendous progress towards regional elimination, revealing forest malaria to be one such challenge. Most foci of transmission remaining in the region are among migrant populations that spend time in the forest and are located far from access to care.2Kar NP Kumar A Singh OP Carlton JM Nanda N A review of malaria transmission dynamics in forest ecosystems.Parasit Vectors. 2014; 7: 265Crossref PubMed Scopus (70) Google Scholar Although most research on forest malaria has focused on the elimination of human malaria, zoonotic malaria in humans arising from spillover from non-human primates is also increasing in prevalence in or near forest settings and wildlife sanctuaries, especially where deforestation is taking place.3Antinori S Bonazzetti C Giacomelli A et al.Non-human primate and human malaria: past, present and future.J Travel Med. 2021; 28taab036Crossref Scopus (4) Google Scholar Evidence on strategies that can reduce malaria transmission in forest settings can therefore support southeast Asia's goals to eliminate human malaria by 2030, and provide novel evidence on how to mitigate the emergence of simian malaria. High-risk populations for forest malaria in southeast Asia are usually adult men working in or near the forest who risk malaria infection during the day, when the Anopheles mosquitoes predominant in the region tend to bite.4Hewitt SE Let's “cut to the chase” on malaria elimination in the Greater Mekong subregion.Trans R Soc Trop Med Hyg. 2019; 113: 161-162Crossref PubMed Scopus (2) Google Scholar Antimalarial medicines can be useful for these populations, particularly if administered to healthy at-risk populations so as to clear low-density afebrile infections that can be responsible for ongoing transmission, and to offer protection from incident infections while plasma drug concentrations are sufficient. Specific decisions on which drug combinations, deployment strategies, and concomitant vector control measures to use should be contextualised on the basis of disease prevalence, species of malaria infection present, and interactions between people at risk and local vectors present. For locations where simian malaria infections are detected, interactions between high-risk populations and non-human primates should also be considered. Vector control methods to be used with chemoprophylaxis will need to target outdoor transmission, an increasingly recognised priority for which several product classes are under evaluation.1Feachem RGA Chen I Akbari O et al.Malaria eradication within a generation: ambitious, achievable, and necessary.Lancet. 2019; 394: 1056-1112Summary Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 5WHOWHO Guidelines for malaria. World Health Organization, Geneva2022https://www.who.int/publications/i/item/guidelines-for-malariaDate accessed: July 18, 2022Google Scholar In The Lancet Infectious Diseases, Rupam Tripura and colleagues6Tripmura R von Seidlein L Sovannaroth S Antimalarial chemoprophylaxis for forest goers in southeast Asia: an open-label, individually randomised controlled trial.Lancet Infect Dis. 2022; (published online Sept 26.)https://doi.org/10.1016/S1473-3099(22)00492-3Google Scholar add to this evidence base, investigating the efficacy of chemoprophylaxis when providing artemether–lumefantrine or multivitamins (control) twice daily for 3 days, followed by the same dosing once a week while travelling in the forest, continuing for an additional 4 weeks after leaving the forest. Study participants were those who reported staying overnight in forests in the Stung Treng province of Cambodia near the border of southern Laos. This open-label, randomised trial enrolled 1480 participants aged 16–65 years in the initial months of the COVID-19 pandemic (March to November, 2020) using low-intensity monthly follow-up designed to be feasible for large-scale implementation. Although the planned sample size was not met due to COVID-19 restrictions, statistically significant results were found for the primary outcome, a composite of clinical malaria or subclinical infection detected by PCR at or within 1 month, 2 months, or 3 months after administration of the first dose of treatment. During these 3 months of follow-up, malaria infections were detected in only 19 (3%) of 713 study participants who received artemether–lumefantrine as compared with 123 (17%) of 714 participants who received multivitamins, translating to a protective efficacy of 85% (95% CI 75–90, p<0·0001) and an absolute risk reduction of 15% (95% CI 12–18, p<0·0001). This study shows that chemoprophylaxis can be a useful strategy for reducing both clinical malaria and subpatent low-density infection when administered to people who spend time in or near the forest in a southeast Asian setting. The study drug chosen for this site, artemether–lumefantrine, was well tolerated with no serious adverse events, consistent with its status as a first-line antimalarial drug in many other countries. The vast majority of infections (166 of 185) detected in this study were Plasmodium vivax, and although it is not possible to assess whether these infections were novel incident infections or relapses, these data suggest that artemether–lumefantrine could potentially have a protective function for both. However, elimination of P vivax malaria requires the clearance of latent hypnozoites using 8-aminoquinolines, which have a dose-dependent haemolytic risk in individuals with inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited condition often found in malarious geographies.1Feachem RGA Chen I Akbari O et al.Malaria eradication within a generation: ambitious, achievable, and necessary.Lancet. 2019; 394: 1056-1112Summary Full Text Full Text PDF PubMed Scopus (151) Google Scholar The authors suggest using tafenoquine with quantitative G6PD testing for the clearance of hypnozoites, whereas we suggest the addition of eight once-weekly doses of primaquine7Milligan R Daher A Villanueva G Bergman H Graves PM Primaquine alternative dosing schedules for preventing malaria relapse in people with Plasmodium vivax.Cochrane Database Syst Rev. 2020; 8CD012656PubMed Google Scholar for two reasons. The first is safety, for each dose of primaquine has a lower haemolytic risk profile than a dose of tafenoquine. The second is cost, for this lower haemolytic risk means that only qualitative G6PD testing is required for primaquine use, which is less expensive than the quantitative testing needed when using tafenoquine. Weekly dosing of primaquine is also compatible with the dosing schedule used in this study, and adherence should therefore not be an issue. Locations elsewhere striving to reduce forest malaria in southeast Asia can use chemoprophylaxis as a strategy, which the authors mention is already being rolled out on an emergency basis among forest goers in Cambodia and Laos, using artesunate–mefloquine and artesunate–pyronaridine, respectively. Emergency measures have furthermore enabled the widescale roll-out of insecticide-treated hammock nets among forest goers,8Canavati SE Kelly GC Vo TH et al.Mosquito net ownership, utilization, and preferences among mobile and migrant populations sleeping in forests and farms in central Vietnam: a cross-sectional study.Am J Trop Med Hyg. 2021; 104: 1917-1924Crossref PubMed Scopus (5) Google Scholar and we recommend this mechanism enable the deployment of additional vector control interventions proven to be safe that could be efficacious outdoors. Implementation strategies can also be informed by this study, where the use of smart directly observed therapy, entailing observation of prophylaxis intake by a forest volunteer, enabled high levels of adherence (97% for artemether–lumefantrine and 98% for multivitamin through self-reporting, with similar results confirmed among a subset of participants on the basis of plasma lumefantrine and desbutyl-lumefantrine concentrations). Wider implementation of this strategy will need to be motivating, engaging, and rewarding for those receiving prophylaxis as well as observers thereof, the latter of whom could be provided with compensation for their role. The development of the evidence base on reducing forest malaria must include simian malaria and zoonotic crossover. As the burden of human malaria decreases, the proportion and number of spillover events will only increase given population growth and deforestation activities for agriculture, mining, and settlement activities, requiring vigilance in locations with high intensity of interaction between humans and non-human primates. Malaysia is the first country to demonstrate this trend, where between 2018 and 2020 there were no indigenous cases of human malaria but 8500 reported cases of Plasmodium knowlesi infections in humans.9Nada-Raja T Kadir KA Divis PCS Mohamad DSA Matusop A Singh B Macaca fascicularis and Macaca nemestrina infected with zoonotic malaria parasites are widely distributed in Sarawak, Malaysian Borneo.Sci Rep. 2022; 1210476Crossref PubMed Scopus (1) Google Scholar Forest malaria strategies are also expected to be applicable in Latin America, where human and simian malaria infections in remote Amazonian regions and deforested locales also challenge malaria elimination efforts.1Feachem RGA Chen I Akbari O et al.Malaria eradication within a generation: ambitious, achievable, and necessary.Lancet. 2019; 394: 1056-1112Summary Full Text Full Text PDF PubMed Scopus (151) Google Scholar The recognised ability of chemoprophylaxis to reduce malaria infection in forest settings must therefore extend beyond current emergency measures to eliminate malaria in southeast Asia, and be applied to preventing the spillover of simian malaria into humans, a growing problem for which few solutions are currently available.10Naserrudin NA Monroe A Culleton R et al.Reimagining zoonotic malaria control in communities exposed to Plasmodium knowlesi infection.J Physiol Anthropol. 2022; 41: 14Crossref PubMed Scopus (4) Google Scholar We declare no competing interests. Antimalarial chemoprophylaxis for forest goers in southeast Asia: an open-label, individually randomised controlled trialAntimalarial chemoprophylaxis with artemether–lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion. Full-Text PDF Open Access