The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial.

BACKGROUND: The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, where artemisinin resistance is prevalent. METHODS AND FINDINGS: After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. CONCLUSIONS: Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. TRIAL REGISTRATION: ClinicalTrials.gov NCT01872702.

Numerical Distributions of Parasite Densities During Asymptomatic Malaria.

BACKGROUND: Asymptomatic parasitemia is common even in areas of low seasonal malaria transmission, but the true proportion of the population infected has not been estimated previously because of the limited sensitivity of available detection methods. METHODS: Cross-sectional malaria surveys were conducted in areas of low seasonal transmission along the border between eastern Myanmar and northwestern Thailand and in western Cambodia. DNA was quantitated by an ultrasensitive polymerase chain reaction (uPCR) assay (limit of accurate detection, 22 parasites/mL) to characterize parasite density distributions for Plasmodium falciparum and Plasmodium vivax, and the proportions of undetected infections were imputed. RESULTS: The prevalence of asymptomatic malaria as determined by uPCR was 27.5% (1303 of 4740 people tested). Both P. vivax and P. falciparum density distributions were unimodal and log normal, with modal values well within the quantifiable range. The estimated proportions of all parasitemic individuals identified by uPCR were >70% among individuals infected with P. falciparum and >85% among those infected with P. vivax. Overall, 83% of infections were predicted to be P. vivax infections, 13% were predicted to be P. falciparum infections, and 4% were predicted to be mixed infections. Geometric mean parasite densities were similar; 5601 P. vivax parasites/mL and 5158 P. falciparum parasites/mL. CONCLUSIONS: This uPCR method identified most infected individuals in malaria-endemic areas. Malaria parasitemia persists in humans at levels that optimize the probability of generating transmissible gametocyte densities without causing illness.

The epidemiology of subclinical malaria infections in South-East Asia: findings from cross-sectional surveys in Thailand-Myanmar border areas, Cambodia, and Vietnam.

BACKGROUND: The importance of the submicroscopic reservoir of Plasmodium infections for malaria elimination depends on its size, which is generally considered small in low transmission settings. The precise estimation of this reservoir requires more sensitive parasite detection methods. The prevalence of asymptomatic, sub-microscopic malaria was assessed by a sensitive, high blood volume quantitative real-time polymerase chain reaction method in three countries of the Greater Mekong Sub-region. METHODS: Cross-sectional surveys were conducted in three villages in western Cambodia, four villages along the Thailand-Myanmar border and four villages in southwest Vietnam. Malaria parasitaemia was assessed by Plasmodium falciparum/pan malaria rapid diagnostic tests (RDTs), microscopy and a high volume ultra-sensitive real-time polymerase chain reaction (HVUSqPCR: limit of detection 22 parasites/mL). All villagers older than 6 months were invited to participate. RESULTS: A census before the surveys identified 7355 residents in the study villages. Parasite prevalence was 224/5008 (4 %) by RDT, 229/5111 (5 %) by microscopy, and 988/4975 (20 %) when assessed by HVUSqPCR. Of these 164 (3 %) were infected with P. falciparum, 357 (7 %) with Plasmodium vivax, 56 (1 %) with a mixed infection, and 411 (8 %) had parasite densities that were too low for species identification. A history of fever, male sex, and age of 15 years or older were independently associated with parasitaemia in a multivariate regression model stratified by site. CONCLUSION: Light microscopy and RDTs identified only a quarter of all parasitaemic participants. The asymptomatic Plasmodium reservoir is considerable, even in low transmission settings. Novel strategies are needed to eliminate this previously under recognized reservoir of malaria transmission.

Elimination of Plasmodium falciparum in an area of multi-drug resistance.

BACKGROUND: Resistance to the artemisinin derivatives in Plasmodium falciparum has emerged in Cambodia and is now spreading throughout South-East Asia. The rapid elimination of P. falciparum seems to be the only viable option to avoid a public health disaster but this is difficult because even in low transmission settings many residents have asymptomatic parasitaemias. METHODS: In response to a large number of malaria cases reported in three remote villages on the Thai-Myanmar border where malaria is endemic and the disease is seasonal, surveys were conducted using an ultra-sensitive qPCR assay (LOD 22 parasites per mL). In one of the villages where it was feasible, mass anti-malarial drug administration was proposed to the population as a potential solution, and this was adopted. RESULTS: In the three villages 204/356 (57.3 %), 212/385 (55.1 %) and 195/286 (68.2 %) of the resident populations were positive by qPCR (approximately one-third P. falciparum and two-thirds P. vivax). Of those positive for P. falciparum 62 % carried single point mutations in the P. falciparum kelch protein (a marker of artemisinin resistance). In one of the villages 217 of 674 inhabitants received at least one dose of dihydroartemisinin-piperaquine chemoprevention in June 2012, 155 (71.4 %) received two consecutive months, and 98 (45.2 %) received three treatment doses. The chemoprevention was generally well tolerated. The sub-microscopic reservoir of P. falciparum malaria was eliminated during the six-month follow-up period (prevalence fell from 7 to 0 %); P. vivax malaria persisted (prevalence fell from 35 to 8 %). From June to October 2012 (rainy season) the number of clinical episodes of P. falciparum was six times lower (46), than during the same period in the previous year (290). CONCLUSION: Mass drug administration with dihydroartemisinin-piperaquine may be an effective strategy to eliminate P. falciparum rapidly where multi-drug resistance is present.