Malaria Control by Mass Drug Administration With Artemisinin Plus Piperaquine on Grande Comore Island, Union of Comoros.

Background: Mass drug administration (MDA) is a powerful tool for malaria control, but the medicines to use, dosing, number of rounds, and potential selection of drug resistance remain open questions. Methods: Two monthly rounds of artemisinin-piperaquine (AP), each comprising 2 daily doses, were administered across the 7 districts of Grande Comore Island. In 3 districts, low-dose primaquine (PMQLD) was also given on the first day of each monthly round. Plasmodium falciparum malaria rates, mortality, parasitemias, adverse events, and genetic markers of potential drug resistance were evaluated. Results: Average population coverages of 80%-82% were achieved with AP in 4 districts (registered population 258 986) and AP + PMQLD in 3 districts (83 696). The effectiveness of MDA was 96.27% (95% confidence interval [CI], 95.27%-97.06%; P < .00001) in the 4 AP districts and 97.46% (95% CI, 94.54%-98.82%; P < .00001) in the 3 AP + PMQLD districts. In comparative statistical modeling, the effectiveness of the 2 monthly rounds on Grande Comore Island was nearly as high as that of 3 monthly rounds of AP or AP + PMQLD in our earlier study on Anjouan Island. Surveys of pre-MDA and post-MDA samples showed no significant changes in PfK13 polymorphism rates, and no PfCRT mutations previously linked to piperaquine resistance in Southeast Asia were identified. Conclusions: MDA with 2 monthly rounds of 2 daily doses of AP was highly effective on Grande Comore Island. The feasibility and lower expense of this 2-month versus 3-month regimen of AP may offer advantages for MDA programs in appropriate settings.

Artemisinin-piperaquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Grande Comore island: an open-label, non-randomised controlled trial.

BACKGROUND: Malaria significantly rebounded in 2018 in the Comoros; this created an urgent need to conduct clinical trials to investigate the effectiveness of artemisinin and its derivatives. METHODS: An open-label, non-randomised controlled trial of artemisinin-piperaquine (AP) and artemether-lumefantrine (AL) was conducted in Grande Comore island from June 2019 to January 2020. A total of 238 uncomplicated falciparum malaria cases were enrolled and divided 1:1 into two treatments. The primary endpoint was the 42-day adequate clinical and parasitological responses (ACPR). Secondary endpoints were parasitaemia and fever clearance at day 3, gametocytes and tolerability. RESULTS: The 42-day ACPR before and after PCR correction were 91.43% (95% CI 83.93-95.76%) and 98.06% (95% CI 92.48-99.66%) for AP treatment, respectively, and 96.00% (95% CI 88.17-98.14%) and 98.97% (95% CI 93.58-99.95%) for AL treatment, respectively. Complete clearance of the parasitaemia and fever for both groups was detected on day 3. Gametocytes disappeared on day 21 in the AP group and on day 2 in AL group. Specifically, the adverse reactions were mild in both groups. CONCLUSIONS: It was found that AP and AL maintained their high efficacy and tolerance in the Comoros. Nonetheless, asymptomatic malaria infections bring new challenges to malaria control.

Mass Drug Administration With Artemisinin-Piperaquine for the Elimination of Residual Foci of Malaria in São Tomé Island.

Background: Mass drug administration with artemisinin-piperaquine (AP-MDA) is being considered for elimination of residual foci of malaria in Democratic Republic of São Tomé and Principe. Methods: Three monthly rounds of AP-MDA were implemented from July to October 2019. Four zones were selected. A and B were selected as a study site and a control site, respectively. C and D were located within 1.5 and 1.5 km away from the study site, respectively. Parasite prevalence, malaria incidence, and the proportion of the Plasmodium falciparum malaria cases were evaluated. Results: After 3 monthly rounds of AP-MDA, the parasite prevalence and the gametocyte carriage rate of P. falciparum in zone A decreased from 28.29(‰) to 0 and 4.99(‰) to 0, respectively. Compared to zone B, the relative risk for the population with Plasmodium falciparum malaria in zone A was lower (RR = 0.458, 95% CI: 0.146-1.437). Malaria incidence fell from 290.49(‰) (the same period of the previous year) to 15.27(‰) (from the 29th week in 2019 to the 14th week in 2020), a decrease of 94.74% in zone A, and from 31.74 to 5.46(‰), a decline of 82.80% in zone B. Compared to the data of the same period the previous year, the cumulative number of P. falciparum malaria cases were lower, decreasing from 165 to 10 in zone A and from 17 to 4 in zone B. The proportion of the P. falciparum malaria cases on the total malaria cases of the country decreased of 90.16% in zone A and 71.34% in zone C. Conclusion: AP-MDA greatly curbed malaria transmission by reducing malaria incidence in the study site and simultaneously creating a knock-on effect of malaria control within 1.5 km of the study site and within the limited time interval of 38 weeks.

Presence of L1014F Knockdown-Resistance Mutation in Anopheles gambiae s.s. From São Tomé and Príncipe.

Malaria, one of the most serious parasitic diseases, kills thousands of people every year, especially in Africa. São Tomé and Príncipe are known to have stable transmission of malaria. Indoor residual spraying (IRS) of insecticides and long-lasting insecticidal nets (LLIN) are considered as an effective malaria control interventions in these places. The resistance status of Anopheles gambiae s.s. from Agua Grande, Caue, and Lemba of São Tomé and Príncipe to insecticides, such as dichlorodiphenyltrichloroethane (DDT) (4.0%), deltamethrin (0.05%), permethrin (0.75%), fenitrothion (1.0%), and malathion (5.0%), were tested according to the WHO standard protocol. DNA extraction, species identification, as well as kdr and ace-1R genotyping were done with the surviving and dead mosquitoes post testing. They showed resistance to cypermethrin with mortality rates ranging from 89.06% to 89.66%. Mosquitoes collected from Agua Grande, Caue, and Lemba displayed resistance to DDT and fenitrothion with mortality rates higher than 90%. No other species were detected in these study localities other than Anopheles gambiae s.s. The frequency of L1014F was high in the three investigated sites, which was detected for the first time in São Tomé and Príncipe. No ace-1R mutation was detected in all investigated sites. The high frequency of L1014F showed that kdr L1014F mutation might be related to insecticide resistance to Anopheles gambiae s.s. populations from São Tomé and Príncipe. Insecticide resistance status is alarming and, therefore, future malaria vector management should be seriously considered by the government of São Tomé and Príncipe.

Efficacy and Safety of Artemisinin-Piperaquine for the Treatment of Uncomplicated Malaria: A Systematic Review.

OBJECTIVE: The World Health Organization recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria to improve the therapeutic efficacy and limit the choice of drug-resistant parasites. This systematic review and meta-analysis aimed to evaluate the comparative efficacy and safety of artemisinin-piperaquine (AP) in the treatment of uncomplicated malaria relative to other commonly used ACTs. METHODS: As per the PRISMA guidelines, the EMBASE, MEDLINE, the Google Scholar Library, and Cochrane library databases were systematically searched from inception until July 2020 with the following terms: "artemisinin-piperaquine" or "AP." Only randomized controlled trials (RCTs) were included. The competing interventions included dihydroartemisinin-piperaquine (DHA-PPQ), artemether-lumefantrine (AL, Coartem), artesunate-melfloquine (ASAM) and artesunate-amodiaquine (ASAQ, Artekin). Single-arm clinical trial on AP was also assessed. The reported outcomes, including the overall response, cure rate, fever and parasite clearance time, hematology, biochemistry, electrocardiogram (ECG), adverse events, recurrence rate, and sensitivity analyses, were systematically investigated. All data were analyzed using the Review Manager 5.3. RESULTS: A total of seven studies were reviewed, including five RCTs and two single-arm studies. A pooled analysis of 5 RCTs (n = 772) revealed a comparable efficacy on polymerase chain reaction (PCR)-confirmed cure rate between AP and competing interventions in treating uncomplicated malaria. As for the fever and parasite clearance time, due to the lack of complete data in some studies, only 3 studies' data could be used. The patients showed good tolerance to all drugs, and some side-effects (such as headache, anoxia, vomiting, nausea, and dizziness) were reported for every group, but they were self-limited and showed no significant difference. CONCLUSIONS: AP appeared to show similar efficacy and safety, with a simpler mode of administration and easier compliance when compared with other ACTs used in the treatment of uncomplicated malaria. Considering that the potential evolution of drug resistance is of a great concern, additional RCTs with high-quality and more rigorous design are warranted to substantiate the efficacy and safety in different populations and epidemiological regions.

Interactions Between Emodin and Efflux Transporters on Rat Enterocyte by a Validated Ussing Chamber Technique.

Emodin, a major active anthraquinone, frequently interacts with other drugs. As changes of efflux transporters on intestine are one of the essential reasons why the drugs interact with each other, a validated Ussing chamber technique was established to detect the interactions between emodin and efflux transporters, including P-glycoprotein (P-gp), multidrug-resistant associated protein 2 (MRP2), and multidrug-resistant associated protein 3 (MRP3). Digoxin, pravastatin, and teniposide were selected as the test substrates of P-gp, MRP2, and MRP3. Verapamil, MK571, and benzbromarone were their special inhibitors. The results showed that verapamil, MK571, and benzbromarone could increase digoxin, pravastatin, and teniposide absorption, and decrease their Er values, respectively. Verapamil (220 µM) could significantly increase emodin absorption at 9.25 µM. In the presence of MK571 (186 µM), the Papp values of emodin from M-S were significantly increased and the efflux ratio decreased. With the treatment of emodin (185, 370, and 740 µM), digoxin absorption was significantly decreased while teniposide increased. These results indicated that emodin might be the substrate of P-gp and MRP2. Besides, it might be a P-gp inducer and MRP3 inhibitor on enterocyte, which are reported for the first time. These results will be helpful to explain the drug-drug interaction mechanisms between emodin and other drugs and provide basic data for clinical combination therapy.