The decline of malaria in Vietnam, 1991-2014.

BACKGROUND: Despite the well-documented clinical efficacy of artemisinin-based combination therapy (ACT) against malaria, the population-level effects of ACT have not been studied thoroughly until recently. An ideal case study for these population-level effects can be found in Vietnam's gradual adoption of artemisinin in the 1990s. METHODS AND RESULTS: Analysis of Vietnam's national annual malaria reports (1991-2014) revealed that a 10% increase in artemisinin procurement corresponded to a 32.8% (95% CI 27.7-37.5%) decline in estimated malaria cases. There was no consistent national or regional effect of vector control on malaria. The association between urbanization and malaria was generally negative and sometimes statistically significant. CONCLUSIONS: The decline of malaria in Vietnam can largely be attributed to the adoption of artemisinin-based case management. Recent analyses from Africa showed that insecticide-treated nets had the greatest effect on lowering malaria prevalence, suggesting that the success of interventions is region-specific. Continuing malaria elimination efforts should focus on both vector control and increased access to ACT.

Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria.

The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).

A Randomized Comparison of Chloroquine Versus Dihydroartemisinin-Piperaquine for the Treatment of Plasmodium vivax Infection in Vietnam.

A total of 128 Vietnamese patients with symptomatic Plasmodium vivax mono-infections were enrolled in a prospective, open-label, randomized trial to receive either chloroquine or dihydroartemisinin-piperaquine (DHA-PPQ). The proportions of patients with adequate clinical and parasitological responses were 47% in the chloroquine arm (31 of 65 patients) and 66% in the DHA-PPQ arm (42 of 63 patients) in the Kaplan-Meier intention-to-treat analysis (absolute difference 19%, 95% confidence interval = 0-37%), thus establishing non-inferiority of DHA-PPQ. Fever clearance time (median 24 versus 12 hours,P= 0.02), parasite clearance time (median 36 versus 18 hours,P< 0.001), and parasite clearance half-life (mean 3.98 versus 1.80 hours,P< 0.001) were all significantly shorter in the DHA-PPQ arm. All cases of recurrent parasitemia in the chloroquine arm occurred from day 33 onward, with corresponding whole blood chloroquine concentration lower than 100 ng/mL in all patients. Chloroquine thus remains efficacious for the treatment of P. vivax malaria in southern Vietnam, but DHA-PPQ provides more rapid symptomatic and parasitological recovery.

Measuring the association between artemisinin-based case management and malaria incidence in southern Vietnam, 1991-2010.

In addition to being effective, fast-acting, and well tolerated, artemisinin-based combination therapies (ACTs) are able to kill certain transmission stages of the malaria parasite. However, the population-level impacts of ACTs on reducing malaria transmission have been difficult to assess. In this study on the history of malaria control in Vietnam, we assemble annual reporting on malaria case counts, coverage with insecticide-treated nets (ITN) and indoor residual spraying (IRS), and drug purchases by provincial malaria control programs from 1991 to 2010 in Vietnam's 20 southern provinces. We observe a significant negative association between artemisinin use and malaria incidence, with a 10% absolute increase in the purchase proportion of artemisinin-containing regimens being associated with a 29.1% (95% confidence interval: 14.8-41.0%) reduction in slide-confirmed malaria incidence, after accounting for changes in urbanization, ITN/IRS coverage, and two indicators of health system capacity. One budget-related indicator of health system capacity was found to have a smaller association with malaria incidence, and no other significant factors were found. Our findings suggest that including an artemisinin component in malaria drug regimens was strongly associated with reduced malaria incidence in southern Vietnam, whereas changes in urbanization and coverage with ITN or IRS were not.

In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam.

BACKGROUND: By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. METHODS: From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. RESULTS: 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). CONCLUSIONS: This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam. TRIAL REGISTRATION: NTC01165372.