Efficacy, safety and tolerability of dihydroartemisinin-piperaquine for treatment of uncomplicated falciparum malaria in pregnancy in Ghana.

Primarily, the study’s original contribution to knowledge is in providing evidence of the safety and efficacy of dihydroartemisinin-piperaquine (DHA-PPQ) use in pregnant women from a clinical trial. DHA-PPQ has potential for use as treatment for uncomplicated malaria in pregnancy. However, there is a paucity of safety data on the use of this drug combination in pregnancy and only two studies have reported its use in pregnancy so far. Additionally, the prevalence of parasite mutations underscoring reported reduced susceptibility to ACTs and SP was assessed to help rationalize drug policy. The diagnostic performance of First Response® malaria rapid diagnostic test (RDT) and perceptions associated with clinical trial participation were assessed in Ghanaian pregnant women to help fill knowledge gaps in these areas. Second and third trimester pregnant women with asymptomatic parasitaemia were randomized to receive DHA-PPQ and artesunate-amodiaquine (ASAQ) in a non-inferiority trial and followed up on days 1, 2, 3, 7, 14, 28 and 42 after start of study treatment, at delivery and 6 weeks post-partum for adverse events, haematological and parasitological outcomes and neonatal morbidity and mortality data. Mutations at the Pfcrt, Pfmdr1, Pfdhfr and Pfdhps genes were investigated using polymerase chain reaction and antigen-antibody reaction-based methods. Results of RDTs at screening were compared to peripheral blood film microscopy used as reference standard. Pregnant women’s perceptions of participating in clinical trials were obtained from in-depth interviews with women who participated in the trials and those who did not. Overall parasitological efficacy for DHA-PPQ was 91.6% (95%CI: 86.7, 95.1) by day 28 and 89.0% (95%CI: 83.6. 93.0) by day 42 in the per protocol population. Efficacy estimates in both arms were comparable. DHA-PPQ was non-inferior to ASAQ with respect to parasite clearance in both analyses populations. There were no harms associated with the use of DHA-PPQ in the second and third trimesters and it fewer adverse events than ASAQ; anorexia (12.0% vs 22.3%; p=0.007), vomiting (19.5% vs 29.4%; p=0.02), dizziness (14.5% vs 26.6%; p=0.003) and general weakness (38.5% vs 62.5%; p<0.0001). Tolerability was high as no participant left the study on account of adverse events experienced. There were no overall changes in white blood cell and differential counts. Close to 90% of parasite isolates from the infected pregnant women were wild type at the Pfcrt gene with a similar prevalence of Pfmdr1 N86 alleles. The Pfdhfr/Pfdhps quintuple mutation containing the 540E allele, known to underlie marked SP resistance, was not observed. Participation in clinical trials appeared to be motivated mainly by anticipated health benefits and trust in the research team especially if they are also health workers. Study women were comfortable with blood sampling in their homes but preferred hospital-based sampling better as it supposedly assures blood samples will be used for desired purposes. They conceptualized treatment-emergent adverse events as independent entities that should be separated from drugs. Dihydroartemisinin-piperaquine is deemed safe and as effective as ASAQ when used to treat uncomplicated malaria during pregnancy. The study results are expected to contribute to evidence that will guide a policy decision on the use of DHA-PPQ use in pregnant women. The predominance of Pfcrt K76 suggests the possibility of using chloroquine again in pregnancy but this will have to be in combination with another antimalarial. The predominance of Pfcrt K76 and Pfmdr1 N86 alleles appear to suggest early declining susceptibility to artemether-lumefantrine, an artemisinin-based combination treatment currently used in pregnancy. Strengthened targeting of ACT treatment through more dedicated malaria infection testing using tools such as RDTs and monitoring are required. Researchers planning similar studies in pregnant women in the study area need to emphasize transportation to health facilities for blood sampling and potential health benefits.

Source: KNUST