Artemisinin-based combination therapy in pregnant women in Zambia: efficacy, safety and risk of recurrent malaria

Abstract

BackgroundIn Zambia, malaria is one of the leading causes of morbidity and mortality, especially among under five children and pregnant women. For the latter, the World Health Organization recommends the use of artemisinin-based combination therapy (ACT) in the second and third trimester of pregnancy. In a context of limited information on ACT, the safety and efficacy of three combinations, namely artemether–lumefantrine (AL), mefloquine–artesunate (MQAS) and dihydroartemisinin–piperaquine (DHAPQ) were assessed in pregnant women with malaria.MethodsThe trial was carried out between July 2010 and August 2013 in Nchelenge district, Luapula Province, an area of high transmission, as part of a multi-centre trial. Women in the second or third trimester of pregnancy and with malaria were recruited and randomized to one of the three study arms. Women were actively followed up for 63 days, and then at delivery and 1 year post-delivery.ResultsNine hundred pregnant women were included, 300 per arm. PCR-adjusted treatment failure was 4.7% (12/258) (95% CI 2.7–8.0) for AL, 1.3% (3/235) (95% CI 0.4–3.7) for MQAS and 0.8% (2/236) (95% CI 0.2–3.0) for DHAPQ, with significant risk difference between AL and DHAPQ (p = 0.01) and between AL and MQAS (p = 0.03) treatments. Re-infections during follow up were more frequent in the AL (HR: 4.71; 95% CI 3.10–7.2; p < 0.01) and MQAS (HR: 1.59; 95% CI 1.02–2.46; p = 0.04) arms compared to the DHAPQ arm. PCR-adjusted treatment failure was significantly associated with women under 20 years [Hazard Ratio (HR) 5.35 (95% CI 1.07–26.73; p = 0.04)] and higher malaria parasite density [3.23 (95% CI 1.03–10.10; p = 0.04)], and still women under 20 years [1.78, (95% CI 1.26–2.52; p < 0.01)] had a significantly higher risk of re-infection. The three treatments were generally well tolerated. Dizziness, nausea, vomiting, headache and asthenia as adverse events (AEs) were more common in MQAS than in AL or DHAPQ (p < 0.001). Birth outcomes were not significantly different between treatment arms.ConclusionAs new infections can be prevented by a long acting partner drug to the artemisinins, DHAPQ should be preferred in places as Nchelenge district where transmission is intense while in areas of low transmission intensity AL or MQAS may be used.

Artemeter-Lumefantrine therapeutic efficacy, safety and plasma levels in patients with uncomplicated falciparum malaria from the Colombian Pacific región

“…The treatment was generally well tolerated and no serious adverse events were observed. This finding is consistent with other studies in which no serious adverse effects were reported 22,[26][27] . Antimalarial drug's efficacy depends not only on the parasite susceptibility to the drug and on its blood concentration but also on the host's immunity.…”

Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges

“…Baseline characteristics were assessed as risk factors of parasite clearance (n = 1) [ 36 ], recrudescence (n = 2) [ 51 , 65 ] and recurrence (n = 3) [ 52 , 67 , 71 ]. One study reported gestation (early second trimester) to be associated with faster parasite clearance than late second trimester but not fever clearance [ 36 ].…”

“…For recrudescence, higher baseline parasitaemia and younger maternal age were associated with higher risk in one study [ 51 ], while the other study did not find significant association with parasitaemia [ 65 ]. Gestational age (n = 2) [ 51 , 65 ], gravidity (n = 1) [ 51 ], haemoglobin concentration (n = 1) [ 51 ], body mass index (n = 1) [ 65 ] and symptomatic infection (n = 1) [ 51 ] were not significant risk factors of recrudescence.…”

“…The relationship between placental malaria, which is a direct consequence of malaria infection, and treatment outcomes for each malaria episode is not fully understood and may be heavily biased by gestational age at infection [ 105 ]. In this context, PCR-uncorrected ACPR, in which the half-life of drugs will play a key role, becomes an important indicator for choosing treatment options especially in high endemic settings [ 51 ]. Efficacy cannot be discussed separately from pregnancy outcomes as drugs may affect the fetus.…”

Metabolism of Piperaquine to Its Antiplasmodial Metabolites and Their Pharmacokinetic Profiles in Healthy Volunteers

“…A rtemisinin drugs (dihydroartemisinin, artemether, and artesunate) are effective against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum (1). To avoid the rapid development of drug resistance, artemisinin drugs are recommended to be used in the clinic as part of combination treatment therapies (artemisinin drug-based combination therapy [ACT]); i.e., the artemisinin drug provides the major contribution to the rapid clearance of P. falciparum, whereas the concomitant partner antimalarial with a prolonged half-life is involved in eliminating residual parasites (2,3). Though the artemisinin derivatives are generally effective, it has been observed that the effectiveness of the main artemisinin drugs in Southeast Asia has been diminished due to parasite resistance (4,5).…”