Four artemisinin-based treatments in African pregnant women with malaria

Abstract

Background: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa.

Methods: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes.

Results: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups).

Conclusions: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).

Figures

Figure 1

Randomization of Patients and the Analysis Populations. A total of five women were excluded after the receipt of the first dose of study medication because of entry-criteria violations. The exclusions from the intention-to-treat population (blue) and the per-protocol population (yellow-green) are based on the efficacy population. The intention-to-treat population excluded women who were lost to follow-up, died, withdrew, or had missing or indeterminate results on polymerase-chain-reaction assay; however, these women were included in the intention-to-treat analyses that used multiple imputations. The per-protocol population also excluded persons with major protocol violations, defined as a violation of the inclusion or exclusion criteria, receipt of a treatment different from the randomly assigned one, missing at least a full day of treatment, intake of other drugs with antimalarial activity, and missing day 63 blood smears.

Figure 2

Differences in PCR-Adjusted and PCR-Unadjusted Treatment Success Rates at Day 63, According to Pairwise Analysis and Country. In the estimation of the polymerase-chain-reaction (PCR)-adjusted cure rate, only recurrent infections that were shown by means of genotyping to be the same infections as those before treatment (recrudescences) were considered to be treatment failures. Conversely, for the estimation of the PCR-unadjusted cure rate, all recurrent infections were considered to be treatment failures. A positive value in the difference reflects a higher cure rate in the treatment listed first. If the difference in the cure rates was less than 5 percentage points (red lines), the treatments were considered to be therapeutically equivalent. Dashed horizontal lines indicate the 95% confidence intervals for the comparisons of treatment groups within a single country; solid horizontal lines are used for comparisons of total data from two countries.