Is Cotrimoxazole Prophylaxis Effective to Prevent Malaria in HIV-Infected Pregnant Women?

TO THE EDITOR—We read with great interest the article by Klement et al [1] describing a noninferiority trial of cotrimoxazole (CMX) prophylaxis vs sulfadoxinepyrimethamine intermittent preventive treatment (IPT-SP) against malaria in human immunodeficiency virus (HIV)– infected pregnant women with CD4 >200 cells/μL. This trial helps fill an important evidence gap regarding the effectiveness of CMX to prevent malaria in this specific population. However, we believe that caution should be taken when concluding that CMX efficacy is “at least similar” with that of IPT-SP. Indeed, the sample size did not allow demonstrating noninferiority, although the noninferiority margin was particularly high (12%). Moreover, some secondary endpoints rather favor IPT-SP, regarding efficacy (trend toward reduced incidence of clinical malaria) as well as safety (less anemia and severe anemia). However, 2 important differences between treatment groups could have disadvantaged CMX. First, as women in the CMX group had a significantly lower baseline CD4 count than those in the IPT-SP group (42% vs 23% <350/μL), their susceptibility to malaria could have been increased [2]. Second, the duration of follow-up was significantly shorter in the IPT-SP group, decreasing the time at risk for malaria. Both factors could have biased the results toward increased malaria episodes in the CMX group and contributed to the absence of significance. Moreover, no information is provided on the details of trial implementation. For instance, given that the median number of antenatal visits was 2 in the IPT group, it would be valuable to know which proportion of women actually received the 3 doses of SP. As a result, it is not clear what is the population of women who fully complied with the protocol and should be included in the per protocol (PP) analysis. Only after a careful reading could we hypothesize that “PP analysis” here was more probably an intention-to-treat (ITT) analysis using the last observation carried forward method. This confusion is problematic for the interpretation of data, because in noninferiority design, the conclusions should rely on both ITT and PP analysis [3]. Finally, in contrast to low birth weight and placental infection, which are recognized indicators in malaria in pregnancy [4, 5], clinical malaria is not currently used as an endpoint. Indeed, parasites typically sequester in the placenta and are frequently not detected in the peripheral blood [5]. Additionally, pregnant women in areas of high malaria transmission often remain asymptomatic, though this might be modulated by HIV infection [6]. In summary, it seems difficult to draw definitive answers from this trial, and we agree with the authors’ conclusions that further research is needed to confirm the effectiveness of CMX to prevent malaria in pregnancy in HIV-infected pregnant women. The randomized controlled trial we recently conducted in Benin [7] showed that prophylaxis with CMX alone was not inferior to the association of CMX and mefloquine IPT on placental infection in women with a CD4 count <350 cells/μL, indicating that CMX used alone provides adequate protection in this population.