Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial

Abstract

BackgroundThe World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.Methods and FindingsA randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28–42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.ConclusionsIPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.Trial RegistrationClinicalTrials.gov (NCT01103063).

New developments in anti-malarial target candidate and product profiles

“…The significant reduction in the incidence of overall malaria infection over the last 15 years has been achieved by protecting the at-risk populations, particularly with insecticide-treated bed nets [55] and spraying with insecticides and larvicides [56]. Vaccination represents another potential strategy, and although recent results with the RTS,S vaccine are encouraging, they are currently far from the level required to drive eradication alone [57, 58].…”

Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin–piperaquine versus intermittent preventive treatment with sulfadoxine–pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial

“…4,10 The search for safe, effective, and well-tolerated alternative drugs to replace sulfadoxine–pyrimethamine for intermittent preventive treatment during pregnancy has proven elusive. 11–16 …”

A Randomized Open-Label Evaluation of the Antimalarial Prophylactic Efficacy of Azithromycin-Piperaquine versus Sulfadoxine-Pyrimethamine in Pregnant Papua New Guinean Women

“…The WHO currently recommends administering sulfadoxine-pyrimethamine (SP) as IPTp at each scheduled antenatal visit after the first trimester in areas with moderate or high rates of malaria transmission (3,4). However, the widespread development of SP-resistant Plasmodium falciparum has prompted the search for alternative IPTp therapies (5)(6)(7), including those containing the macrolide antibiotic azithromycin (AZ) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…Its modest antimalarial efficacy as monotherapy (21,(25)(26)(27) is increased when it is coadministered with a pharmacologically compatible partner drug (25). To date, AZ has been combined successfully with SP and chloroquine (CQ) in IPTp in a number of African countries (16,18,20,25) and Papua New Guinea (PNG) (9,10). However, the effectiveness of combinations with these conventional agents can be compromised by using failing drugs as partners (28), suggesting that novel antimalarials should also be assessed for this role.…”

“…A single safety and pharmacokinetic study of AZ-PQ given as 1 g AZ plus 960 mg PQ daily for 3 days to pregnant PNG women showed that it was safe and generally well tolerated (14) apart from gastrointestinal side effects, which have also been reported when AZ (10,18,21) and PQ (32, 34) are given separately. As an extension of this study, we conducted a randomized efficacy study using the same AZ-PQ regimen and conventional SP treatment in pregnant women from PNG.…”