Summary Background Every year, more than 32 million pregnancies in sub-Saharan Africa are at risk of malaria infection and its adverse consequences. The effectiveness of the intermittent preventive ...treatment with sulfadoxine–pyrimethamine strategy recommended by WHO is threatened by high levels of parasite resistance. We aimed to assess the efficacy and safety of two alternative strategies: intermittent screening with malaria rapid diagnostic tests and treatment of women who test positive with dihydroartemisinin–piperaquine, and intermittent preventive treatment with dihydroartemisinin–piperaquine. Methods We did this open-label, three-group, randomised controlled superiority trial at four sites in western Kenya with high malaria transmission and sulfadoxine–pyrimethamine resistance. HIV-negative pregnant women between 16 and 32 weeks' gestation were randomly assigned (1:1:1), via computer-generated permuted-block randomisation (block sizes of three, six, and nine), to receive intermittent screening and treatment with dihydroartemisinin–piperaquine, intermittent preventive treatment with dihydroartemisinin–piperaquine, or intermittent preventive treatment with sulfadoxine–pyrimethamine. Study participants, study clinic nurses, and the study coordinator were aware of treatment allocation, but allocation was concealed from study investigators, delivery unit nurses, and laboratory staff. The primary outcome was malaria infection at delivery, defined as a composite of peripheral or placental parasitaemia detected by placental histology, microscopy, or rapid diagnostic test. The primary analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov , number NCT01669941. Findings Between Aug 21, 2012, and June 19, 2014, we randomly assigned 1546 women to receive intermittent screening and treatment with dihydroartemisinin–piperaquine (n=515), intermittent preventive treatment with dihydroartemisinin–piperaquine (n=516), or intermittent preventive treatment with sulfadoxine–pyrimethamine (n=515); 1368 (88%) women comprised the intention-to-treat population for the primary endpoint. Prevalence of malaria infection at delivery was lower in the intermittent preventive treatment with dihydroartemisinin–piperaquine group than in the intermittent preventive treatment with sulfadoxine–pyrimethamine group (15 3% of 457 women vs 47 10% of 459 women; relative risk 0·32, 95% CI 0·18–0·56; p<0·0001), but not in the intermittent screening and treatment with dihydroartemisinin–piperaquine group (57 13% of 452 women; 1·23, 0·86–1·77; p=0·26). Compared with intermittent preventive treatment with sulfadoxine–pyrimethamine, intermittent preventive treatment with dihydroartemisinin–piperaquine was associated with a lower incidence of malaria infection during pregnancy (192·0 vs 54·4 events per 100 person-years; incidence rate ratio IRR 0·28, 95% CI 0·22–0·36; p<0·0001) and clinical malaria during pregnancy (37·9 vs 6·1 events; 0·16, 0·08–0·33; p<0·0001), whereas intermittent screening and treatment with dihydroartemisinin–piperaquine was associated with a higher incidence of malaria infection (232·0 events; 1·21, 1·03–1·41; p=0·0177) and clinical malaria (53·4 events; 1·41, 1·00–1·98; p=0·0475). We recorded 303 maternal and infant serious adverse events, which were least frequent in the intermittent preventive treatment with dihydroartemisinin–piperaquine group. Interpretation At current levels of rapid diagnostic test sensitivity, intermittent screening and treatment is not a suitable alternative to intermittent preventive treatment with sulfadoxine–pyrimethamine in the context of high sulfadoxine–pyrimethamine resistance and malaria transmission. However, dihydroartemisinin–piperaquine is a promising alternative drug to replace sulfadoxine–pyrimethamine for intermittent preventive treatment. Future studies should investigate the efficacy, safety, operational feasibility, and cost-effectiveness of intermittent preventive treatment with dihydroartemisinin–piperaquine. Funding The Malaria in Pregnancy Consortium , which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine.
Summary Background Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and ...received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. Methods We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)–Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks–4 months, 5–17 months), and by baseline CD4% (<10, 10–14, 15–19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov , number NCT01148459. Findings Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6–51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3–46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8–1·6). 20 (20·2%, 95% CI 12·8–29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3–19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7–11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1–9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients). Interpretation RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes. Funding GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.
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