Chloroquine as weekly chemoprophylaxis or intermittent treatment to prevent malaria in pregnancy in Malawi: a randomised controlled trial.

BACKGROUND: Sulfadoxine-pyrimethamine resistance threatens efficacy of intermittent preventive treatment of malaria during pregnancy, and alternative regimens need to be identified. With the return of chloroquine efficacy in southern Africa, we postulated that chloroquine either as an intermittent therapy or as weekly chemoprophylaxis would be more efficacious than intermittent sulfadoxine-pyrimethamine for prevention of malaria in pregnancy and associated maternal and newborn adverse outcomes. METHODS: We did an open-label, single-centre, randomised controlled trial at Ndirande Health Centre, Blantyre, in southern Malawi. We enrolled pregnant women (first or second pregnancy) at 20-28 weeks' gestation who were HIV negative. Participants were randomly assigned in a 1:1:1 ratio using a computer-generated list to either intermittent sulfadoxine-pyrimethamine (two doses of 1500 mg sulfadoxine and 75 mg pyrimethamine, 4 weeks apart), intermittent chloroquine (two doses of 600 mg on day 1, 600 mg on day 2, and 300 mg on day 3), or chloroquine prophylaxis (600 mg on day 1 then 300 mg every week). The primary endpoint was placental malaria in the modified intent-to-treat population, which consisted of participants who contributed placental histopathology data at birth. Secondary outcomes included clinical malaria, maternal anaemia, low birthweight, and safety. This trial is registered with ClinicalTrials.gov, number NCT01443130. FINDINGS: Between February, 2012, and May, 2014, we enrolled and randomly allocated 900 women, of whom 765 contributed histopathological data and were included in the primary analysis. 108 (14%) women had placental malaria, which was lower than the anticipated prevalence of placental malaria infection. Protection from placental malaria was not improved by chloroquine as either prophylaxis (30 [12%] of 259 had positive histopathology; relative risk [RR] 0·75, 95% CI 0·48-1·17) or intermittent therapy (39 [15%] of 253; RR 1·00, 0·67-1·50) compared with intermittent sulfadoxine-pyrimethamine (39 [15%] of 253). In protocol-specified analyses adjusted for maternal age, gestational age at enrolment, bednet use the night before enrolment, anaemia at enrolment, and malaria infection at enrolment, women taking chloroquine as prophylaxis had 34% lower placental infections than did those allocated intermittent sulfadoxine-pyrimethamine (RR 0·66, 95% CI 0·46-0·95). Clinical malaria was reported in nine women assigned intermittent sulfadoxine-pyrimethamine, four allocated intermittent chloroquine (p=0·26), and two allocated chloroquine prophylaxis (p=0·063). Maternal anaemia was noted in five women assigned intermittent sulfadoxine-pyrimethamine, 15 allocated intermittent chloroquine (p=0·038), and six assigned chloroquine prophylaxis (p>0·99). Low birthweight was recorded for 31 babies born to women allocated intermittent sulfadoxine-pyrimethamine, 29 assigned intermittent chloroquine (p=0·78), and 41 allocated chloroquine prophylaxis (p=0·28). Four women assigned intermittent sulfadoxine-pyrimethamine had adverse events possibly related to study product compared with 94 women allocated intermittent chloroquine (p<0·0001) and 26 allocated chloroquine prophylaxis (p<0·0001). Three women had severe or life-threatening adverse events related to study product, of whom all were assigned intermittent chloroquine (p=0·25). INTERPRETATION: Chloroquine administered as intermittent therapy did not provide better protection from malaria and related adverse effects compared with intermittent sulfadoxine-pyrimethamine in a setting of high resistance to sulfadoxine-pyrimethamine. Chloroquine chemoprophylaxis might provide benefit in protecting against malaria during pregnancy, but studies with larger sample sizes are needed to confirm these results. FUNDING: US National Institutes of Health

TSCQ study: a randomized, controlled, open-label trial of daily trimethoprim-sulfamethoxazole or weekly chloroquine among adults on antiretroviral therapy in Malawi: study protocol for a randomized controlled trial.

BACKGROUND: Before antiretroviral therapy (ART) became widely available in sub-Saharan Africa, several studies demonstrated that daily trimethoprim-sulfamethoxazole (TS) prophylaxis reduced morbidity and mortality among HIV-infected adults. As a result, the World Health Organization (WHO) recommended administering TS prophylaxis to this group. However, the applicability of the results to individuals taking ART and living in sub-Saharan Africa has not been definitively evaluated. This study aims to determine if TS prophylaxis benefits HIV-infected Malawian adults after a good response to ART. If TS prophylaxis does indeed show benefit, it is important to determine if this is due to its antibacterial and/or antimalarial properties. METHODS/DESIGN: A randomized, controlled, open-label, phase III trial of continued standard of care prophylaxis with daily trimethoprim-sulfamethoxazole (TS) compared to discontinuation of standard of care TS prophylaxis and starting weekly chloroquine (CQ) prophylaxis or discontinuation of standard of care TS prophylaxis. The study will randomize 1400-1500 HIV-infected adults (equally divided over the three study arms) with a nondetectable viral load and a CD4 count of 250/mm(3) or more from antiretroviral therapy clinics in Blantyre and Zomba. The expected rate of primary endpoint events of death and WHO stage 3 and 4 events is 6.8 per 100 person-years of follow-up in all participants. Assuming the number of events follows a Poisson distribution and average participant follow-up after 10 % loss to follow-up is 41.6 months, the study will have approximately 85 % power to rule out a reduction of 35 % or more in primary endpoint events in the TS or CQ arms compared to discontinuation of TS prophylaxis-i.e., to show that discontinuation of TS prophylaxis is noninferior to either TS or CQ, with a noninferiority margin of 35 %. Ethical and regulatory approvals were obtained from the University of Malawi College of Medicine Research Ethics Committee; the Malawi Pharmacy, Medicines and Poisons Board; and the University of Maryland Baltimore Institutional Review Board. DISCUSSION: The study began recruitment activities at the Ndirande site in November 2012. The sponsor agreed to extend and expand the study in early 2015, and a second site, Zomba, was added for recruitment and follow-up in mid-2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01650558 (registered on 6 July 2012). PROTOCOL VERSION: Letter of amendment #1 to the DAIDS-ES 10822 TSCQ Malawi Protocol, Version 4.0, 16 December 2014

Brain Swelling and Death in Children with Cerebral Malaria

BACKGROUND: Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS: We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS: Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS: Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors