Improved Growth and Anemia in HIV-Infected African Children Taking Cotrimoxazole Prophylaxis
MRC Clinical Trials Unit, London, United Kingdom.Clinical Infectious Diseases (Impact Factor: 8.89). 04/2011; 52(7):953-6. DOI: 10.1093/cid/cir029
The impact of cotrimoxazole (CTX) on growth and/or anemia was investigated in 541 human immunodeficiency virus-infected, antiretroviral therapy-naive Zambian children enrolled in the Children with HIV Antibiotic Prophylaxis trial. Compared with children randomized to receive placebo, children randomized to receive CTX had slower decreases in weight-for-age (P=.04) and height-for-age (P=.01), and greater increase in hemoglobin level (P=.01). These findings argue for expanded early CTX use.
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ABSTRACT: HIV infection affects the clinical pattern of malaria. There is emerging evidence to suggest that previously documented interactions may be modified by recently scaled-up HIV and malaria interventions. Prophylaxis with trimethoprim-sulfamethoxazole (TS) in combination with use of insecticide-treated nets can markedly decrease the incidence of malaria in HIV-infected pregnant and nonpregnant adults and children even in the setting of antifolate resistance-conferring mutations that are currently common in Africa. Nonetheless, additional interventions are needed to protect HIV-infected people that reside in high-malaria-transmission areas. Artemether-lumefantrine and dihydroartemisinin-piperaquine are highly efficacious and safe for the treatment of uncomplicated malaria in HIV-infected persons. Coadministration of antiretroviral and antimalarial drugs creates the potential for pharmacokinetic drug interactions that may increase (causing enhancement of malaria treatment efficacy and post-treatment prophylaxis and/or unanticipated toxicity) or reduce (creating risk for treatment failure) antimalarial drug exposure. Further studies are needed to elucidate potentially important pharmacokinetic interactions between commonly used antimalarials, antiretrovirals and TS and their clinical implications. Data on the benefits of long-term TS prophylaxis among HIV patients on antiretroviral therapy who have achieved immune-reconstitution are limited. Studies to address these questions are ongoing or planned, and the results should provide the evidence base required to guide the prevention and treatment of malaria in HIV-infected patients.Future Virology 07/2012; 7(7):699-708. DOI:10.2217/FVL.12.59 · 1.01 Impact Factor
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ABSTRACT: BACKGROUND: No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). METHODS: In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. This trial is registered, ISRCTN24791884. FINDINGS: 1206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and groups A (n=397), B (n=404), and C (n=405). 47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1·13, 95% CI 0·73-1·73, p=0·59; non-inferiority criterion met). However, in years 2-5, rates were higher in children on clinically driven monitoring (1·3 vs 0·4 per 100 child-years, difference 0·99, 0·37-1·60, p=0·002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0·98, 0·83-1·16, p=0·83). Mean CD4 percentage change did not differ between ART groups at week 72 (16·5% [SD 8·6] vs 17·1% [8·5] vs 17·3% [8·0], p=0·33) or week 144 (p=0·69), but four-drug groups (B, C) were superior to three-drug group A at week 36 (12·4% [7·2] vs 14·1% [7·1] vs 14·6% [7·3], p<0·0001). Excess grade 3 or 4 events in groups B (one or more events reported by 157 [40%] children in A, 190 [47%] in B; HR [B:A] 1·32, 1·07-1·63) and C (218 [54%] children in C; HR [C:A] 1·58, 1·29-1·94; global p=0·0001) were driven by asymptomatic neutropenia in zidovudine-containing groups (B, C; 86 group A, 133 group B, 184 group C), but resulted in drug substitutions in only zero versus two versus four children, respectively. INTERPRETATION: NNRTI plus NRTI-based three-drug or four-drug ART can be given across childhood without routine toxicity monitoring; CD4 monitoring provided clinical benefit after the first year on ART, but event rates were very low and long-term survival high, suggesting ART rollout should take priority. CD4 benefits from four-drug induction were not durable, but three-NRTI long-term maintenance was immunologically and clinically similar to NNRTI-based ART and could be valuable during tuberculosis co-treatment.The Lancet 03/2013; 381(9875):1391-403. · 45.22 Impact Factor
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ABSTRACT: To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect. Systematic review and meta-analysis. Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science. Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention. Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. In random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions. Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. The antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.BMJ (online) 01/2014; 348:g2267. · 17.45 Impact Factor
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