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A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.

ABSTRACT: BACKGROUND:Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole. METHODS:We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolescents in Uganda and Zimbabwe. Eligible participants were older than 3 years of age, had been receiving ART for more than 96 weeks, were using insecticide-treated bed nets (in malaria-endemic areas), and had not had Pneumocystis jirovecii pneumonia. Coprimary end points were hospitalization or death and adverse events of grade 3 or 4. RESULTS:A total of 758 participants were randomly assigned to stop or continue co-trimoxazole (382 and 376 participants, respectively), after receiving ART for a median of 2.1 years (interquartile range, 1.8 to 2.3). The median age was 7.9 years (interquartile range, 4.6 to 11.1), and the median CD4 T-cell percentage was 33% (interquartile range, 26 to 39). Participants who stopped co-trimoxazole had higher rates of hospitalization or death than those who continued (72 participants [19%] vs. 48 [13%]; hazard ratio, 1.64; 95% confidence interval [CI], 1.14 to 2.37; P?=?0.007; noninferiority not shown). There was no evidence of variation across ages (P=0.93 for interaction). A total of 2 participants in the prophylaxis-stopped group (1%) died, as did 3 in the prophylaxis-continued group (1%). Most hospitalizations in the prophylaxis-stopped group were for malaria (49 events, vs. 21 in the prophylaxis-continued group) or infections other than malaria (53 vs. 25), particularly pneumonia, sepsis, and meningitis. Rates of adverse events of grade 3 or 4 were similar in the two groups (hazard ratio, 1.20; 95% CI, 0.83 to 1.72; P=0.33), but more grade 4 adverse events occurred in the prophylaxis-stopped group (hazard ratio, 2.04; 95% CI, 0.99 to 4.22; P=0.05), with anemia accounting for the largest number of events (12, vs. 2 with continued prophylaxis). CONCLUSIONS:Continuing co-trimoxazole prophylaxis after 96 weeks of ART was beneficial, as compared with stopping prophylaxis, with fewer hospitalizations for both malaria and infection not related to malaria. (Funded by the United Kingdom Medical Research Council and others; ARROW Current Controlled Trials number, ISRCTN24791884.).

SUBMITTER: Bwakura-Dangarembizi M

PROVIDER: S-EPMC4264559 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.

Bwakura-Dangarembizi Mutsawashe M Kendall Lindsay L Bakeera-Kitaka Sabrina S Nahirya-Ntege Patricia P Keishanyu Rosette R Nathoo Kusum K Spyer Moira J MJ Kekitiinwa Adeodata A Lutaakome Joseph J Mhute Tawanda T Kasirye Philip P Munderi Paula P Musiime Victor V Gibb Diana M DM Walker A Sarah AS Prendergast Andrew J AJ

The New England journal of medicine 20140101 1

<h4>Background</h4>Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole.<h4>Methods</h4>We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolesce ...[more]

PMID: 24382064

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Project description:There are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis.Of 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96 weeks on ART, children older than 3 years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models.After a median of 4 years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95% CI, 1.5-2.4), and was highest in the first 12 weeks following ART initiation (8.8/100 child-years (5.2-13.4) versus 1.2/100 child-years (0.8-1.6) after 52 weeks). A higher TB risk was independently associated with younger age (<3 years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTI?+?2NRTI. Over the median 2 years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue)?=?3.0 (95% CI, 1.1-8.3), P?=?0.028). TB risk was also independently associated with lower current CD4 percent (P <0.001).TB incidence varies over time following ART initiation, and is particularly high during the first 3 months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96 weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB.

Project description:ImportanceAdvantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission.ObjectiveTo evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure.Design, setting, and participantsRandomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization.InterventionsParticipants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148).Main outcomes and measuresRisk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points.ResultsThe Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to ∞) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to ∞). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.Conclusions and relevanceAmong HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.Trial registrationclinicaltrials.gov Identifier: NCT01146873.

Project description:BackgroundCo-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults.MethodsParticipants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779.Findings3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on ART was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or BMI (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68].InterpretationOur results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa.FundingUK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Project description:IntroductionCo-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale-up of maternal antiretroviral therapy, most children remain HIV-exposed uninfected (HEU) and the benefits of universal co-trimoxazole are uncertain. We assessed the effect of co-trimoxazole on mortality and morbidity of children who are HEU.MethodsWe performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa-Wide Information, SciELO and WHO Global Index Medicus for peer-reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co-trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity.ResultsWe screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co-trimoxazole prophylaxis started at 2-6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub-studies found that antimicrobial resistance was higher in infants receiving co-trimoxazole. Two trials in Uganda investigating prolonged co-trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence.DiscussionStudies show no clinical benefit of co-trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co-trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non-malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings.ConclusionsIn low-mortality settings with few HIV transmissions and well-performing early infant diagnosis and treatment programmes, universal co-trimoxazole may not be required.

Project description:BackgroundFood insecurity can contribute to poor adherence to both tuberculosis treatment and HIV antiretroviral therapy (ART). Interventions that target food insecurity have the potential to increase treatment adherence, improve clinical outcomes, and decrease mortality. The goals of this study were to compare the feasibility, acceptability, and potential impact of implementing two different forms of nutrition support for HIV-TB co-infected adults in the Casamance region of Senegal.MethodsWe conducted a randomized pilot implementation study among HIV-TB co-infected adults initiating treatment for TB (ClinicalTrials.gov Identifier: NCT03711721). Subjects received nutrition support in the form of a local food basket or Ready-to-Use Therapeutic Food (RUTF), distributed on a monthly basis for six months.ResultsA total of 178 monthly study encounters were completed by 26 HIV-TB co-infected adults; 14 received food baskets and 12 received RUTF. For both the food basket and RUTF, 100% of subjects obtained the supplement at every study encounter, transferred the supplement from the clinic to their household, and consumed the supplement. The food basket had greater acceptability and was more likely to be shared with members of the household. Adherence to TB treatment and ART exceeded 95%, and all outcomes, including CD4 cell count, hemoglobin, nutritional status, and food security, improved over the study period. All subjects completed TB treatment and were smear negative at treatment completion. The total cost of the local food basket was approximately $0.68 per day versus $0.99 for the RUTF.ConclusionThe implementation of nutrition support for HIV-TB co-infected adults in Senegal is feasible and may provide an effective strategy to improve adherence, treatment completion, and clinical outcomes for less than 1 USD per day. Further studies to determine the impact of nutrition support among a larger population of HIV-TB co-infected individuals are indicated.

Project description:BackgroundCo-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear.MethodsHEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14-34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761.FindingsFrom June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference -0·2%, 95% CI -1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3-4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3-4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3-4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21).InterpretationProphylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV.FundingUS National Institutes of Health.

Dataset Information

A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.

Publications

A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.

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