BACKGROUNDUniversal antiretroviral therapy (ART) with annual population testing and a multidisease, patient-centered strategy could reduce new human immunodeficiency virus (HIV) infections and improve community health. METHODSWe randomly assigned 32 rural communities in Uganda and Kenya to baseline HIV and multidisease testing and national guideline-restricted ART (control group) or to baseline testing plus annual testing, eligibility for universal ART, and patient-centered care (intervention group). The primary end point was the cumulative incidence of HIV infection at 3 years. Secondary end points included viral suppression, death, tuberculosis, hypertension control, and the change in the annual incidence of HIV infection (which was evaluated in the intervention group only). RESULTSA total of 150,395 persons were included in the analyses. Population-level viral suppression among 15,399 HIV-infected persons was 42% at baseline and was higher in the intervention group than in the control group at 3 years (79% vs. 68%; relative prevalence, 1.15; 95% confidence interval [CI], 1.11 to 1.20). The annual incidence of HIV infection in the intervention group decreased by 32% over 3 years (from 0.43 to 0.31 cases per 100 personyears; relative rate, 0.68; 95% CI, 0.56 to 0.84). However, the 3-year cumulative incidence (704 incident HIV infections) did not differ significantly between the intervention group and the control group (0.77% and 0.81%, respectively; relative risk, 0.95; 95% CI, 0.77 to 1.17). Among HIV-infected persons, the risk of death by year 3 was 3% in the intervention group and 4% in the control group (0.99 vs. 1.29 deaths per 100 person-years; relative risk, 0.77; 95% CI, 0.64 to 0.93). The risk of HIV-associated tuberculosis or death by year 3 among HIV-infected persons was 4% in the intervention group and 5% in the control group (1.19 vs. 1.50 events per 100 person-years; relative risk, 0.79; 95% CI, 0.67 to 0.94). At 3 years, 47% of adults with hypertension in the intervention group and 37% in the control group had hypertension control (relative prevalence, 1.26; 95% CI, 1.15 to 1.39). CONCLUSIONSUniversal HIV treatment did not result in a significantly lower incidence of HIV infection than standard care, probably owing to the availability of comprehensive baseline HIV testing and the rapid expansion of ART eligibility in the control group. (Funded by the National Institutes of Health and others; SEARCH ClinicalTrials.gov number, NCT01864603.

clinicaltrials.gov Identifier: NCT01864683.

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BackgroundChildren are highly susceptible to tuberculosis; thus, there is need for safe and effective preventive interventions. Our objective was to evaluate the efficacy of isoniazid in prevention of tuberculosis morbidity and mortality in children aged 15 years or younger by performing a meta-analysis of randomized controlled trials. To our knowledge, this is the first meta-analysis evaluating efficacy of isoniazid prophylaxis in prevention of tuberculosis in children.MethodsA systematic search of the literature was done to identify randomized controlled trials evaluating isoniazid prophylaxis efficacy among children. Each study was evaluated for relevance and validity for inclusion in the analysis. Subgroup analyses were conducted based on study quality, HIV status, tuberculosis endemicity, type of prophylaxis and age of participants.ResultsEight studies comprising 10,320 participants were included in this analysis. Upon combining data from all eight studies, isoniazid prophylaxis was found to be efficacious in preventing development of tuberculosis, with a pooled RR of 0.65 (95% CI 0.47, 0.89) p = 0.004 , with confidence intervals adjusted for heterogeneity. Among the sub-group analyses conducted, only age of the participants yielded dramatic differences in the summary estimate of efficacy, suggesting that age might be an effect modifier of the efficacy of isoniazid among children, with no effect realised in children initiating isoniazid at four months of age or earlier and an effect being present in older children. Excluding studies in which isoniazid was initiated at four months of age or earlier yielded an even stronger effect (RR = 0.41 (95% CI 0.31, 0.55) p <0.001). Data on the effect of isoniazid on all-cause mortality, excluding studies in which isoniazid was initiated in infants, yielded an imprecise estimate of mortality benefit (RR = 0.58 (95% CI 0.31, 1.09) p = 0.092).ConclusionIsoniazid prophylaxis reduces the risk of developing tuberculosis by 59% among children aged 15 years or younger excluding children initiated during early infancy for primary prophylaxis (RR = 0.41, 95% CI 0.31, 0.55 p < 0.001) . However, further studies are needed to assess effects on mortality and to determine prophylaxis effectiveness in very young children and among HIV-infected children.