Early initiation of antiretroviral therapy in HIV-infected adults and adolescents: A systematic review

Objectives: The objective of this review was to update evidence on when to initiate antiretroviral therapy (ART) to inform revision of the 2013 WHO guidelines for ART in low and middle-income countries. Design: A systematic review and meta-analysis. Methods: We comprehensively searched the published literature and conferences for randomized controlled trials (RCTs) and cohorts. Outcomes were mortality, clinical progression, virologic failure, immunologic recover, and severe adverse events. We pooled data across studies and estimated summary effect sizes. We graded the quality of evidence from the literature for each outcome. Results: We identified 24 studies; 3 were RCTs. Studies found reduced risk of mortality [1 RCT: hazard ratio 0.77, 95% confidence interval (CI) 0.34-1.76; 13 cohorts: relative risk (RR) 0.66, 95% CI 0.55-0.79], progression to AIDS or death (2 RCTs: RR 0.48, 95% CI 0.26-0.91; 9 cohorts: RR 0.70, 95% CI 0.40-1.24) and diagnosis of a non-AIDSdefining illness (1 RCT: RR 0.14, 95% CI 0.03-0.64; 1 cohort: RR 0.47, 95% CI 0.23-0.98), and an increased risk of grade 3/4 laboratory abnormalities in patients initiating ART at at least 350 cells/ml (1 RCT: RR 1.49, 95% CI 1.25-1.77). The quality of evidence was low or very low for clinical outcomes due to few events and imprecision, and high for adverse events. Conclusions: Our findings contributed to the evidence base for the revised 2013 WHO guidelines on ART, which recommend initiating ART at CD4\+ T-cell counts of 350-500 cells/ml, but not above 500 cells/ml compared to initiating it later when CD4⁺ T-cell counts fall below 350 cells/ml.