Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis

Background To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. Methods We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework. Findings We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92). Interpretation The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable. Funding WHO.