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

Abstract

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.

Keywords: Antiretroviral therapy; First-line; HIV; Network meta-analysis.

Fig. 1

Flow diagram for study selection of trial publications of clinical trials comparing antiretroviral therapy on adults and adolescents living with HIV.

Fig. 2

Network of evidence for adults and adolescents. Legend: Circles (nodes) in the diagrams represent individual treatments, lines between circles represent availability of head-to-head evidence between two treatments, and the numbers on the lines are the number of RCTs informing each head-to-head comparison. Blue: NNRTIs; Green: Protease inhibitors; Orange: Integrase inhibitors. ATV/r: ritonavir-boosted atazanavir; BIC: bictegravir; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EVG/c: Elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine.

Fig. 3

Comparisons of treatments with respect to viral suppression over time relative to treatment initiation. ATV/r: ritonavir-boosted atazanavir; BIC: bictegravir; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EVG/c: Elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine.

Fig. 4

Forest plot of odds ratios obtained through network meta-analyses comparing dolutegravir to standard and low-dose efavirenz: for (A) measures of efficacy and (B) measures of tolerability and safety DTG: dolutegravir; EFV₆₀₀: standard-dose efavirenz; EFV₄₀₀: low-dose efavirenz; AE: adverse events; SAE: serious adverse events; OR: odds ratio; CrI: credible interval; MA: meta-analysis; NMA:network meta-analysis.

Fig. 5

Modelled risk of birth and maternal outcomes among women using dolutegravir and efavirenz DTG: dolutegravir; EFV: efavirenz; SGA: small for gestational age Proportion of patients with virologic response with the following definitions: - Plasma HIV RNA <50 copies/ml at week 24 - Rate of strategy discontinuation and treatment changes - Proportion of death - Proportion of patients loss to follow-up24 weeks; Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml24 and 48 weeks; Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 4848 weeks; Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0At the time of virologic failure; Evolution of CD4 cell counts from baseline to week 4848 weeks; Frequency, type and time to a new AIDS-defining event or deathThrough out the trial; Frequency, type, time to grade 3 or 4 adverse eventThrough out the trial; Rate of success of TB treatment48 weeks; Anti-TB resistance rate48 weeks; Evolution of raltegravir and efavirenz trough concentrationThrough out the trial.