Efficacy and safety of dolutegravir relative to commonly-used 3rd-agents at 96-weeks in treatment-naïve HIV-1-infected patients: a systematic review and network meta-analysis

Background: Network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated relative efficacy and safety of dolutegravir (DTG) vs. guideline-recommended 3rd-agents efavirenz (EFV), rilpivirine (RPV), raltegravir (RAL), elvitegravir-cobicistat (EVG/c), ritonavir-boosted darunavir (DRV/r), atazanavir (ATV/r), and lopinavir (LPV/r) in treatment-naïve HIV-1-infected patients at 96-weeks via network meta-analysis.
Methods: Systematic review identified Phase 3/4 RCTs (up to August 2013) including 3rd-agents of interest in combination with 2 backbone NRTIs. Bayesian fixed effects models estimated relative probability of HIV-RNA < 50 copies/mL, change in CD4 cells/µL (adjusted for NRTI backbone type [TDF/FTC, ABC/3TC, or other]), lipid changes, and discontinuation due to adverse events (AEs).
Results: 14 studies (>8,500 patients) were combined in the analyses. Backbone-adjusted/unadjusted efficacy and safety results are presented in Table 1. DTG had a statistically higher probability of virologic suppression compared to all treatments and significantly greater increases in CD4 cells against EFV and RPV.

Table 1: Odds ratios and mean differences (change from baseline) for efficacy and safety at 96wk [mean (95% CrI)]

DTG compared to# studiesATV/rDRV/rEFVEVG/cLPV/rRALRPV
Odds of Virologic Suppression -- backbone adjusted132.12 (1.22, 3.44)*2.04 (1.04, 3.66)*1.72 (1.24, 2.33)*1.68 (1.03, 2.61)*3.08 (1.78, 5.02)*1.39 (1.03, 1.84)*1.78 (1.14, 2.65)*
Odds of Virologic Suppression -- backbone unadjusted101.91 (1.13, 3.06)*1.85 (0.96, 3.24)1.55 (1.16, 2.02)*1.52 (0.96, 2.30)2.78 (1.64, 4.43)*1.33 (0.99, 1.75)1.60 (1.05, 2.33)*
CD4 change from baseline -- backbone adjusted1417.93 (-7.88, 43.61)4.80 (-34.19, 44.64)37.72 (16.08, 59.94)*17.24 (-12.1, 46.74)-11.08 (-40.61, 19.13)10.30 (-10.18, 30.82)32.45 (1.69, 62.79)*
CD4 change from baseline -- backbone unadjusted1018.00 (-7.79, 43.83)4.81 (-34.52, 44.38)37.78 (16.16, 60.04)*17.21 (-12.37, 46.61)-11.00 (-40.23, 19.17)10.22 (-10.54, 30.93)32.50 (2.39, 63.09)*
Total Cholesterol (mg/dL) change from baseline10-0.59 (-5.82, 4.60)-6.66 (-14.7, 1.28)-14.1 (-18.37, -9.88)*-5.86 (-11.52, -0.24)*-15.64 (-21.72, -9.73)*4.5 (0.74, 8.26)*9.81 (4.42, 15.2)*
HDL (mg/dL) change from baseline101.12 (-0.57, 2.81)0.92 (-1.79, 3.65)-3.64 (-4.94, -2.36)*-0.76 (-2.58, 1.06)-2.08 (-4.07, -0.10)*1.16 (-0.12, 2.46)3.31 (1.58, 5.07)*
LDL (mg/dL) change from baseline9-1.14 (-3.04, 0.80)-7.13 (-10.21, -4.04)*-7.79 (-9.31, -6.25)*-2.48 (-4.48, -0.47)*-5.13 (-7.53, -2.68)*1.84 (0.52, 3.17)*5.34 (3.40, 7.25)*
Triglycerides (mg/dL) change from baseline10-16.32 (-28.80, -3.68)*-14.43 (-34.38, 5.49)-11.93 (-21.63, -2.29)*-6.59 (-20.26, 6.93)-52.31 (-67.04, -37.78)*13.49 (3.81, 23.14)*6.62 (-6.34, 19.64)
Odds of Discontinuation due to AEs80.34 (0.09, 0.85)*0.57 (0.10, 1.91)0.30 (0.16, 0.49)*0.45 (0.17, 0.96)*0.21 (0.04, 0.60)*0.77 (0.37, 1.43)0.68 (0.31, 1.31)
[Table 1]

[Note: CrI = Credible Interval; *Statistically significant comparisons (does not include 1 for OR or 0 for CD4 cell change); Lipids and discontinuation due to AEs are backbone unadjusted]
Conclusions: Indirect comparisons demonstrated sustained and favorable virologic suppression rates, CD4 increases, and lipid changes for DTG when compared to commonly used first-line treatments through 96 weeks.

D. Patel1, S. Snedecor1, W.Y. Tang1, L. Sudharshan1, J. Lim2, R. Cuffe3, S. Pulgar4, K. Gilchrist5, R. Refoios Camejo6, J. Stephens1, G. Nichols7
1Pharmerit International, Bethesda, United States, 2GalxoSmithKline, Stockley Park, United Kingdom, 3Viiv Healthcare, Middlesex, United Kingdom, 4Becton Dickinson, Franklin Lakes, United States, 5GlaxoSmithKline, Renaissance, United States, 6GlaxoSmithKline, Brentford, United Kingdom, 7GlaxoSmithKline, Research Triangle Park, United States