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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
Abstract Content:
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)]
[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.
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 | # studies | ATV/r | DRV/r | EFV | EVG/c | LPV/r | RAL | RPV |
| Odds of Virologic Suppression -- backbone adjusted | 13 | 2.12 (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 unadjusted | 10 | 1.91 (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 adjusted | 14 | 17.93 (-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 unadjusted | 10 | 18.00 (-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 baseline | 10 | -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 baseline | 10 | 1.12 (-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 baseline | 9 | -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 baseline | 10 | -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 AEs | 8 | 0.34 (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) |
[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.