48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis

Abstract

Background: A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1-infected patients.

Methods: A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed.

Results: Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions.

Conclusion: Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1-infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c).

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Chart.

PubMed/MEDLINE, Embase, and Cochrane databases were searched to identify randomized controlled trials evaluating efficacy and/or safety of ATV/r, DRV/r, DTG, EFV, EVG/c, LPV/r, RAL, or RPV in treatment-naive HIV-1–infected patients. Records were screened by independent researchers, who selected study titles and abstracts for full text review. Following several rounds of exclusion based on multiple criteria, 31 trials and publications were selected for subsequent analysis. *Additional records were identified via ClinicalTrials.gov, the Food and Drug Administration (FDA), scientific discussions of the European Medicines Agency (EMA)/European Public Assessment Reports (EPAR), and third-agent package inserts. Each of these were found to be included in initial search records and noted as such. ^†Reasons for exclusion at time of full text review: non-randomized trial; Phase 1/Phase 2 trials; patient population age <13 years; outcomes not of interest; trial duration <12 weeks; and out-of-network comparator. ^‡34 publications were matches to ClinicalTrials.gov registry results (NCTs) to ensure comprehensive extraction of all available data pertaining to outcomes of interest.

Figure 2. Network of treatment comparisons contained within the identified clinical trials.

The major classes of third agents studied in the selected trials are indicated along the perimeter of the figure: NNRTIs, green; integrase inhibitors and PIs, purple; connectors, yellow. Black lines connecting each of the treatments of interest (red dots) represent a publication or clinical trial containing those two agents. Connector agents are drugs identified in 2 or more trials, and which were compared to 2 or more treatments of interest; connector agents are also members of the PI class. ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; DTG = dolutegravir; DRV/r = ritonavir-boosted darunavir; EFV = efavirenz; EVG/c = cobicistat-boosted elvitegravir; FPV/r = ritonavir-boosted fosamprenavir; LPV/r = lopinavir-boosted ritonavir; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; SQV/r = ritonavir-boosted saquinavir.

Figure 3. Comparison of immunologic endpoints with dolutegravir versus third agents of interest.

(A) Odds ratio [95% CrI] for virologic suppression (HIV RNA<50 c/mL) of DTG compared with other third agents. Odds ratio values greater than 1 indicate the comparison favors DTG; CrI intervals that do not contain 1 are considered statistically significant. (B) Mean [95% CrI] CD4+ cell increase with dolutegravir versus third agents of interest. Crls of mean differences that do not contain 0 are considered statistically significant. ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; Crl = credible interval; DTG = dolutegravir; DRV/r = ritonavir-boosted darunavir; EFV = efavirenz; EVG/c = cobicistat-boosted elvitegravir; FPV/r = ritonavir-boosted fosamprenavir; LPV/r = lopinavir-boosted ritonavir; NFV = nelfinavir; RAL = raltegravir; RPV = rilpivirine; SQV/r = ritonavir-boosted saquinavir. *Indicates statistically significant comparison.

Figure 4. Relative changes in cholesterol and triglyceride parameters for dolutegravir versus third agents of interest.

Mean changes (mg/dL [95% Crl] in lipid levels with DTG compared with other third agents are shown for (A) total cholesterol (TC), (B) HDL cholesterol, (C) LDL cholesterol, and (D) triglycerides. In all cases, Crls of mean differences that do not include 0 are considered statistically significant. ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; DTG = dolutegravir; DRV/r = ritonavir-boosted darunavir; EFV = efavirenz; EVG/c = cobicistat-boosted elvitegravir; FPV/r = ritonavir-boosted fosamprenavir; HDL = high-density lipoprotein; LDL = low-density lipoprotein; LPV/r = lopinavir-boosted ritonavir; NFV = nelfinavir; RAL = raltegravir; RPV = rilpivirine; SQV/r = ritonavir-boosted saquinavir; TC = total cholesterol. *Indicates statistically significant comparison.