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

PLoS One. 2014 Sep 4;9(9):e105653. doi: 10.1371/journal.pone.0105653. eCollection 2014.

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).

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / adverse effects
  • Antiretroviral Therapy, Highly Active / adverse effects
  • Antiretroviral Therapy, Highly Active / methods*
  • CD4 Lymphocyte Count
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Dideoxynucleosides / administration & dosage
  • Drug Combinations
  • Emtricitabine
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1*
  • Heterocyclic Compounds, 3-Ring / administration & dosage*
  • Heterocyclic Compounds, 3-Ring / adverse effects
  • Humans
  • Lamivudine / administration & dosage
  • Lipids / blood
  • Lopinavir / administration & dosage
  • Nitriles / administration & dosage
  • Organophosphonates / administration & dosage
  • Oxazines
  • Piperazines
  • Pyridones
  • Pyrimidines / administration & dosage
  • Pyrrolidinones / administration & dosage
  • Raltegravir Potassium
  • Randomized Controlled Trials as Topic
  • Rilpivirine
  • Ritonavir / administration & dosage
  • Tenofovir
  • Time Factors
  • Treatment Outcome
  • Viral Load / drug effects

Substances

  • Anti-HIV Agents
  • Dideoxynucleosides
  • Drug Combinations
  • Heterocyclic Compounds, 3-Ring
  • Lipids
  • Nitriles
  • Organophosphonates
  • Oxazines
  • Piperazines
  • Pyridones
  • Pyrimidines
  • Pyrrolidinones
  • abacavir, lamivudine drug combination
  • Deoxycytidine
  • Lopinavir
  • Lamivudine
  • Raltegravir Potassium
  • Tenofovir
  • dolutegravir
  • Rilpivirine
  • Emtricitabine
  • Adenine
  • Ritonavir

Grants and funding

This study was funded by ViiV Healthcare. Pharmerit International, ViiV Healthcare and GlaxoSmithKline provided support in the form of salaries for all authors as employees but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.