title: 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Pharmerit International, Bethesda, Maryland, United States of America.
authors.forename: Dipen A
authors.initials: DA
authors.lastname: Patel
authors.affiliation: Pharmerit International, Bethesda, Maryland, United States of America.
authors.forename: Sonya J
authors.initials: SJ
authors.lastname: Snedecor
authors.affiliation: Pharmerit International, Bethesda, Maryland, United States of America.
authors.forename: Wing Yu
authors.initials: WY
authors.lastname: Tang
authors.affiliation: Pharmerit International, Bethesda, Maryland, United States of America.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Sudharshan
authors.affiliation: GlaxoSmithKline, Stockley Park, United Kingdom.
authors.forename: Jessica W
authors.initials: JW
authors.lastname: Lim
authors.affiliation: ViiV Healthcare, Middlesex, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Cuffe
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pulgar
authors.affiliation: GlaxoSmithKline, Renaissance, Pennsylvania, United States of America.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Gilchrist
authors.affiliation: GlaxoSmithKline, Brentford, United Kingdom.
authors.forename: Rodrigo Refoios
authors.initials: RR
authors.lastname: Camejo
authors.affiliation: Pharmerit International, Bethesda, Maryland, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stephens
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Garrett
authors.initials: G
authors.lastname: Nichols
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods*; D018791:CD4 Lymphocyte Count; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015224:Dideoxynucleosides / Q000008:administration & dosage; D004338:Drug Combinations; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D008055:Lipids / Q000097:blood; D061466:Lopinavir / Q000008:administration & dosage; D009570:Nitriles / Q000008:administration & dosage; D063065:Organophosphonates / Q000008:administration & dosage; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011743:Pyrimidines / Q000008:administration & dosage; D011760:Pyrrolidinones / Q000008:administration & dosage; D000068898:Raltegravir Potassium; D016032:Randomized Controlled Trials as Topic; D000068696:Rilpivirine; D019438:Ritonavir / Q000008:administration & dosage; D000068698:Tenofovir; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D000099226:Dolutegravir; D000099227:Abacavir
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D003841:Deoxycytidine; D015224:Dideoxynucleosides; D004338:Drug Combinations; D000068679:Emtricitabine; D006575:Heterocyclic Compounds, 3-Ring; D019259:Lamivudine; D008055:Lipids; D061466:Lopinavir; D009570:Nitriles; D063065:Organophosphonates; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011743:Pyrimidines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000068696:Rilpivirine; D019438:Ritonavir; D000068698:Tenofovir; D000099226:Dolutegravir; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir