Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study

Lancet Infect Dis. 2012 Jan;12(1):27-35. doi: 10.1016/S1473-3099(11)70249-3. Epub 2011 Oct 18.

Abstract

Background: Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed.

Methods: We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT00708162.

Findings: Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI -6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009).

Interpretation: Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence.

Funding: Gilead Sciences.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alanine Transaminase / blood
  • Anti-Retroviral Agents / adverse effects
  • Anti-Retroviral Agents / therapeutic use*
  • Aspartate Aminotransferases / blood
  • Atazanavir Sulfate
  • CD4 Lymphocyte Count
  • Diarrhea / chemically induced
  • Double-Blind Method
  • Drug Therapy, Combination / adverse effects
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV Integrase Inhibitors / therapeutic use
  • HIV Protease Inhibitors / therapeutic use
  • HIV-1* / immunology
  • Humans
  • Lopinavir / therapeutic use
  • Male
  • Middle Aged
  • Oligopeptides / therapeutic use
  • Pyridines / therapeutic use
  • Pyrrolidinones / administration & dosage
  • Pyrrolidinones / adverse effects
  • Pyrrolidinones / therapeutic use*
  • Quinolones / administration & dosage
  • Quinolones / adverse effects
  • Quinolones / therapeutic use*
  • RNA, Viral / blood
  • Raltegravir Potassium
  • Ritonavir / therapeutic use
  • Treatment Outcome
  • Viral Load

Substances

  • Anti-Retroviral Agents
  • HIV Integrase Inhibitors
  • HIV Protease Inhibitors
  • JTK 303
  • Oligopeptides
  • Pyridines
  • Pyrrolidinones
  • Quinolones
  • RNA, Viral
  • Lopinavir
  • Raltegravir Potassium
  • Atazanavir Sulfate
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Ritonavir

Associated data

  • ClinicalTrials.gov/NCT00708162