A randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naive HIV-infected individuals

AIDS. 2016 Jan 2;30(1):57-63. doi: 10.1097/QAD.0000000000000876.

Abstract

Objective: To assess the antiviral activity, pharmacokinetics, and safety of doravirine in nonnucleoside reverse transcriptase inhibitor-naïve, HIV-infected men.

Design: Double-blind, randomized, two-panel, dose-escalation study.

Methods: In two sequential panels, 18 individuals received doravirine [25 mg (Panel A) or 200 mg (Panel B)] or matching placebo once daily for 7 days. Plasma samples were collected daily for measurement of HIV-1 RNA levels and doravirine pharmacokinetics.

Results: For the mean change from baseline in HIV RNA (log10 copies/ml) at 24 h after the day 7 dose, the mean difference (90% confidence interval) between doravirine and placebo was -1.37 (-1.60, -1.14) in the 25-mg group and -1.26 (-1.51, -1.02) in the 200-mg group. None of the participants had viral breakthrough. Increases in mean AUC0-24 h, Cmax, and C24 h were slightly less than dose-proportional, with median Tmax of 1.0-2.0 h. Steady state was achieved after 3-5 days of once-daily dosing. At steady state, accumulation ratios (day 7/day 1) for AUC0-24 h, Cmax, and C24 h were 1.2-1.6. The calculated effective t1/2 (10-16 h) was similar to that in HIV-uninfected individuals. Adverse events were limited in number, transient, and generally mild to moderate in intensity. One participant had a serious adverse event of elevated liver enzymes (judged probably not drug related) in concurrence with a newly acquired hepatitis C infection.

Conclusion: Doravirine monotherapy demonstrated robust antiviral activity at both dose levels, without evidence of viral resistance, and was generally well tolerated. Doravirine pharmacokinetics in HIV-infected individuals were similar to those in uninfected individuals receiving similar doses in prior studies.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / analysis
  • Anti-HIV Agents / pharmacokinetics
  • Double-Blind Method
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • HIV Infections / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Placebos / administration & dosage
  • Plasma / chemistry
  • Plasma / virology
  • Pyridones / administration & dosage*
  • Pyridones / adverse effects
  • Pyridones / analysis
  • Pyridones / pharmacokinetics
  • RNA, Viral / analysis
  • Treatment Outcome
  • Triazoles / administration & dosage*
  • Triazoles / adverse effects
  • Triazoles / analysis
  • Triazoles / pharmacokinetics
  • Young Adult

Substances

  • Anti-HIV Agents
  • Placebos
  • Pyridones
  • RNA, Viral
  • Triazoles
  • doravirine