Antiviral activity, safety, and pharmacokinetics/ pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults

Objective: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy. Design: A phase IIa, randomized, double-blind, dose-ranging study. Methods: In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50mg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis. Results: Thirty-five patients (n ¼9 for DTG 2 and 10mg, n ¼10 for DTG 50mg, and n ¼7 for placebo) were enrolled. Baseline characteristics were similar across dosegroups.SignificantreductionsinplasmaHIV-1RNAfrombaselinetoday11were observed for all DTG dose groups compared with placebo (P <0.001), with a mean decrease of 1.51‐2.46log10copies/ml. In addition, a well characterized dose‐response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50mg achieved plasma HIV-1 RNA less than 50copies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25‐50%). Plasma HIV-1 RNA reduction was best predicted by Ct using an Emax model. The most common adverse events were diarrhea, fatigue, and headache; the majority of ad verse events were mild or moderate in severity. Conclusion: Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/ pharmacodynamics relationship, which support once-daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2011, 25:1737‐1745