Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262)

Abstract

Objective: To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients.

Design: Phase IIb, single-arm, open-label, multicenter study.

Methods: One hundred and twelve antiretroviral-naive, HIV-1-infected patients received DRV/r 800/100 mg once daily and RAL 400 mg twice daily. Primary endpoint was virologic failure by week 24. Virologic failure was defined as confirmed viral load of 1000 copies/ml or more at week 12, or an increase of more than 0.5 log(10) copies/ml in viral load from week 4 to 12, or a confirmed viral load of more than 50 copies/ml at or after week 24. Protease and integrase genes were sequenced in patients experiencing virologic failure.

Results: Virologic failure rate was 16% [95% confidence interval (CI) 10-24] by week 24 and 26% (95% CI 19-36) by week 48 in an intent-to-treat analysis. Viral load at virologic failure was 51-200 copies/ml in 17/28 failures. Adjusting for age and sex, virologic failure was associated with baseline viral load of more than 100,000 copies/ml [hazard ratio 3.76, 95% CI (1.52-9.31), P = 0.004] and lower CD4 cell count [0.77 per 100 cells/μl increase (95% CI 0.61-0.98), P = 0.037]. When trough RAL concentrations were included as a time-varying covariate in the analysis, virologic failure remained associated with baseline viral load more than 100,000 copies/ml [hazard ratio = 4.67 (95% CI 1.93-11.25), P < 0.001], whereas RAL level below detection limit in plasma at one or more previous visits was associated with increased hazard [hazard ratio = 3.42 (95% CI 1.41-8.26), P = 0.006]. All five participants with integrase mutations during virologic failure had baseline viral load more than 100,000 copies/ml.

Conclusion: DRV/r plus RAL was effective and well tolerated in most patients, but virologic failure and integrase resistance were common, particularly in patients with baseline viral load more than 100,000 copies/ml.

Trial registration: ClinicalTrials.gov NCT00830804.

Conflict of interest statement

Conflicts of interest

The project described was supported by Award Number U01AI068636 and U01AI68634 from the National Institute of Allergy and Infectious Diseases and supported by the National Institute of Mental Health (NIMH) and National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The project is supported in part by grants funded by the National Center for Research Resources. The authors would like to thank the study volunteers. We also thank Merck for providing raltegravir and Tibotec Therapeutics for providing darunavir.

B.T. has served as an advisor and received research support and honoraria from Tibotec. E.P.A. has served as a consultant to Tibotec and Merck. D.R.K. is a consultant to Merck and has received honoraria and research support from the company. J.J.E is a consultant to Abbott, GlaxoSmithKline, Merck, ViiV and Tibotec, and has received research support (to UNC) from GlaxoSmith-Kline and Merck.

Figures

Fig. 1

Proportion of participants with HIV-1 RNA level less than 50 and less than 200 copies/ml.

Fig. 2

Kaplan–Meier plots of time to virologic failure (VF) using intent-to-treat approach.