Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

Taiwo, Babafemi MBBS*; Acosta, Edward P. PharmD; Ryscavage, Patrick MD; Berzins, Baiba MPH*; Lu, Darlene PhD§; Lalezari, Jay MD; Castro, Jose MD; Adeyemi, Oluwatoyin MD#; Kuritzkes, Daniel R. MD**; Eron, Joseph J. MD††; Tsibris, Athe MD**; Swindells, Susan MBBS‡‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 October 2013 - Volume 64 - Issue 2 - p 167–173
doi: 10.1097/QAI.0b013e3182a03d95
Clinical Science

Objective: To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)–sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study.

Methods: Twenty-four antiretroviral-naive R5 HIV-1–infected participants received maraviroc 150 mg and darunavir/ritonavir (DRV/r) 800/100 mg (MVC/DRV/r) once daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies per milliliter at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared with decay rates from efavirenz (EFV) plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs, and EFV plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4, 12, 24, and 48.

Results: Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells per cubic millimeter and 4.62 (4.18, 4.80) log10 copies per milliliter, respectively. VF occurred in 3 of 24 participants {12.5% [95% confidence interval (CI): 2.7 to 32.4]} at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 [8.3% (95% CI: 1.0 to 27.0)]. The week 48 failures were 2 of the 4 participants (50%) with baseline VL >100,000 copies per milliliter. Week 96 VF rate was 2/20 [10% (95% CI: 1.2 to 31.7)]. Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2NRTIs (P = 0.0063) and similar to EFV-based regimens. Individual maraviroc trough concentrations collected between 20 and 28 hours post dose (n = 59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL.

Conclusions: MVC/DRV/r 150/800/100 mg once daily has potential for treatment-naive patients with R5 HIV-1.

*Division of Infectious Diseases, Northwestern University, Chicago, IL;

Division of Clinical Pharmacology, University of Alabama, Birmingham, AL;

University of Maryland, Baltimore, MD;

§Statistical and Data Analysis Section, Harvard School of Public Health, Boston, MA;

Quest Clinical Research, San Francisco, CA;

Division of Infectious Diseases, University of Miami, Miami, FL;

#CORE Center, Chicago, IL;

**Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA;

††Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC; and

‡‡Division of Infectious Diseases, University of Nebraska, Omaha, NE.

Correspondence to: Babafemi Taiwo, MBBS, Division of Infectious Diseases, Northwestern University, Chicago, IL 60611 (e-mail: b-taiwo@northwestern.edu).

Supported by an Investigator Initiated Study Grant to Northwestern University from Pfizer, which also provided maraviroc and ritonavir. Janssen provided darunavir.

Presented at XIX International AIDS Conference, July 2012, Washington, DC; and the Conference of Retroviruses and Opportunistic Infections, March 2013, Atlanta, GA.

B.T. has served as a consultant and/or received research funding to Northwestern University from Tibotec, ViiV, Pfizer, GlaxoSmithKline and Monogram. D.R.K. is a consultant to and/or has received research funding from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Roche and ViiV. J.J.E. is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, Merck, ViiV, Gilead and Tibotec/Janssen, and has received research support (to UNC) from GlaxoSmithKline and Merck. E.A. has been a consultant to ViiV and Tibotec. S.S. reports receipt of research grants to the University of Nebraska Medical Center from GlaxoSmithKline and Pfizer for clinical trials unrelated to this project. J.C. has received payment including service on Speaker’s Bureau from Bristol-Myers Squibb, ViiV and Gilead.

This study was conceived and developed by B.T., P.R., D.K., J.E., and S.S. Lead investigators at the research sites were B.T. (Northwestern University), S.S. (University of Nebraska), O.A. (Core Centerl, Chicago, IL), J.L. (Quest Clinical Research, California), and J.C. (University of Miami). A.T. was the study virologist, B.B. the study manager, and D.L. was the statistician. All authors contributed to preparation of the article and approved the final version. MIDAS research staff: Northwestern University (Meredith Rathert, Byron Yip, Nina Lambert), University of Nebraska (Frances Van Meter), Quest Clinical Research (Devin Walsh), University of Miami (Tom Tanner), and CORECenter (Julia Lee).

Received May 03, 2013

Accepted June 10, 2013

© 2013 by Lippincott Williams & Wilkins