Clinical trials of HIV antiretroviral therapy: CCR5 antagonists
- Paul E Sax, MD
Paul E Sax, MD
- Clinical Director, Division of Infectious Diseases
- Brigham and Women's Hospital
- Professor of Medicine
- Harvard Medical School
Classes of antiretroviral medications with activity against HIV include nucleoside analogs, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, and CCR5 receptor antagonists.
CCR5 antagonists exert their antiviral activity against HIV by blocking entry of CCR5-tropic viruses into the CD4 T cell. Only one agent in this class, maraviroc, has been approved for use in treatment-experienced HIV-infected patients.
This topic summarizes the clinical trials that have been performed with maraviroc in both treatment-naive and treatment-experienced patients. Data regarding other CCR5 antagonists in advanced stages of development (eg, vicriviroc) are discussed elsewhere.
Clinical trial data regarding other classes of HIV antiretroviral medications are found elsewhere. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors" and "Clinical trials of HIV antiretroviral therapy: Non-nucleoside reverse transcriptase inhibitors" and "Clinical trials of HIV antiretroviral therapy: Protease inhibitors".)
MECHANISM OF ACTION
CCR5 antagonists are characterized as HIV entry inhibitors.
- Moore JP, Kitchen SG, Pugach P, Zack JA. The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 2004; 20:111.
- Hunt PW, Harrigan PR, Huang W, et al. Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia. J Infect Dis 2006; 194:926.
- Soriano V, Geretti AM, Perno CF, et al. Optimal use of maraviroc in clinical practice. AIDS 2008; 22:2231.
- Corbeau P, Reynes J. CCR5 antagonism in HIV infection: ways, effects, and side effects. AIDS 2009; 23:1931.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf (Accessed on May 01, 2014).
- Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008; 300:555.
- Vandekerckhove L, Verhofstede C, Vogelaers D. Maraviroc: integration of a new antiretroviral drug class into clinical practice. J Antimicrob Chemother 2008; 61:1187.
- Trinh L, Han D, Huang W, et al. Technical validation of an enhanced sensitivity Trofile HIV coreceptor tropism assay for selecting patients for therapy with entry inhibitors targeting CCR5. Antivir Ther 2008; 13 Suppl 3:A128.
- McGovern RA, Thielen A, Mo T, et al. Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies. AIDS 2010; 24:2517.
- McGovern RA, Thielen A, Portsmouth S, et al. Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial. J Acquir Immune Defic Syndr 2012; 61:279.
- Swenson LC, Mo T, Dong WW, et al. Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients. J Infect Dis 2011; 203:237.
- Swenson LC, Mo T, Dong WW, et al. Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc. Clin Infect Dis 2011; 53:732.
- MacArthur RD, Novak RM. Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. Clin Infect Dis 2008; 47:236.
- Saag M, Goodrich J, Fätkenheuer G, et al. A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis 2009; 199:1638.
- Fatkenheuer G, Pozniak A, Johnson M, et al. Evaluation of doing frequency and food effect on viral load reduction during short-term monotherapy with UK-427,857 a novel CCR5 antagonist. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4489.
- Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 2006; 80:4909.
- Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 359:1429.
- Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of Maraviroc plus optimized background therapy in viremic ART-experienced patient infected with CCR5-tropic HIV-1: 24 week results of a phase 2b/3 study in the US and Canada. Conference on Retroviruses and Opportunistic Infections, February 25-28, 2007, Los Angeles. Abstract #104bLB.
- Fätkenheuer G, Nelson M, Lazzarin A, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008; 359:1442.
- Dolin R. A new class of anti-HIV therapy and new challenges. N Engl J Med 2008; 359:1509.
- Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis 2010; 201:803.
- Vandekerckhove L, Verhofstede C, Vogelaers D. Maraviroc: perspectives for use in antiretroviral-naive HIV-1-infected patients. J Antimicrob Chemother 2009; 63:1087.
- Two new drugs for HIV infection. Med Lett Drugs Ther 2008; 50:2.
- Mayer H. Case study of a patient with serious hepatotoxicity in maraviroc IIB/III trial. Presented at Targeting HIV Entry - First International Workshop. Bethesda, MD, December 3, 2005.
- Clotet B. CCR5 inhibitors: promising yet challenging. J Infect Dis 2007; 196:178.
- Gathe J, et al. Phase 3 Trials of Vicriviroc in Treatment-experienced Subjects Demonstrate Safety but Not Significantly Superior Efficacy over Potent Background Regimens Alone. Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco, CA, Abst# 54LB.
- Landovitz RJ, Angel JB, Hoffmann C, et al. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. J Infect Dis 2008; 198:1113.
- Dunkle M, et al. 50th ICAAC; Boston, MA; September 12-15, 2010; Abst. H-938a.