Maraviroc: the evidence for its potential in the management of HIV

Proof of concept review Maraviroc: the evidence for its potential in the management of HIV Louise Profit Core Medical Publishing, Knutsford, UK Abstract Introduction: New antiretroviral agents that are more convenient, better tolerated with fewer short- and long-term side effects, and that have novel resistance patterns are needed at all lines of therapy in patients infected with human immunodeficiency virus (HIV). Therefore, next generation products of current classes and alternative classes of antiretroviral agents are needed. The CC-chemokine receptor 5 (CCR5) antagonists are a novel class of antiretroviral agents that prevent the entry of HIV into host cells by blocking the CCR5 coreceptor. Within this class, maraviroc is the agent furthest along in development. Aims: The aim of this review is to evaluate the emerging evidence for the use of the CCR5 antagonist maraviroc in antiretroviral treatment-naïve and treatment-experienced patients with HIV-1 infection. Evidence review: Preliminary evidence from phase I/IIa short-term studies suggest that maraviroc monotherapy is effective at reducing HIV viral load, and is generally well tolerated. In-vitro evidence suggests that maraviroc will be effective in drug-naïve patients with CCR5-tropic virus, as well as in those with CCR5-tropic virus who have developed HIV resistance to existing antiretroviral regimens. However, it is not known how quickly resistance may develop to maraviroc in clinical practice. Clinical potential: Current evidence supports the continued development of maraviroc as a potentially useful, alternative treatment for the management of HIV infection. Maraviroc monotherapy has a high potency and long half-life, allowing single-pill dosing. Therefore, it is expected that maraviroc will have a beneficial effect on patient adherence and viral load in combination with other antiretroviral agents. Maraviroc is only effective against CCR5-tropic virus, which predominates throughout infection but is more common in patients at the early asymptomatic stage of infection. Key words: CCR5 antagonist, evidence, human immunodeficiency virus, maraviroc, outcomes, UK-427,857 Core evidence proof of concept summary for maraviroc in HIV infection Outcome measure Emerging evidence Disease-oriented evidence HIV viral load Mean maximum viral load reduction between 1.6 and 1.84 log10 copies/mL after 10 days of monotherapy with maraviroc at clinical doses Rebound of viral load Delay in viral rebound after discontinuation of maraviroc monotherapy Selectivity Maraviroc selectively binds to CCR5, causing an allosteric change, and preventing R5 HIV from entering CD4 cells Resistance In vitro, maraviroc is effective against HIV variants resistant to existing antiretroviral agents. Preliminary evidence of CD4 cell increases in dual-tropic patients. Further confirmation is required Patient-oriented evidence Tolerability Maraviroc is well tolerated in short-term studies, with a similar tolerability to placebo Cardiovascular effects No evidence of prolongation of QTc interval. Postural hypotension at unit doses ≥600 mg Liver toxicity One case of serious hepatotoxicity reported. The DSMB considered this case highly unlikely to be related to maraviroc treatment, but could not rule out a contribution by maraviroc. Phase III data are required to fully assess hepatotoxicity Drug interactions Maraviroc is metabolized by CYP3A4 and is a substrate for Pgp. Dose adjustments are required when administered concomitantly with potent CYP3A4 inhibitors or inducers CCR5, CC-chemokine receptor 5; CYP3A4, cytochrome P450 3A4; DSMB, Data Safety Monitoring Board; HIV, human immunodeficiency virus; Pgp, P-glycoprotein; R5 HIV, HIV that only uses the CCR5 receptor. Maraviroc | proof of concept review Scope, aims, and objectives Maraviroc (UK-427,857; Pfizer) is a CC-chemokine receptor 5 (CCR5)-receptor antagonist in development for the treatment of human immunodeficiency virus (HIV) infection. It is currently being evaluated in phase IIb/III trials in adults with HIV-1 infection. The objective of this article is to review the preclinical and early clinical development evidence for the effectiveness of maraviroc against HIV-1 infection, and to assess its therapeutic potential. Table 1 | Evidence base included in the review Category Abstracts 28 21 records excluded 22 0 records included 6 21 Initial search Search update, new records Methods English language medical literature databases were searched for appropriate articles related to the treatment of HIV infection with maraviroc. The searches were conducted on May 16, 2006 using the search terms “maraviroc OR UK-427,857.” The cut-off date was from the beginning of the database to the date of the search unless otherwise stated. • PubMed, http://www.ncbi.nlm.nih.gov • EMBASE, http://www.datastarweb.com • BIOSIS, http://www.datastarweb.com • Database of Abstracts of Reviews of Effects (DARE), http://www.york.ac.uk/inst/crd/crddatabases.htm • Cochrane Database of Systematic Reviews (CDSR), http://www.cochrane.org/index0.htm • Public Library of Science, http://www.plos.org/journals/index.html Number of records Full papers 1 1 records excluded 1 0 records included 0 1 1 1 Level 2 clinical evidence (RCT) For definition of levels of evidence, see Editorial Information on inside back cover. RCT, randomized controlled trial. • XV International AIDS Society (IAS) Conference, all conferences from 2001 to 2005, http://www.iasociety.org • XVI International HIV Drug Resistance Workshop 2005, http://www.intmedpress.com/General/showSectionSub.cfm?S ectionID=2&SectionSubID=1&SectionSubSubID=1 • 10th–13th Conferences on Retroviruses and Opportunistic Infections (CROI), 2003–2006, http://www.retroconference.org • 5th International Workshop on Clinical Pharmacology of HIV Therapy, 2004 • 7th International Congress on Drug Therapy in HIV Infection, 2004 • Clinical Evidence (BMJ), http://www.clinicalevidence.com • 10th European AIDS Conference, 2005 • Clinical trial registers http://www.clinicaltrials.gov, and http://www.clinicalstudyresults.org • National Institute for Health and Clinical Excellence (NICE), http://www.nice.org.uk • National Guideline Clearinghouse, http://www.guideline.gov After removal of duplicates, a total of 28 records were retrieved from PubMed and EMBASE; no additional citations were identified from the other databases (Table 1). Records were manually reviewed and 22 citations were excluded: nonsystematic reviews (n=3), and citations that mentioned maraviroc but did not investigate its preclinical or clinical use (n=19). No systematic reviews of maraviroc have been published. ClinicalTrials.gov identified four ongoing phase IIb/III clinical trials. Guidelines for the treatment of HIV were identified from the website of the British HIV Association (http://www.bhiva.org) and the AIDSinfo website (http://AIDSinfo.nih.gov). Online abstracts from the follo (...truncated)