Maraviroc: A Coreceptor CCR5 Antagonist for Management of HIV Infection

Raymond Yost; Timothy R. Pasquale; Eric G. Sahloff

Disclosures

Am J Health Syst Pharm. 2009;66(8):715-726. 

In This Article

Place in Therapy

Maraviroc is the first in a novel class of antiretroviral agents, CCR5 coreceptor antagonists, to be approved for marketing by FDA. Maraviroc acts as a highly selective and potent inhibitor of CCR5-tropic virus and has been shown to lack efficacy in patients with dual- or mixed or CXCR4-tropic virus.[9,10,11] Thus, the antiviral effect of maraviroc will depend on the viral strain encountered. CCR5 antagonists are thought to be more effective earlier in the disease because of the predominance of CCR5-tropic virus at earlier stages. However, the strongest data for maraviroc comes from the MOTIVATE trials in which it displayed significant and high virological efficacy in combination with OBR in treatment-experienced patients infected with CCR5-tropic virus and multiple resistant mutations who were not responding to therapy.[9,10,29] Based on results of the MERIT trial, maraviroc is not approved or recommended in treatment-naive patients.[11]

CCR5-tropic virus is the predominant virus encountered, though CXCR4-tropic virus strains are more likely encountered, in patients with advanced HIV disease. Results from Phase III clinical trials showed that approximately half of the treatment-experienced patient population screened in these trials harbored CCR5-tropic viral strains, with an unknown percentage of minority quasispecies showing CXCR4- tropism. The Trofile coreceptor tropism assay is commercially available to detect the presence of CCR5, CXCR4, or dual- or mixed-tropic virus. The tropism assay can detect CXCR4-tropic virus nearly 100% of the time when it comprises at least 10% of the total viral population and 85% of the time when it comprises 5% of the total viral population.[27]

A tropism assay is recommended before initiating treatment with a CCR5 antagonist or in those patients experiencing virological failure on a CCR5 antagonist.[27] The tropism assay requires a viral load of > 1000 copies/mL, and the results are available in two weeks. Upon receiving confirmation of the presence of CCR5-tropic virus, maraviroc can be initiated in combination with two or more additional active agents selected based on available genotypic and phenotypic data and clinical evidence.

One concern with the CCR5 antagonists is that they may induce a tropism change to either a dual- or mixed-tropic virus or a predominately CXCR4-tropic virus. This is concerning because CXCR4-tropic virus is generally associated with a faster disease progression. In one Phase III clinical trial, more patients in the maraviroc group had a change in tropism to a dual-tropic or CXCR4-tropic virus at the time of treatment failure compared with placebo.[9,10,14] It may be more likely that CXCR4-using variants emerge from a preexisting reservoir rather than by coreceptor tropism switch.

Additional concerns regarding the potential for increased infection, malignancies, and hepatotoxicity with the use of maraviroc exist. As more information on the long-term use of this agent becomes available, the association between maraviroc and these conditions will be better defined. Until then, vigilance should be exercised when monitoring maraviroc use.

Overall, maraviroc has been generally well tolerated to date, is conveniently administered, and offers a novel mechanism of action. Maraviroc's place in therapy for the near future appears to be for the management of treatment-experienced patients currently receiving OBR and identified as having CCR5-tropic virus. Considering maraviroc failed to meet noninferiority criteria compared with efavirenz, the lack of long-term safety data, and the need to perform a tropism assay before initiating therapy, maraviroc use in treatment-naive patients is not currently recommended.

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