Maraviroc: new drug. Multiple antiretroviral treatment failure: too soon to reach conclusions

Abstract

(1) The choice of treatment for HIV-infected patients in whom several lines of antiretroviral therapy have failed is particularly difficult. Some antiretroviral drugs (enfuvirtide and some HIV protease inhibitors) remain effective, at least in the short term. (2) Maraviroc is the first CCR5 antagonist to be licensed for use in this setting. It acts by blocking one of the two coreceptors, CCR5, needed for HIV entry into CD4+ lymphocytes. It is approved for use in HIV-infected patients with multiple antiretroviral failure. (3) Two double-blind placebo-controlled trials including 1076 patients infected by HIV strains using only the CCR5 coreceptor tested the effect of adding maraviroc at a dose of 300 mg twice a day to an optimised treatment. After 8 weeks, maraviroc was more effective than placebo in reducing viral load (undetectable in 45.5% versus 16.7% of patients) and in increasing the CD4+ cell count (+124 cells/mm3 versus +61 cells/mm3); both of these differences are statistically significant. (4) After treatment with maraviroc, 50% to 60% of patients harboured viruses that did not exclusively rely on CCR5 for host cell entry. The possible clinical consequences of this change in tropism are unclear. (5) A double-blind trial of maraviroc included 190 patients with multiple antiretroviral failure who were infected by HIV variants not requiring CCR5 for host cell entry; maraviroc was not shown to be effective. (6) Data obtained with other CCR5 antagonists, and preclinical data obtained with maraviroc, point to a possible increase in the risk of hepatitis, infections, cancer, and QT prolongation. More data are also needed concerning the risk of muscle toxicity and ischaemic cardiovascular events. (7) Maraviroc is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of interactions with CYP 3A4 inducers and inhibitors. (8) In practice, given the absence of long-term evaluation, clinical assessment of maraviroc is too limited to recommend the use of this drug outside the clinical trial setting.