Abstract and Introduction
Abstract
Background: Maraviroc is unique among approved antiretroviral drugs in targeting the host-cell chemokine coreceptor type-5 receptor. With its novel mechanism of action, we sought to describe the 5-year safety profile of maraviroc.
Methods: Two large phase 3 studies of maraviroc enrolled HIV-infected treatment-experienced patients and followed them up for 5 or more years. Survival and selected clinical end points were identified and assessed.
Results: A total of 938 enrolled patients received maraviroc-containing regimens. Rates of death and selected clinical events (eg, hepatic failure, malignancy, and myocardial infarction) were low during follow-up.
Conclusions: Maraviroc was generally safe in treatment-experienced participants for >5 years.
Introduction
Maraviroc is a first-in-class selective chemokine coreceptor type-5 (CCR5) antagonist that demonstrated antiretroviral activity in early phase 2a studies of HIV-infected patients with CCR5-tropic (R5) virus. Maraviroc has a unique mechanism of action among approved antiretrovirals in binding to a host protein, the CCR5 receptor, rather than a viral target. Maraviroc binds to the CCR5 receptor and prevents the interaction of the external membrane glycoprotein of R5 HIV-1, gp120, with the host cell receptor. Given the unique mode of action and use of a host-cell target, initial concerns existed about the potential safety of CCR5 antagonists, including maraviroc. Also, early development of other investigational CCR5 antagonists demonstrated potential class-specific effects: aplaviroc was associated with severe hepatotoxicity, and further clinical development was stopped; vicriviroc was initially associated with malignancies in a phase 2 study, although this was not confirmed in larger phase 3 studies.
In HIV-1–infected treatment-experienced patients with R5 virus in the MOTIVATE 1 and MOTIVATE 2 phase 3 trials, maraviroc together with an optimized background antiretroviral regimen demonstrated superior 48-week virological efficacy compared with placebo with no significant safety concerns; these findings led to US Food and Drug Administration approval of the drug. Follow-up results at 2 years demonstrated sustained antiretroviral activity and no new safety concerns. Given the unique mechanism of action of CCR5 antagonists, and the potential for longer-term safety issues, the US Food and Drug Administration requested extended 5-year follow-up for all study subjects receiving these compounds. In this study, we report the pooled safety findings from the MOTIVATE 1 and MOTIVATE 2 phase 3 studies for >5 years, the longest-term safety data available with a CCR5 antagonist.