Maraviroc in HIV Patients: 5-Year Safety Data
Maraviroc was approved by the US Food and Drug Administration in 2007 as part of combination antiretroviral therapy for adults infected with CCR-tropic (R5) HIV-1 on the basis of 48-week results from the 2 phase 3 MOTIVATE studies. Two-year follow-up, including a year of open-label maraviroc, revealed durable virological suppression and no new safety issues. With extended follow-up for >5 years, we found the incidence of death and selected clinical end points was low in this HIV-infected treatment-experienced patient population exposed to maraviroc. Because HIV-infected patients take antiretroviral drugs for prolonged periods and are living longer, it is critical to continue to assess the long-term safety and tolerability of antiretroviral regimens. Few phase 3 antiretroviral clinical trials have formally assessed longer-term safety in study participants, with a few exceptions such as the STARTMRK studies of raltegravir with 5 years of reported data.
Although the labeling information for maraviroc contains a boxed warning for hepatotoxicity, a previous analysis of the maraviroc clinical development program revealed no increased hepatotoxicity compared with comparator regimens with follow-up of up to 96 weeks. Our extended analysis of the phase 3 maraviroc studies found hepatic failure events were uncommon (n = 5, 0.5%).
Consistent with a previous report of pooled maraviroc phase 2b/3 studies with a median of 82 weeks of follow-up, we found no excess occurrence of malignancies in maraviroc-treated patients after >5 years. The malignancy rate of 2.4 events per 100 patient-years in the present 2 treatment-experienced studies of maraviroc was comparable to the malignancy rate reported in a pooled analysis of the BENCHMRK 1 and 2 studies of raltegravir that enrolled a similar study population of treatment-experienced patients with advanced HIV disease failing their antiretroviral regimen who randomized to raltegravir (3.0 events per 100 patient-years) or matching placebo (2.6 events per 100 patient-years), in addition to optimized background antiretroviral therapy (OBT). Although in a previous phase 2 study of another investigational CCR5 antagonist, vicriviroc, 12 (11%) of 113 of subjects who received vicriviroc developed malignancies, ultimately 2 larger phase 3 studies of vicriviroc reported malignancies occurred rarely and without differences between the vicriviroc and placebo arms, and therefore did not confirm an association.
In the current studies of treatment-experienced patients with virological failure on their prestudy antiretroviral regimen, the myocardial infarction/cardiac ischemia rate was 1.1 events per 100 patient-years. This was consistent with a previous analysis of ischemic cardiovascular events from this study with shorter follow-up. Other cohorts have reported lower rates of cardiac events, for example, in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, the rate of myocardial infarctions was 0.32 events per 100 patient-years, and in a Kaiser Permanente cohort, the rate of coronary heart disease events (including myocardial infarction) was 0.35 events per 100 patient-years. Two important differences between our study and these cohort studies are important to recognize: (1) our study used a broader definition of cardiac events that included cardiac ischemia and (2) our study population was treatment-experienced and had advanced HIV disease (median prestudy CD4 count <200 cells/μL) in contrast to the patient populations in the D:A:D and Kaiser cohorts who were treatment-naive patients throughout all stages of HIV infection.
The expanded access program for maraviroc enrolled and assessed 1032 participating patients who had a median maraviroc exposure of 174 days and found the safety and occurrence of adverse events were generally similar to the current MOTIVATE studies. An additional study, the Prospective Observational Epidemiologic Study of Maraviroc's Safety (POEM; Study A4001067), currently is in progress and will continue to compare safety data for 5 years in 1500 patients on maraviroc with 1500 patients not taking a CCR5 antagonist.
In summary, in a population of HIV-infected treatment-experienced patients with >5 years of exposure to maraviroc, the incidence of death and other selected clinical events, including hepatic failure, malignancies, and myocardial infarctions, was low, and no new safety signals were reported. Maraviroc appears generally safe and well tolerated for at least 5 years in treatment-experienced patients.
Discussion
Maraviroc was approved by the US Food and Drug Administration in 2007 as part of combination antiretroviral therapy for adults infected with CCR-tropic (R5) HIV-1 on the basis of 48-week results from the 2 phase 3 MOTIVATE studies. Two-year follow-up, including a year of open-label maraviroc, revealed durable virological suppression and no new safety issues. With extended follow-up for >5 years, we found the incidence of death and selected clinical end points was low in this HIV-infected treatment-experienced patient population exposed to maraviroc. Because HIV-infected patients take antiretroviral drugs for prolonged periods and are living longer, it is critical to continue to assess the long-term safety and tolerability of antiretroviral regimens. Few phase 3 antiretroviral clinical trials have formally assessed longer-term safety in study participants, with a few exceptions such as the STARTMRK studies of raltegravir with 5 years of reported data.
Although the labeling information for maraviroc contains a boxed warning for hepatotoxicity, a previous analysis of the maraviroc clinical development program revealed no increased hepatotoxicity compared with comparator regimens with follow-up of up to 96 weeks. Our extended analysis of the phase 3 maraviroc studies found hepatic failure events were uncommon (n = 5, 0.5%).
Consistent with a previous report of pooled maraviroc phase 2b/3 studies with a median of 82 weeks of follow-up, we found no excess occurrence of malignancies in maraviroc-treated patients after >5 years. The malignancy rate of 2.4 events per 100 patient-years in the present 2 treatment-experienced studies of maraviroc was comparable to the malignancy rate reported in a pooled analysis of the BENCHMRK 1 and 2 studies of raltegravir that enrolled a similar study population of treatment-experienced patients with advanced HIV disease failing their antiretroviral regimen who randomized to raltegravir (3.0 events per 100 patient-years) or matching placebo (2.6 events per 100 patient-years), in addition to optimized background antiretroviral therapy (OBT). Although in a previous phase 2 study of another investigational CCR5 antagonist, vicriviroc, 12 (11%) of 113 of subjects who received vicriviroc developed malignancies, ultimately 2 larger phase 3 studies of vicriviroc reported malignancies occurred rarely and without differences between the vicriviroc and placebo arms, and therefore did not confirm an association.
In the current studies of treatment-experienced patients with virological failure on their prestudy antiretroviral regimen, the myocardial infarction/cardiac ischemia rate was 1.1 events per 100 patient-years. This was consistent with a previous analysis of ischemic cardiovascular events from this study with shorter follow-up. Other cohorts have reported lower rates of cardiac events, for example, in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, the rate of myocardial infarctions was 0.32 events per 100 patient-years, and in a Kaiser Permanente cohort, the rate of coronary heart disease events (including myocardial infarction) was 0.35 events per 100 patient-years. Two important differences between our study and these cohort studies are important to recognize: (1) our study used a broader definition of cardiac events that included cardiac ischemia and (2) our study population was treatment-experienced and had advanced HIV disease (median prestudy CD4 count <200 cells/μL) in contrast to the patient populations in the D:A:D and Kaiser cohorts who were treatment-naive patients throughout all stages of HIV infection.
The expanded access program for maraviroc enrolled and assessed 1032 participating patients who had a median maraviroc exposure of 174 days and found the safety and occurrence of adverse events were generally similar to the current MOTIVATE studies. An additional study, the Prospective Observational Epidemiologic Study of Maraviroc's Safety (POEM; Study A4001067), currently is in progress and will continue to compare safety data for 5 years in 1500 patients on maraviroc with 1500 patients not taking a CCR5 antagonist.
In summary, in a population of HIV-infected treatment-experienced patients with >5 years of exposure to maraviroc, the incidence of death and other selected clinical events, including hepatic failure, malignancies, and myocardial infarctions, was low, and no new safety signals were reported. Maraviroc appears generally safe and well tolerated for at least 5 years in treatment-experienced patients.