CROI Conference, Denver, CO February 8, 2006 (cont.)

Cardiovascular Disease and Antiretroviral Therapy

There were several important studies related to the relationship between antiretroviral therapy and cardiovascular disease. The D:A:D Study included 23,437 patients followed in 11 cohorts from Europe, Australia and the United States since 1999. At the time of the analysis reported at this meeting there were 94,469 patient-years of follow-up. These investigators previously demonstrated that there was an increased risk of cardiovascular events associated with duration of combination antiretroviral therapy. The current analysis assessed the relationship between exposure to protease inhibitors verses nonnucleoside reverse transcriptase inhibitor-containing regimens and cardiovascular events. They showed that protease inhibitor exposure was associated with increased risk of such events, which was not seen in association with nonnucleoside reverse transcriptase inhibitor use. While this is the largest prospective study demonstrating a relationship between cardiovascular events and duration of combination therapy, it is worth noting that it is a cohort study and has numerous limitations. Moreover, results could change as the types of therapies used change with time as well as increased focus on modifying other risk factors such as tobacco use, diet and management of other diseases such as diabetes and hypertension. In fact, there was a report from the HIV Outpatient Study (HOPS), showing that there has been modifications in the way patients are managed over time, particularly related to improved management of cardiovascular risk factors such as dyslipidemia and hypertension that might have resulted in the observed leveling off in the number of cardiovascular events seen in this group.

A related study looked at carotid artery changes which have been shown to correlate with cardiovascular disease. The study enrolled 45 groups of three, and within each group there was a subject HIV-infected on a protease inhibitor, another HIV-infected not on a protease inhibitor, and a third that was not HIV-infected. Within each group the study subjects were similar with regards to other cardiovascular risk factors such as smoking, age and gender. The investigators previously published the baseline data showing no differences in carotid measurements between the 3 groups. At this meeting they reported the 3-years of follow-up showing no difference in the change in carotid measures between the groups. Therefore, at least based upon this non-invasive test, there did not appear to be an increased risk of cardiovascular disease associated with the use of protease inhibitors.

Antiretroviral Therapy in Development

Integrase Inhibitors

Drugs in an exciting new class of antiretroviral agents called integrase inhibitors were reported at this meeting. One such drug in development by Merck is called 0518. They have previously reported 10 day monotherapy data showing nearly a 100-fold decrease in blood viral load. At this meeting they presented data from a study that included highly treatment-experienced subjects who were resistant to many available drugs. Study subjects were given best available therapy alone or along with either 200, 400 or 600 mg twice per day of the integrase inhibitor. The primary endpoint was change in viral load and CD4. This was an early look at the data for subjects who reached 16 weeks on therapy. The investigators found that overall there was approximately a 100-fold reduction in viral load in those who received the integrase inhibitor as part of therapy, compared to less than 10-fold in those who received best available therapy without the new drug. The drug appeared to be well-tolerated without significant laboratory abnormalities.

Data with another integrase inhibitor, Gilead Sciences 9137 was also presented. In this case they treated subjects with different doses of the drug. These studies showed that the optimal doses resulted in an approximate 100-fold reduction of viral load compared to a minimal change seen in the group that received no therapy. In addition, there were no apparent adverse events noted at this time.

CCR5 Inhibitor

Another study reported on the use of the CCR5 inhibitor vicriviroc in those who have never received antiretroviral therapy before. This novel class of drugs had been moving forward in clinical development by three different companies. Several months ago it was announced that development one of these drugs, aplavirac was stopped because of several cases of severe liver toxicity. Not long after that we heard about the data safety monitoring board stopping the study presented at this meeting. This study randomized subjects to different doses of vicriviroc given for two weeks by two nucleoside reverse transcriptase inhibitors with each of the different doses of the drug or with efavirenz as the standard of care arm. The study was prematurely stopped because there was lower rate of viral suppression in those receiving vicriviroc compared to the standard of care group. The difference was most significant in those on the low doses of the experimental drug. It is important to note that the number of study subjects was relatively small and further analysis is necessary to fully understand why the outcomes with the new drug may have been worse than the standard of care. Ongoing trials are underway with another drug, maraviroc, and are currently planned for vicriviroc.

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Last Editorial Review: 2/15/2006