Conference - February 8, 2006 Transcript

Update #3, Wednesday, February 8 from the Retroviruses and Opportunistic Infections, National Meeting

Dr. Eric Daar offers perspectives of interest on topics from the 13th Conference on Retroviruses and Opportunistic Infections (held in Denver, Colorado February 5-8, 2006)

This is a report from the final day of the 13th Conference on Rotaviruses and Opportunistic Infections in Denver, Colorado. There were numerous presentations particularly related to complications of antiretroviral therapy and novel and emerging treatments. I will focus on these topics along with select epidemiologic studies.

Circumcision and HIV Transmission

A Plenary presentation by Tom Quinn from the National Institutes of Health and Johns Hopkins University provided an overview on the background and rationale for considering the role of male circumcision as a strategy to reduce HIV transmission. He summarized that there are numerous factors that determine the infectiousness of an HIV-infected individual. He commented that person's viral load as well as viral load in genital secretions, along with the presence or absence of circumcision, the stage of their clinical disease, the presence of genital ulcers or other sexually transmitted diseases, cervical pathology, certain other characteristics of a given strain of HIV and even the use of antiretroviral therapy may influence infectiousness. Factors that might increase the risk for someone to acquire HIV include the viral load in blood as well as genital secretions of their sexual partner, the presence or absence of circumcision, genital ulcers, sexually transmitted infections, cervical pathology, as well as genetic factors. He provided some history and perspective on circumcision, including medical benefits such as lower risks of cervical cancer amongst partners of men who have been circumcised as well as a reduced risk of penile cancer and localized infections, both sexual and otherwise in those who have been circumcised.

In a variety of epidemiologic studies looking at communities in which circumcision is common (greater than 80 percent) verses uncommon (less than 20 percent, it has been shown that circumcision is associated with low frequency of HIV infection. There was a pivotal study from Rakai published in the New England Journal several years ago by Tom Quinn and his colleagues showing that viral load was an important predictor of HIV transmission amongst discordant couples. They also noted that independent of viral load amongst 50 individuals in which the male partner was circumcised, there were no cases of transmission. A potential biologic explanation includes the fact that many target cells for HIV infection are present under-surface of the foreskin which otherwise are not present in circumcised individuals. Ultimately this led to the initiation of 3 randomized controlled trials, one in South Africa, another in Uganda and Kenya. These communities have populations with a low frequency of circumcision and were randomly assigned to circumcision or no circumcision. Recently, the report from one of these 3 trials, all of which include over 2500 to 5000 patients, was reported when the data safety monitoring board terminated the trial because it found circumcision to be clearly associated with lower risk of transmission. This study was looking at the risk for men to acquire infection from women; with more information is needed from the other trials to confirm these findings as well as to assess the effect on transmission to women.

Tolerability of Antiretroviral Therapy in the Developing World

There were two important studies presented by the CDC, one in Uganda and one in Nairobi, looking at the side effects associated with the roll-out of antiretroviral therapy in the developing world. The largest of the two studies was from Uganda where they looked at 1000 patients between 2003 and 2004- about 75% women who were treated as part of a home-based AIDS care program with mostly D4T, 3TC and nevirapine- a common regimen used in the developing world. The investigators followed these people for the development of toxicities and found that peripheral neuropathy was seen in about 36%, 10% being severe, with rash in 6%, 2% being reported as severe. In addition, 2% of subjects developed hypersensitivity reaction (presumably to nevirapine). Overall, up to 40% of the patients in this group developed some toxicity, 14% being severe. Therefore, while there are clear clinical benefits that are going to be associated with the roll-out of therapy, it will be important to monitor for toxicities to assure patient safety.

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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