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

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.