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Lack of Circumcision, Immunity Linked to HIV Vaccine Failure


 

BOSTON — The increased risk of HIV infection observed in the now-defunct trial of Merck's experimental trivalent HIV vaccine V520 was greatest in uncircumcised men with high preexisting immunity to the vaccine's delivery vector, the adenovirus type 5, according to a post hoc analysis of the trial data.

“Uncircumcised men with high immunity to [adenovirus type 5] were more than four times more likely to develop HIV infection than men given the placebo vaccine,” Dr. Susan Buchbinder reported at the 15th Conference on Retroviruses and Opportunistic Infections.

The international clinical trial of V520 was halted in September 2007 because it failed to block or slow the rate of HIV infections in the high-risk study population (primarily gay men and female sex workers who had multiple sex partners in the 6 months prior to study initiation). Additionally, the HIV infection rate was higher in the vaccine arm than in the placebo arm, said Dr. Buchbinder of the San Francisco Department of Public Health.

Overall, 49 of 914 vaccine recipients developed HIV infection, compared with 33 of 922 placebo recipients. Because all but one of the reported infections occurred among the study's male volunteers, post hoc analyses have concentrated on the men in the study, she said.

Although the difference in infection rates between the vaccine and placebo groups across the entire study population was only “marginally statistically significant,” in the subgroup of participants with high levels of adenovirus type 5 (Ad5) immunity—defined as antibody levels greater than 200 U—the statistical significance between the two groups was more robust. In univariate and multivariate models, high Ad5 immunity was associated with a threefold increased risk of HIV infection in vaccine recipients, Dr. Buchbinder noted.

Univariate and multivariate analyses also identified the lack of circumcision as a risk factor for infection. “Uncircumcised males [with high Ad5 immunity] who received the vaccine were approximately four times more likely than those who received placebo to become infected with HIV,” Dr. Buchbinder reported. Circumcision, on the other hand, appeared to blunt the increased vulnerability to infection associated with Ad5 immunity, in that the HIV infection risk among circumcised men with high titers to Ad5 was not statistically significant, she said. Similarly, the increased infection risk observed in uncircumcised men with low titers was not statistically significant.

Men in the study with high Ad5 immunity tended to come from countries and communities with low rates of circumcision.

An evaluation of viral loads across the study population did not identify an obvious correlation between Ad5 immunity and viral load. “We are awaiting additional data on herpes simplex virus 2, [human leukocyte antigen] typing, and sexual network clustering to explore possible confounding factors for HIV acquisition,” Dr. Buchbinder added.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

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