February 6, 2008
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As CROI 2008 in Boston drew to a close, we asked David Wohl, associate professor of medicine at the University of North Carolina at Chapel Hill, and co-director of HIV services for the North Carolina Department of Corrections, what he felt was the most significant research presented at the conference.
David Wohl: People often come up to me after I come back from the Retro conference and ask me, "What was the most important thing you learned at this conference?" There were plenty of head-to-head clinical trials. There were plenty of posters on cohort data about what happens when you observe people for a long period of time. There were novel data about new drugs and new targets for drugs.
David Wohl, M.D.
But I think one thing that really struck me here is just how darn good circumcision is at preventing the transmission of HIV infection. And, interestingly, how circumcision, of all the things that you could possibly think about, turned out to be one of the most important factors in a vaccine trial to prevent HIV infection.
So get this: Here's a vaccine, a potent vaccine, that's considered to be the great hope for eliminating HIV on our planet. This is the Merck vaccine. It's an adenovirus vector vaccine, a trivalent vaccine that appeared to be immunogenic, and preliminary studies moved rapidly into clinical trial phase. Studies launched and 3,000 people enrolled across the country. As anyone who reads a newspaper found out, at the end of last year, the study was stopped abruptly after a planned interim analysis found that there was no efficacy of the HIV vaccine in preventing acquisition of infection among men and women with high-risk behaviors.1
This was very, very disappointing. It's really put a chill on vaccine research across the planet. A number of different studies that were being planned to check on the utility of new vaccines were halted. Other studies that were ongoing, with similar vaccines, were halted, regardless of what stage they were in. So I think that that was a very important study. It's called the STEP study. It was being conducted by the company, Merck, along with the HIV Vaccine Trials Network, a federally-funded organization from the U.S.
What the investigators from that study did at this particular conference was look at what happened during the study, and what predicted whether or not someone would become infected with HIV.2
It had already been known that whether or not an individual had some baseline immunity to the adenovirus vector helped differentiate those who were at risk for acquiring HIV, despite the vaccine, and those who were not.3
Specifically, people who had some baseline immunity, some immune response to the adenovirus vector, seemed not to get much benefit from this vaccine.
Specifically, when you look overall in this study, 49 people who received the vaccine acquired HIV infection, compared to 33 in the placebo. But when you break it down by whether or not an individual has some reactivity to adenovirus at baseline, those who were Ad5 -- that's the short term for adenovirus 5-type that was used in this vaccine -- had an Ad5 response that was low. There was hardly any difference between the two study arms. So 28 in the vaccine arm, compared to 24 acquisitions of HIV in the placebo.
However, when you look at those who had a robust response to the adenovirus vector, 21 in the vaccine arm developed HIV infection, compared to 9 who received the placebo. So if anything, it looked like that having had previous immune responses to adenovirus may have put people at increased risk of acquiring HIV after receiving the HIV vaccine, a very disconcerting finding.
In this multivariable analysis that was conducted and reported here at CROI, there were a number of things that were looked at -- certainly the vaccine versus placebo, and the baseline adenovirus immunity -- but also, circumcision by self report, age, race, region of the world where a person was enrolled, and baseline risk factors for HIV in the previous six months, including number of male partners, type of anal sex that people were having, substance abuse and STDs.2
Basically, at the end of the day, things that seemed to signal that there was a relationship included the adenovirus 5 immunity, as was mentioned previously. In this multivariable analysis adenovirus 5 immunity continued to be a strong indicator of risk for HIV infection, again, with those who had previous exposure to adenovirus having an increased risk of acquiring HIV.
But what also came out surprisingly to me was circumcision. When you look at men who were circumcised, they had a much lower risk of acquiring HIV, compared to those who were not circumcised. I should mention that of those people who did acquire HIV, all were men, except for one individual who was a woman. So this is largely a phenomenon that's happening across men, and not women, in this study.
Importantly, when you look at both circumcision and adenovirus immunity, an intriguing picture emerges. For those men who were uncircumcised and had very low adenovirus a very interesting picture emerges. When you look at men who were circumcised, and had high titers to adenovirus 5 at baseline -- so that' the kind of immunity that put people at risk for acquiring HIV -- if you were circumcised, that seemed to blunt your increased vulnerability to HIV infection following vaccination.
So people who were circumcised did much better regardless of their adenovirus 5 immunity at baseline, compared to uncircumcised men. Certainly, the lowest risk was among those men who had very low titers of adenovirus 5 antibodies and were circumcised.
Now, look at the people who had adenovirus 5 titers that were very low, and were uncircumcised. They had a much higher risk of developing HIV, of acquiring HIV, than those who were circumcised.
So putting this together, what we see is that, for some reason, being uncircumcised seems to undo some of the effect we saw with having a low titer to HIV infection. Uncircumcision, not being circumcised, put people at increased risk of acquiring HIV, and circumcision, conversely, protected people from HIV infection.
I think this is a really important finding. When I go home and people say, "What was one of the most important things you learned at the conference?" It would be that if you have a penis, and you plan to have sex with it, it should be circumcised.
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