The Body Covers: The 14th Conference on Retroviruses and Opportunistic Infections
New Frontiers in HIV Prevention: Male Circumcision and Pre-Exposure Prophylaxis in the United States -- An Interview at CROI 2007 With Patrick Sullivan, Ph.D., and Lynn Paxton, M.D., M.P.H.
February 27, 2007
Patrick Sullivan: Sure. Well, I think one of the very exciting things that has happened in the field of HIV prevention in the last year is [that] results of trials from Africa have been published that indicate that in Africa, circumcision is associated with a 50% to 60% reduction in men's risk of getting HIV from their female sex partners. [These studies were published in PLoS Medicine and Current Opinion in Infectious Diseases.] As we try and think about how that information impacts what we do in prevention in the United States, this study that we present is one piece of that. We recognize that there are really important differences between the setting in Africa, where the trials were done, and the U.S. epidemic. The African trials don't tell us anything about whether circumcision might be protective for men who have sex with men in the United States.
In the circumcision study that we presented, we wanted to get an idea of whether, if circumcision were found to be effective in reducing the risk of HIV acquisition for men who have sex with men, would U.S. MSM [men who have sex with men] consider that as [part of] a set of prevention tools for themselves? What we found is that most of the uncircumcised men who we interviewed at Gay Pride events in 2006 would be willing to consider getting circumcised as an adult, if it were shown to be associated with reduced risk of HIV infection.
I think this is important, because it suggests that some MSM and, in our work, especially black MSM, were willing to consider incorporating circumcision into a set of prevention approaches that they would use for themselves. That's one of the things that we want to emphasize: If this is shown to be effective, [and] none of the biomedical interventions that we're talking about are going to be 100% effective, it always needs to be part of a set of things that people take on as protective behaviors for themselves. That [set] might [also] include condom use, reducing the number of sexual partners, and other prevention approaches that we know can contribute to reducing risk.
Did this study find any kind of division -- racially or ethnically -- among the people who were, or weren't, willing to get a circumcision if it meant that it might reduce their risk of contracting HIV?
Patrick Sullivan: We had two findings that related to race and ethnicity. One is that we found that the majority of [men] we interviewed who were uncircumcised were men of color. That goes along with what we know about some trends in circumcision in different communities in the United States.
We also found that blacks were more willing than men of other racial and ethnic groups to consider circumcision if it were shown to be effective in reducing the risk of HIV transmission.
Was the study able to determine why this was?
Patrick Sullivan: No. This particular survey didn't ask follow-up questions to really detail the reasons why. We are doing some more work to try and flesh out our understanding of what some of those reasons might be.
What is the current estimated rate of circumcision within the United States?
Patrick Sullivan: Within the United States, it's probably in the neighborhood of four out of five men [who] are circumcised. There are some variations in that -- in different parts of the country, for example. But as a national rate, about four [out of] five. We found in our survey that 82% of men who have sex with men who we interviewed reported being circumcised.
You said about half of those people who were not circumcised said that they would pretty strongly consider it?
Patrick Sullivan: Right. Actually, 54% of those who were uncircumcised said that they would consider getting circumcised as an adult, if it were shown to reduce their risk of HIV infection.
Do you have any idea as to how strongly they were actually considering this option? Was it the kind of thing where you were able to [say], "Well, actually, we have a scalpel right here if you'd like to get it done right now," and then see how the rates actually adjust?
Patrick Sullivan: I think there's always some disconnect between what people say they might hypothetically do -- "If it were shown to be effective, would you consider doing this in the future?" -- that we know is just part of the discipline of survey research; that those sorts of future intentions will change somewhat when a specific circumstance is presented. If this is found to be effective -- and I think the proof will be in the pudding -- ... [the rate] may well be lower than what we got in these sort of hypothetical questions.
That's fair enough. Considering, though, that so many people have already been circumcised in the United States, what kind of impact do you think male circumcision -- if it were to be introduced specifically as an HIV prevention method, and there were campaigns instituted to try to get people, particularly HIV-negative black MSMs to seek out circumcision -- what kind of impact on the HIV epidemic in the United States could we expect to see?
Patrick Sullivan: That's actually a great question, because how we look at things, as public health practitioners, is at the population level. I think it's true that the potential impact of circumcision as an HIV prevention intervention in any country is going to depend on what proportion of the population is already circumcised. In the U.S., I think on the population level there is a little bit less room for impact because of the high prevalence of circumcision. I think the challenge is to think about those groups and those areas in which there may be a lower prevalence of circumcision and, in the end, make good information available about how, if it were shown to be effective, circumcision might be one part of a set of prevention strategies that men adopt.
OK. Let's move on to the second study, then. First of all, could you elucidate quickly what actually is pre-exposure prophylaxis, or PREP?
Patrick Sullivan: Pre-exposure prophylaxis refers to the use of drugs that are used to treat HIV infection, but in the case of pre-exposure prophylaxis, they are used before someone has a risk exposure. Particularly, I think, in the study that we're reporting, we're interested in the extent to which men who have sex with men take antiretroviral drugs before having sexual risk exposures, in hopes of reducing their chances of getting HIV.
What did this study find?
Patrick Sullivan: Well, the bottom line of this study is that we found that it's pretty rare that men who have sex with men are actually using PREP at this time. We find that that's an encouraging thing, because the use of PREP to reduce the risk of HIV infection is currently being evaluated in clinical trials. Until the results of those clinical trials are in, we really don't know whether this is something that's going to actually reduce risk. There have been some media reports and some ... discussion in the community that suggested that a fair number of MSM might be using PREP to try to reduce their risk of HIV infection. That's why we evaluated this: to try and understand whether that was really going on.
Yes. I think I recall a study coming out, maybe a year, a year and a half ago, that suggested somewhere around 8 percent of people surveyed had actually tried pre-exposure prophylaxis within the United States. This study suggests a number that is drastically lower. I think it was, what? One person?
Patrick Sullivan: Just one person out of over 400 interviewed.
Was it the same with HIV-infected people doling out drugs to others as an HIV prevention method? It was only one person out of 60-some-odd?
Patrick Sullivan: Sixty, yes.
What accounts for that kind of discrepancy?
Patrick Sullivan: Well, actually, we did a previous study at CDC in which we evaluated this, using a single question on a survey that was done in 2004. We did find a higher proportion of men who reported in that survey that they had tried PREP. Based on that finding -- that's part of the reason that we did this more extensive follow up.
There are several things that were different between those two surveys. One of the things that was different is that, in the surveys that we're reporting here, where we didn't find much PREP use, these were actually interviewer-administered surveys where the respondents had a chance to ask questions and maybe clarify their understanding of what was being asked. I think even those of us who deal with these issues of pre-exposure prophylaxis and post-exposure prophylaxis, or PREP and PEP, on a day-to-day basis, can get tongue-tied over those [questions] sometimes. I think just the fact of having an interviewer-administered survey and the ability to ask clarifying questions may have helped the men understand what they were being asked better. We did find in the current survey that use of PEP, or post-exposure prophylaxis, was somewhat higher than PREP. Those [two] could have been confused in the earlier survey.
We also ... stepped up the level of the methods that were used. We used a systematic sampling approach in a later work that should give a more representative look at the men attending these Gay Pride events. The surveys ask in general about the same thing, but the methods, I would say, in the later ones were a little more sophisticated, and probably are a little more representative of men's actual behaviors.
As you mentioned, this is sort of a perception/use study of a method that is currently employed in clinical trials to investigate just how well this particular method, PREP, can work in helping to prevent HIV. Dr. Paxton, you're the international coordinator of the clinical trials that seek to determine whether PREP can actually work, right?
Lynn Paxton: Yes, I'm the coordinator for the Centers for Disease Control-led studies looking at this question.
Can you describe what those studies are actually seeking to investigate?
Lynn Paxton: Certainly. We're looking at both the safety of two particular drugs used in these trials to prevent HIV transmission, and we're looking at the efficacy. We're looking to see whether or not they're safe for use, and whether or not they work.
We currently have three trials that are going on. We have a trial in the United States that's being conducted among 400 men who have sex with men in three cities: Atlanta, Boston and San Francisco. We're looking to see whether the use of tenofovir [TDF, Viread], a single drug, is safe to be used among this cohort.
We also have complementary trials that are going on in Thailand and Botswana. The trial in Thailand is among injection drug users. Two thousand is the total population that will be enrolled into these trials. We're looking to see whether or not oral tenofovir is both safe and effective in preventing injection drug use transmission of HIV.
Our third trial is taking place in Botswana, and the population in which we're conducting this trial are young, heterosexual adults: young men and women between the ages of 18 and 29. We're looking at a combination drug ... Truvada, which is a combination of tenofovir and emtricitabine [FTC, Emtriva] in one pill. Again, we're looking to see whether or not this drug combination is both safe and effective in preventing HIV transmission among this group.
You're really covering all your bases with these drugs.
Lynn Paxton: We are doing our best.
Why tenofovir and Truvada? What makes them so promising as potential drugs for PREP?
Lynn Paxton: That's a very important question. Actually, the notion of PREP, or using an antiretroviral to prevent transmission, first started being talked about at the end of the 1990s as a potentially good idea to look into. But at that time, we did not have an appropriate drug that was safe enough to be used on a long-term basis among the people who do not [have] HIV infection [and] that had a low enough incidence of side effects that would even consider using it.
Then tenofovir came on the market in 2001. This was found to be, when used by HIV-infected people, not only effective in lowering the viral load, but also very, very well tolerated, with a low level of side effects. With the advent of this particular drug, the notion of pre-exposure prophylaxis really started to take off. ...
In addition, tenofovir, when used as part of a treatment regimen for HIV-infected individuals, appears to have what we call a relatively high genetic barrier to development of resistance, which is very important when you're looking at a drug that you would want to use both in treatment of HIV and in the prevention of HIV. You want something that is unlikely to induce resistance in the virus.
The reason being that in case these people take the drug as pre-exposure prophylaxis and still become HIV-infected, they'll be able to take every drug, hopefully.
Lynn Paxton: Yes. They would have a lesser chance of limiting their own treatment options in the future.
These trials are still enrolling, so it's still very, very early to say -- I'm imagining it's going to be several years, at least, until we get real results. But is there any indication based on studies that have been done so far -- smaller studies, maybe animal studies -- that suggest which way the wind is going to blow?
Lynn Paxton: [Laughing] If I knew which way the wind was going to blow in the crystal ball, well, I would have a Nobel Prize now. But there have been numerous animal studies that have been done, looking at this very question. The preponderance of these studies, which look at different routes of transmission -- you know, intravenous, rectal, or vaginal -- and have looked at various drugs -- injectable tenofovir, oral tenofovir, injectable Truvada, oral Truvada, various things -- they tend to indicate that this is effective, at least in monkeys, at preventing transmission. Also, in humans. The Family Health International did conduct a trial among women in three countries in Africa -- in Ghana, Cameroon, and Nigeria -- and found that [for] the 936 women who were enrolled in this trial ... that tenofovir was safe. There were no more adverse events in the tenofovir group than in the placebo group. Tantalizingly, they found that they had eight sero-conversions; eight people who became HIV-infected. Six of those were in the arm getting placebo, and only two were in the arm getting tenofovir. However, I emphasize that this study was not powered to look at efficacy, and that we were not able to say with any statistical significance that this shows that it's efficacious. But that is what their results showed.
What would you say to people who are either HIV infected and going to go out and have unprotected sex, or just want to take an extra precaution by sharing their drugs with their partners? Or HIV-negative people who say, "You know, maybe there's something to this. It seems early research is saying there may be some protective value."
Lynn Paxton: What I would definitely say is that this is an unproven therapy. This is why we are doing the trials. Until we prove, show that this is effective, we strongly recommend against trying to use these drugs. We basically say: "Don't do this at home." Because we feel that it's not been proven.
What we always emphasize is that we do have things that are proven to work: condoms, knowing your partner's sero status, abstinence. These things are known to work. Even at the completion of these trials, if [they] show that [PREP] is effective -- and I sincerely hope that it will prove to be effective -- even then, as Dr. Sullivan has already pointed out, it will never be 100% effective, and it will always only be a component of this other assortment of proven interventions that we already have out there. What I urge people to do is: Go with what we know works now.
Patrick Sullivan: I agree completely, and would maybe go a little step further, and say: Not only are these therapies not proven, but people could actually be putting themselves at risk by taking medications in the hopes that they would avoid HIV infection. They may actually get drugs in their system that do allow selection of a resistant strain of HIV, for example, or could have toxicities from those drugs that they haven't anticipated. People actually may put themselves at risk by doing this in advance.
Lynn Paxton: Along those lines: These drugs offer no protection against other sexually transmitted diseases, such as syphilis, gonorrhea, HPV [human papillomavirus] -- all things that can increase a person's risk of acquiring HIV. There are many reasons not to go down this route at this point in time.
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