February 3, 2008
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This is a summary from researchers of a wide range of issues related to HIV prevention in the developing world. They'll touch on many issues, including male circumcision, mother-to-child HIV transmission and whether treating other sexually transmitted diseases can help reduce HIV transmission. The panel of researchers who provided a summary of their studies included David Serwadda, M.B.Ch.B., of the Makerere University School of Medicine in Kampala, Uganda, and Ronald Gray, M.B.B.S., Aaron Tobian, M.D., Ph.D., and Maria Wawer, M.D., of Johns Hopkins University in Baltimore, Md.
John Mellors: Triumph and defeat, success and failure. That's the theme for this conference.
On the success side, we have in the front row, four remarkable investigators: Drs. Serwadda, Wawer, Gray and Sewankambo from Uganda and Johns Hopkins, who really pushed the field forward, and have had the singular most important finding in HIV prevention in the last decade, and arguably in the epidemic: that circumcision of men protects men and women from HIV infection. Now we learn it protects men from HSV-2 herpes simplex virus infection, and also improves the vaginal health of women. These are remarkable achievements, and they are going to present their achievements at the N'Galy-Mann Lecture. We're also going to have them up on the podium in a few minutes. That's real, solid progress. And what's beautiful about it is, it's a great collaboration between Uganda and the United States. So, if you have something hopeful and positive in your article, I think you should highlight this.
There's also good news that will be highlighted later in the week on preventing maternal-to-child transmission, and how best to do that. There is one caveat though: The harder we push with antiretrovirals to prevent transmission, the more resistance we get with babies. That's an important theme. But [there is] progress on two fronts: circumcision and its health benefits, and maternal-to-child transmission.
The failure -- but not the defeat, we hope -- deals with the topic of preventive, or disease-modifying, vaccines. As you know, the most cost-effective public health measure is a highly protective vaccine. That has eluded the best scientists in the world for over two decades, and it looks like it's going to continue for the foreseeable future. That will be exemplified on Tuesday by presentations from academic investigators from Merck, describing the results of the STEP trial, which showed that the Adeno-5 gag-pol-nef vaccine failed to protect from HIV infection. That wasn't unexpected.1 What was unexpected is, there's a strong trend that the vaccine increased susceptibility to infection, which has led to discontinuation of trials using that product. Also, the idea that a vaccine could modify disease, meaning prep the immune system to control HIV better, seems to have been refuted by the results of the vaccine trial.
Secondly, on a more negative note, is the much-anticipated trial of acyclovir [Zovirax] to suppress herpes simplex virus infection.2 It seems not to have conferred any protective benefit for HIV infection. This is particularly disappointing to me as a clinical and translational investigator, because there was good data, and good evidence, that acyclovir not only suppressed shedding of HSV-2, herpes simplex virus 2, but lowered the level of viremia in those people who were on it, and lowered the level of virus in the genital tract. But in a larger-scale trial: no protective effect. Trying to figure out why, and what the next steps are, is really what this conference is about.
Maria Wawer, M.D.
We'll be reviewing some of our data, both from epidemiology [and from] a trial of STD control for HIV prevention, which didn't show any effect on reducing HIV transmission through the treatment and control of bacterial STDs. But then, from that trial, which did not have an effect and was very disappointing, what we have learned about viral dynamics, transmission, different viral subtypes and how they act differently, but also what we learned about male circumcision and its potential protective effects in HIV-negative males, which basically added to a growing body of literature about the importance of male circumcision. From this, we were very fortunate to be one of three groups that started a trial of male circumcision in negative males. And as you all know, and as we will briefly summarize, all three trials, in three different populations, had highly significant effects in reducing acquisition of HIV in negative males. Very different populations. Different surgical procedures. Different HIV epidemics. And yet, the results were virtually identical.
This is probably, for us, one of the most heartening findings, and stands right up with prevention of mother-to-child transmission as an intervention that really can work. Challenges remain in its implementation. We will be presenting, tomorrow, data which suggest again how the virus is clever, and how things are never as clear as one would hope for them to be.
From our observational data, we had also hoped that male circumcision of positive men might reduce transmission of HIV to their negative partners. But data from a parallel trial of male circumcision in HIV-positive males in our trial did not show reduced transmission to women.3 And indeed, if the male resumed intercourse early after circumcision, before his wound was fully healed, we have some evidence that there might be increased transmission from the positive male to the female partner.
This, obviously, leads to additional challenges to programs and how we will deal with this issue. On the other hand, our colleague, Aaron Tobian, will present data in a talk that shows, as was indicated in the earlier summary, that male circumcision does appear to have benefits for female vaginal health, and also will discuss the reduced acquisition of HSV-2 in men who are also circumcised.4 So, some real benefits, but also some additional challenges which arise.
With respect to the Rakai program, we will also discuss some of the challenges it takes to keep a collaboration like this going. And when I say challenges, I don't mean within the group. I mean, this has just been the most fun collaboration anybody could hope and pray for. But between the virus and the real world, there are challenges galore. I'll pass to my colleagues.
David Serwadda, M.B.Ch.B.
Community-based programs, or research programs, of this nature are very, very challenging. We are often asked: How have you been in this population, carrying out all these research programs for the last 20 years? It is quite a very big challenge. But I think part of the answer is going to be -- and I will discuss this with you -- how we have been able to partner up with a community, in terms of providing services to these communities. You just can't be in these communities and just carry out research activities without providing services. So we are going to discuss with you in our lecture what we have learned, in terms of providing home-based voluntary testing and counseling, and what this has thus done to uptake. It has dramatically increased the uptake from 5% to about over 80% in provision of people knowing their results. What has been the benefit or the impact of health education over the years in these communities?
We are also going to look at the challenges of providing antiretroviral treatment in these communities. Since the PEPFAR [the President's Emergency Plan for AIDS Relief], which was initiated in 2004, we have had the opportunity to really have antiretroviral drugs at our disposal. However, providing antiretroviral drugs in rural populations in Africa has its challenges. We are going to look at how has been the uptake, which has been fairly reasonable; but there have been limitations, in terms of using WHO staging criteria in evaluating who is eligible.
For example, we find that in our datasets, if you just look at people who are in WHO stage 1 and 2 who are eligible, half of our population is eligible for treatment in that stage. Yet, by definition, they wouldn't be eligible for treatment. That's missing out about half our population set that should be on treatment.
We are also going to look at the fact that now circumcision can actually reduce HIV acquisition. What are our plans of really scaling this service to be available? We are very interested in monitoring the impact of incidence. We are very interested in monitoring the impact of behavior over time. Those two remain very unanswered questions. If you provide these services, how do people's behaviors change over time? We are interested in finding if people tend to increase their risk behavior, hoping that circumcision will give them perfect protection. This is very important in long-term impact of what circumcision can do on a population.
We would like to present all this and share the lessons learned in Uganda. University, government, donors and the challenges of actually funding and sustaining this program will be discussed in our lecture.
Ronald Gray: Can I also add that there are a number of posters of colleagues from this Rakai collaboration? These are particularly [the posters of] colleagues from Tom Quinn's lab at Hopkins, which illustrate the importance of doing studies in large populations, but being able to go down to the molecular level in your understanding of this virus. There will be a number of posters that will look at the effects of subtype on disease progression, and issues of what viruses transmit from a positive to a negative partner. I think it illustrates the philosophy of our colleagues that we go from the population down to the virus and the details, both biologic and behavioral, of the host, to understand this terrible disease.
John Mellors: Can I interject -- and David introduced this -- that there are really two stories here? One is of designing and executing well-conducted studies. That's a challenge. The other story is doing that while you're juggling the egos and agenda of many people and agencies, governments, donors, academic institutions. I'm sure they all have what might be considered, in retrospect, amusing stories, but at the time were not so amusing, about how forces came together to try to halt what they were doing overnight. And then to get a reprieve by diplomacy. They are all nodding. Because I'm a novice in international investigation. And it can be completely bewildering.
Reporter #1: You talk about the number of problems there. I know this is not immediately in your sphere, but your next-door neighbor, Kenya, is going through tremendous problems right now. Does that have any impact upon ongoing research efforts that you're aware of?
David Serwadda: Not really, but there is that potential. For example, much of Uganda's imports go through Kenya, through the port of Mombasa, particularly fuel. To the extent that fuel, apart from its impact on the economy, does, we run a fuel-based program. And if we do not have fuel, it really has an impact on our ability to carry out our fuel activities. Usually when fuel shortages come up, cost goes up. The increase will compound the problems of our cost of operations. So, yes. We could have problems in terms of the way we operate if these problems continue. We are really very concerned about that.
John Mellors: I want to introduce one other panel member. There's another important story: that the torch is being passed to the next generation. Aaron Tobian is going to present the data on the effects of male circumcision on prevention of HSV-2 infection and vaginal health in women.4 Aaron, if you would summarize, in a minute or two, what the key take-home messages are.
Aaron Tobian, M.D., Ph.D.
For the HSV-2 story, there were almost 6,400 men that were initially screened. We found 3,500 men were HIV negative, and also HSV-2 negative, that were also uncircumcised. These men were previously randomized, and we followed them up after two years. What we found is that there's a 25% reduction in HSV-2 acquisition in those men who were circumcised.
The second trial enrolled the wives of those men who were circumcised, to evaluate female transmission of sexually transmitted infections. Thus there are over 1,600 HIV-negative females married to these HIV-negative men in the circumcision trial. We followed them for 12 months. What we found is, those women who were married to the circumcised men had a decrease in symptomatic genital ulcer disease by 25%, a decrease in Trichomonas vaginalis by almost 50%, and a decrease in bacterial vaginosis by 20%.
Genital ulcer disease, HSV-2 and bacterial vaginosis are all cofactors for HIV. Therefore, the finding in this study may influence a protective effect of male circumcision and HIV acquisition.
Reporter #2: You said that you had a 25% decrease in HSV-2 acquisition in your circumcised group. Did you get any sense of the effect on HIV acquisition as a result of that down regulation?
Ronald Gray: This is something we're trying to sort out. We see a marked reduction in symptomatic genital ulcer disease in HIV-negative men, in HIV-positive men, and thus far, in the HIV-negative wives of circumcised men. That's about a 50% reduction in symptomatic disease in all those groups. So far, we've only seen this 25% reduction in HSV-2 acquisition. So there is something else that is affecting the symptomatic ulceration. We're in the process of trying to disentangle the mechanisms through which male circumcision may reduce HIV: a direct anatomic effect by removing vulnerable tissue -- foreskin; and secondary effects by reducing genital ulceration, particularly that due to HSV-2. But those analyses are in process.
John Mellors: This is getting pretty complicated now. I would ask, perhaps, Maria, to summarize what your studies show in terms of positive and negative, and their female sexual partners, for the infectious diseases that you've studied.3
Maria Wawer: Thank you very much. Both Aaron and myself will be presenting these data tomorrow, but we were asked to discuss this at the press conference today. Basically, now that male circumcision has been shown to reduce HIV acquisition in negative males, programs are going to be rolling out. It's very important to know what the effects of male circumcision might be in HIV-positive men; but also in women partners of both negative men, as Aaron was just discussing, and HIV-positive men.
It's inevitable that some HIV-positive men will seek circumcision. Circumcision is the only HIV prevention modality -- intervention -- that leaves a physical mark on somebody. If guys are all together, bathing in the river, everybody will know who is, or is not, circumcised, in many populations. For that reason, we think that positive men will seek circumcision, partly in order not to be stigmatized as the only guy in the village who's still not circumcised -- that means you must be HIV positive. The social consequences of circumcision go beyond just the intervention for HIV prevention.
We conducted a trial funded by the Gates Foundation that was parallel to the trial of HIV-negative men that Aaron and Ron were just discussing. In this trial, in Rakai, any HIV-positive guy who volunteered to be in a trial of male circumcision was enrolled into the Gates-funded trial and was randomized to receive immediate circumcision or circumcision delayed for two years. And what is more, both spouses of the negative men that were discussed by Aaron and spouses of the positive men were invited to participate in follow-up, to see what the effect of male circumcision might be on women's spouses.
Both the positive men and all the spouses signed informed consents. Everybody was provided with intensive HIV prevention education, condoms, offered free HIV counseling, offered free couples counseling. In other words, a real effort to make sure that they knew the consequences of being in the trial, and that they were offered maximum protection.
The main group that we will be discussing tomorrow are 93 couples, in which the male was positive and the woman was negative at enrollment, and they enrolled at the same time, and the male was circumcised. Then, in the control arm, 68 males who enrolled at the same time as their HIV-negative female partner. 93 couples in the intervention arm, 68 couples in the control arm, with a positive male and a negative female.
These couples were followed for up to two years. The principal results that we will be presenting are that in the HIV-positive males, men in the circumcision arm had approximately a 50% lower risk of having genital ulcers. This is very much a positive effect for the males. This is genital ulcer either observed at the time of their follow-up visits, or genital ulcer that they reported having had in between the study follow-up visits. And given that genital ulceration is a serious health problem in HIV-positive men, this is a benefit.
However, what we found in the women partners is that, unlike we had expected from previous observational data -- and I should make a quick aside, that in previous observational data prior to the trial, we had seen lower HIV rates in women married to HIV-positive circumcised men, compared to women married to HIV-positive uncircumcised men. However, in the trial, we did not observe lower HIV incidence in those women who were married to the men randomized to circumcision. The rate of transmission to women married to the circumcised men was 14.4 per 100 person-years, compared with 9.1 per 100 person-years to the women married to the uncircumcised men in the trial.
The difference between these two groups was not statistically significant. The numbers in the study were small, so this did not rate significance. It could be a finding by chance alone. But nonetheless, we were not seeing a trend towards protection that we would have expected, and hoped for.
We are now doing much more detailed analyses as to why we may have had this unexpected, and somewhat disappointing, result. What our data suggest is that the preponderance of the excess transmissions among women married to circumcised men may have occurred in the postoperative period, and particularly in those couples who reported having started sex before the surgical wound was fully certified as being healed. In other words, couples that resumed sex while there was still potential inflammation, or potential friability of the surgical wound, may have had a higher rate of transmission from the positive man to the negative woman. Our numbers do show higher transmission. Again: The difference is not statistically significant, which is why I say there may have been higher transmission.
What it does suggest is that the early postoperative period is a very important period, a period where it is imperative that people not resume sex because of the potential for increased risk. As an aside, in our trial of negative men, what we found is that the protective effects of circumcision became significant and apparent only after the six-month follow-up period. So even in negative men, resuming sex postoperatively, while the wound is still somewhat unhealed, may not confer any benefit, whereas once the wound is fully healed, we start seeing benefit in negative men.
The message that has to be given in circumcision programs is that, whether a couple has a positive man or a negative man, it's really imperative that the couple waits to have sex until the wound is fully healed.
Would anybody else like to add anything to that brief synopsis?
David Serwadda: I think it's also very important to put everything in perspective. While the results in reduction of transmission to spouses of HIV positives is somewhat a setback, it's very important to note that circumcision is still going to be a big benefit, because the majority of young adolescent boys in Africa are still HIV negative; and therefore, the impact of reduction of disease in circumcision is still potentially huge.
Maria Wawer: That's absolutely right. But basically, if fewer men become positive, those men will not be transmitting HIV to their partners. So the overall population level benefits are still very likely -- we're sure there will be population level benefits.
John Mellors: Let's follow that nice summary with a recap and a comment from Ron and Aaron. Just summarize one more time the non-HIV-related benefits of circumcision in negative men on their acquisition and their partners' disease.
Aaron Tobian: In HIV-negative men, there's 25% reduction in genital herpes caused by herpes simplex virus 2. And in the wives of the HIV-negative men, there's almost a 50% reduction in Trichomonas, a 20% reduction in bacterial vaginosis, and a 25% reduction in genital ulcer disease.
John Mellors: Ron, do you want to make a point?
Ronald Gray: Can I add to the point that was made by Maria and David? This trial of HIV-positive men was examining the question of: Does circumcision affect direct transmission from a positive male to a negative female partner? The big public health question, which will take time to answer, is not only if circumcision protects negative men from becoming infected where we get a secondary protection of their partner; but also, will the reduction of genital ulceration and other genital infections in women ultimately protect them from HIV. We do not have that answer with respect to secondary protection at this time. So there's still hope.
Maria Wawer: Population level studies are going to be imperative.
John Mellors: Questions? Let's start from the back and move forward.
Reporter #3: Thank you. First, I think the work you're doing is terrific. Question: I can see in my mind why you would expect a rationale for a reduction in transmission from someone to an HIV-negative male who has been circumcised, in that the most likely targets of HIV have been cut away. I'm not sure I understand why you would hypothecate a reduction from a positive male to a female if the major source of the transmission was from the semen in the first place, unless you're arguing that, in the context in which you're working, there are sores that are also eliminated from circumcision, which are a cofactor, or a major factor, in transmission. So I'm a little bit confused. I have the United States as my model. I can see right away why a circumcised male couldn't catch HIV as easily. But I can't see why I'd expect a circumcised male to be less likely the source of infection if they were positive. Could you help elaborate that?
Ronald Gray: Yes. We assume that most male to female transmission is via the semen. But we actually don't have evidence that that is truly the case. Our prior observational studies did show that if the male positive partner's viral load was below 50,000 copies, and he was circumcised, there were no transmissions to his wife. That strongly argued that there must be some component of male to female transmission via the foreskin. Whether that is due to breaches of the mucosa, an ulceration, or whether there is indeed shedding of HIV from the poorly keratinized inner mucosa of the foreskin, is unknown. But these are issues that we are going to be pursuing by doing immunohistochemical and virologic studies on the foreskin specimens that we derive from the trial. And there is a poster by Kristine Johnson at this meeting showing just how incredibly rich in HIV target cells and inflammatory problems the foreskin is.5 We may have underestimated the foreskin in male to female transmission.
Maria Wawer: Also, as you were suggesting, there is a lot of genital ulceration that is really on the foreskin. And genital ulcers, certainly shedding of HIV from ulcers, is a known phenomenon.
John Mellors: The fact that doing circumcision can influence transmission, and not in the direction it was hoped, indicates that foreskin, and that region of the genital tract, are important.
Reporter #4: I'm wondering, especially for Maria: When you talk about resuming sexual activity after waiting until the circumcision wound is completely healed, what time frame is that looking at?
Maria Wawer: In the HIV-positive men, about three quarters were fully healed at 30 days, one month. Among negative men, it's closer to 83% who are fully healed at 30 days. So there appears to be a slightly longer healing time in positive men, rather than the negative men. Overall, to be on the safe side, we would tell men that they should not resume sex for six weeks, perhaps up to eight weeks. But we're doing more detailed follow-up studies to see whether we can come up with something that is a reasonable guideline to give programs. If programs could examine everybody on a weekly basis and observe when somebody was fully healed and then say, "OK, you're fully healed. Now, still, please be careful. Use condoms, etc. Don't increase your risk behavior. But you're fully healed," then that would be the ideal situation. Since we know that in many programs that may not be ideal, in our health messages we will probably want to err on the side of reasonable caution.
John Mellors: We have about five minutes for questions. Please make them succinct.
Reporter #5: Some time ago, David, you gave a figure for the increasing uptake of voluntary counseling and testing in the community, as a result of the program activities. But I missed the figures. What was the increase? You said 5% or something?
David Serwadda: We actually are pioneering trying to give results back into the homes, as opposed to the participant coming to a specified center. When we started off, about 5% of the population was interested in getting their results. But now we find that over 80% of our participants are interested and able to get their results.
Reporter #5: And what proportion of the population never had been tested?
David Serwadda: When we started off, our population sample was probably 1,200. But now we are talking about 14,000 people.
Maria Wawer: David, let me just add: In these 50 communities -- these are the Rakai cohort communities, the population study communities that have participated with us, as David indicated, for many years -- we test everybody in the community every year. About 90 to 95% of people each year agree to be tested, of those who are in a community. Every year, they have the opportunity to receive their results. Cumulatively, by now, of the overall population, over 90% of adults know their results. There's still a small proportion who have never wanted to learn the results. And every year, there are about 10 to 15% new individuals who move in, and they are entered into the cohort, they are tested, and they are offered free results.
At the population level, it's in the high 80s, low 90s, of all adults knowing their result. It's cumulative, because not everybody wants to get the result every year. Once they are positive, then unfortunately they don't need to get the result again. Once you're positive, you're positive. Is that fair, David?
David Serwadda: Mm-hmm.
Reporter #6: How do you define ulceration? For instance, do you either have it, or you don't? Or do you have the ability to detect, essentially, an almost microscopic ulceration? Does it have to be visible? I'm just wondering if you could foul the results if you have something that isn't readily observed.
Ronald Gray: When we interview, we ask people if they have [had] an observed ulcer in the period of time since we last saw you. And do you have one currently? Or have you had one in the past seven days? Among people reporting a current or recent ulcer, we do a physical exam, and then take a swab from that ulcer with a multiplex PCR to pick up syphilis, chancroid and herpes, HSV-2. Somewhere between 50 to a third of those ulcers will reveal a pathogen, of which the overwhelming majority, over 90%, are herpes. However, in a substantial proportion of those ulcers, we do not see a sexually transmitted pathogen, which suggests that they may be either chromatic, they might be an old resolved herpes that has become secondarily infected, or of other etiology. And we don't fully understand that at this time.
John Mellors: I need to emphasize that we're winding this up, so, brief questions, and brief answers. Why don't you just come on up? Alternate sides.
Reporter #7: Maybe you've heard about a Swiss declaration on transmission of HIV and viral load. This declaration is largely based on your study. What do you think of it? They say there is no transmission of HIV with low viral load, and no STI.
John Mellors: This is completely unrelated. This is a study that just was published last week, showing that in individuals suppressed on antiretroviral therapy, the transmissions didn't occur.6 That's not part of this.
Reporter #7: It's not a study. It's just an analysis ... with a different study. And one of the ...
John Mellors: It's observational data.
Reporter #7: ... studies cited is the Rakai study.
Maria Wawer: Certainly, if there is excellent viral suppression, then from our own observational data presented over the years, we see either no, or very limited, transmission, with very low viral loads, either from coital act or as incidence over the year. I think where one has to be careful with respect to HIV prevention is that, even somebody who is well suppressed could potentially, for whatever reason -- coinfection, intermittent problems with dosing, or whatever -- have some breakthrough HIV detectable viral load. So I think we have to be careful not to put all our eggs in any one prevention basket. Certainly, antiretrovirals are very important in reducing transmission from HIV positives. But I would no more say to somebody, "Just trust antiretrovirals," then I would say, "Just use condoms." We need to provide people with a broad range of HIV prevention services in order to truly, truly protect partners.
John Mellors: This study that was published in the Swiss journal: Is that part of the Rakai project?
Maria Wawer: No.
Ronald Gray: I have not seen the study. I've just got e-mails about it. All I can say is that I think it is a very dangerous conclusion. The reason is that, in our own data, we now have seen cases where, at the time we tested someone, the viral load was below detection, but they transmitted. That's because the viral load is not stable, particularly because of coinfections, or possibly other factors. So I agree a hundred percent: We have to reinforce the prevention messages.
Reporter #8: The 25% reduction seen in HSV-2 acquisition in the circumcision trials: Was that only in clinical disease? Or were participants also screened for asymptomatic infection with HSV-2 antibodies?
Aaron Tobian: That's asymptomatic. We took everyone that was negative initially, and then followed them up two years later by IGG serology assay. That's the 25% reduction.
Ronald Gray: They might have been symptomatic, but serologically, we saw a reduction in incidence.
John Mellors: We're going to finish up with two questions in the front.
Reporter #9: The results from the three African trials were very dramatic. CDC recently did a study in -- I believe it was in MSM in the U.S., and they found no protection from circumcision. Can you help folks try and understand why in one set, you see it, and in the other, you don't?
Ronald Gray: I was at the CDC meeting that considered the implications for the U.S. (A) With MSM it's much more complex, because you've got both insertive and receptive behaviors. Secondly, these are observational studies. Among the MSM, there are contradictions. Some show apparent protective effects, particularly with insertive intercourse. Others do not. I think the jury is out with respect to circumcision in MSM at this time. It was not a trial.
John Mellors: Last person.
Reporter #10: I was just wondering: Is there one overall number you can give us, as far as the reduction in women's risk of vaginal infections? You've been giving the number for Trichomonas and genital ulcers, etc. Is there one number you can boil that down to?
Aaron Tobian: Bacterial vaginosis and genital ulcers are both risk factors for HIV acquisition. But you cannot boil all these different sexually transmitted infections and symptoms down to one number.
Ronald Gray: Give a range.
Aaron Tobian: 20% of bacterial vaginosis; 50% decrease in Trichomonas. Both of these are major sexually transmitted infections that clinics all over the United States see, if you're at your primary care physician.
This transcript has been lightly edited for clarity.
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