Treating HSV-2 and trying PrEP: what the trials tell us so far: an interview with Myron S. Cohen, MD.
Article Type: Interview
Subject: Herpes simplex (Distribution)
Herpes simplex (Drug therapy)
Herpes simplex (Research)
Herpes simplex (Risk factors)
Disease transmission (Health aspects)
Disease transmission (Control)
Disease transmission (Research)
HIV infection (Risk factors)
HIV infection (Distribution)
HIV infection (Drug therapy)
HIV infection (Research)
Author: Mascolini, Mark
Pub Date: 06/22/2009
Publication: Name: Research Initiative/Treatment Action! Publisher: The Center for AIDS: Hope & Remembrance Project Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 The Center for AIDS: Hope & Remembrance Project ISSN: 1520-8745
Issue: Date: Summer, 2009 Source Volume: 14 Source Issue: 1
Topic: Event Code: 690 Goods & services distribution; 310 Science & research Advertising Code: 59 Channels of Distribution Computer Subject: Company distribution practices
Persons: Named Person: Cohen, Myron S.
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 220766445
Full Text: Dr. Cohen is J. Herbert Bate Distinguished Professor of Medicine and Microbiology, Immunology & Public Health in the School of Medicine, University of North Carolina (UNC) at Chapel Hill, Chief of the Division of Infectious Diseases, and Director of the UNC Institute for Global Health and Infectious Diseases.

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Suppressing HSV-2 to prevent HIV transmission

Mascolini: Why hasn't HSV-2 suppression worked as a strategy to prevent HIV transmission?

Cohen: There are several possibilities. One is the possibility that the belief that HSV-2 suppression can prevent HIV transmission is flawed. This possibility might bleed over into even bigger assumptions that relate sexually transmitted diseases (STDs) in general to a higher risk HIV transmission events. There are, however, many, many studies indicating that STDs facilitate HIV transmission.

The second possibility, which I think is much more likely, is that we don't really have Occam's razor [see note 1]. The underlying assumption is that if HSV-2 is contributing substantially to HIV transmission--by increasing both infectiousness and susceptibility--then a drug like acyclovir or the newer version, valacyclovir, would serve as Occam's razor. In other words, taking one of those drugs on a regular basis would prevent HIV-1 transmission events. The problem is that those drugs appear to lack the power to do what we'd like them to do. (2,3)

Mascolini: Why do they lack the power?

Cohen: First, you have to give the drugs at just the right time to just the right people, and that's proven difficult. If you're giving those drugs to the wrong people at the wrong time, they're not going to work. Second, people have to take the pills. If they don't reliably take their pills, then clearly you get less than optimal benefit.

Third, we've learned these medications don't completely suppress episodes of HSV-2 recurrence. Or when they do suppress HSV-2 recurrence, research about to be published shows that the tissue affected by HSV-2 remains abnormal for a very long time. Persistent abnormalities in the tissue may underlie the circumstances that render people more susceptible to HIV.

With all these moving targets, even if the hypothesis is correct, we may not have the tool that provides a benefit. Perhaps the only possible correct tool is a vaccine that prevents people from acquiring HSV-2. But we don't have such a vaccine, and there's no such vaccine on the horizon. So we don't have Occam's razor.

Mascolini: Are continuing studies of HSV-2 suppression worth the effort?

Cohen: There's one ongoing study, the Partners in Prevention trial, that's due to be reported soon. * This study involves more than 2500 discordant couples. The "index case" must have HIV infection and HSV-2 infection and a high CD4 count, while the partner is uninfected. Instead of taking antiretrovirals, the index case takes acyclovir--or placebo--to see if acyclovir will suppress HSV-2 replication and potentially HSV-2 shedding and perhaps lower the risk that the HIV-positive partner will transmit HIV to the negative partner.

It's going to be difficult to interpret Partners in Prevention for some of the reasons I already mentioned: because acyclovir adherence is imperfect and because acyclovir doesn't work perfectly. Also, acyclovir has some antiretroviral activity affecting replication of HIV. (4) Direct suppression of HIV by acyclovir may confuse any interpretation about the impact of acyclovir on HSV-2.

* Results of the double-blind, placebo-controlled Partners in Prevention trial were released shortly after this interview. Twice-daily acyclovir taken by HIV-1/HSV-2-co-infected people who were not taking antiretrovirals did not prevent HIV-1 transmission to their HIV-1-negative partner. There were 41 new HIV infections in couples in the acyclovir group and 43 in the placebo group, a non-significant difference. Acyclovir did lower the frequency of genital ulcers 73% and reduced HIV load by an average 0.25 log (about 40%), but those benefits had no impact on HIV transmission.

Mascolini: In a Lancet review of biomedical interventions to prevent HIV transmission, Padian and colleagues wrote that "introduction of [HSV-2 suppressive] interventions [with acyclovir or valacyclovir] at a population level is probably not feasible, especially since the prevalence of HSV-2 infection is high in many low-resource settings." (5) Do you agree?

Cohen: My response is complicated. The extreme prevalence of HSV-2 might offer a unique opportunity for prevention, if acyclovir worked well. But HSV-2 suppression didn't work in HPTN 039 (3) for the reasons we just discussed; HIV acquisition was not prevented. And the public health potential for HSV-2 suppression in people who are HIV positive is controversial. If you were going to suppress HSV-2 in HIV-infected people to suppress HIV replication, why wouldn't you just suppress HIV with antiretroviral agents? Indeed, we are moving rapidly toward earlier and more aggressive use of antiretrovirals.

The acyclovir trials were planned as a proof of concept as much as a public health intervention, and unfortunately the concept has not borne fruit. That leads to concern about where all of this is going, as discussed in the editorial by Maria Wawer and Ronald Gray that accompanied the HPTN 039 trial results. (6)

Mascolini: In a review of HIV prevention that you wrote in the Journal of the International AIDS Society, you said HIV prevention will succeed only if "the menu of options is driven by scientific results and not ideology." (7) I assume that means you think the menu of options has been driven by ideology, at least in part.

Cohen: I think that is true. People get very enamored of belief systems; we're all subject to this. We're working on a hypothesis, and we get very committed to that hypothesis. This is especially true for mathematical modeling experiments. Every week I get a call saying the answer to some clinical or public health question has been resolved. Then I look at this paper and it's a Utopian model. Modeling is modeling; it's not data. Modelers make assumptions, build a model on the assumptions, and then they are done. The problem is sooner or later someone needs to prove or disprove the assumptions in the model, and the veracity of the conclusions. But randomized clinical trials are expensive and time consuming, to say the least.

Mascolini: Do you think this approach--suppressing HSV-2 to prevent HIV--has a future?

Cohen: Depending on how ongoing studies come out, I think you'll see every article end saying "we have to make an HSV-2 vaccine." If anti-HSV-2 agents are not Occam's razor, (1) then the only thing that could become Occam's razor is a vaccine. The problem with saying we should make an HSV-2 vaccine is, number one, we don't know how to do it, and, number two, so many people are already infected with HSV-2.

Herpesviruses are trying to fill a biological space. The vast majority of the human species is already infected with HSV-1. Most of us have had Epstein-Barr virus. And in the last 30 years HSV-2 has caused lots of infections, most of which are subsymptomatic. Herpesviruses are trying to fill the entire planetary space. The race is for us to make a vaccine before it fills the space.

Pre-exposure and postexposure prophylaxis

Mascolini: Can the prolonged use of tenofovir and emtricitabine being studied in current preexposure prophylaxis (PrEP) trials be a practical in-the-field strategy?

Cohen: First, I anticipate that antiretrovirals used topically or systemically are going to prevent acquisition of HIV, especially heterosexual penilevaginal acquisition. I think the bar is higher for preventing HIV acquisition by anal intercourse. If these trials demonstrate the ability to prevent HIV acquisition, the challenge will be to identify a viable strategy for using pre-exposure prophylaxis.

But let's be clear about one thing: All the current trials of oral agents are not exclusively PrEP trials; they're really some combination of PrEP and PEP [postexposure prophylaxis]. People are taking the pills daily, so you don't know whether it was the dose before or the dose after that had maximal benefit. In fact, the monkey studies suggest that it's the dose after that's more important. (8) So I think that needs to be clarified.

I should add that topical tenofovir is being studied as PrEP in South Africa by Salim Abdool Karim. But if Truvada (tenofovir/emtricitabine) works in the oral PrEP/PEP trials we're doing now, the first thing to figure out is whether we're going to have to give people pills every day for a long period of time, or whether we have to do another trial to see if coitally dependent or interrupted oral therapy is possible.

The next priority will be to identify target groups who will benefit sufficiently to justify the cost and risk of PrEP. In my own mind, if these antiretrovirals prevent HIV acquisition in people who practice receptive anal intercourse--a very high-risk group--it might be possible to offer benefit to that group at a public health level. Intravenous drug users in some settings are another very high-risk group. It may be possible to offer benefit to that group at a public health level.

To me the highest priority group would be adolescent girls in sub-Saharan Africa who are HIV-negative, because young women are going from adolescent exploratory behavior to adulthood. We need to help them stay HIV negative over some period of time. So I think the use of PrEP in that setting has real appeal, along with educational campaigns and some sort of birth-control intervention. I've been a champion of that particular group for some time, though it's been difficult to get an appropriate trial off the ground for them. But that's the group in which I can see an immediate benefit from PrEP, partly because the prevention window is time limited. If they're 17 years old and negative and trying to get to 21 and negative, it's not 20 years of PrEP, it's 3 or 4 years of PrEP.

Mascolini: Ate antiretrovirals like tenofovir and emtricitabine reasonable PrEP candidates when they pose a resistance risk that may make them useless as therapeutic agents?

Cohen: There's no doubt that the risk of resistance with using these agents for PrEP is a serious concern. The shift from tenofovir to Truvada occurred for two reasons: First, tenofovir alone failed to provide durable protection in a macaque study. (9) Second, tenofovir has a high barrier to resistance, but the barrier becomes even higher when you add emtricitabine.

To prevent resistance with PrEP, a community monitoring system will be required. Resistance monitoring is already a part of the ongoing trials. We do not want to see primary resistance to emtricitabine and tenofovir because they ate part of the backbone of our current therapy.

Insights on microbicides and vaccines

Mascolini: This issue of RITA! includes two separate interviews on microbicide and vaccine research, but I'm curious to hear your perspective on work in those fields.

Cohen: The vaccine field is making progress. It may not be entirely visible, because we're waiting for another candidate vaccine, but the basic science is moving very fast right now.

I believe the PRO 2000 microbicide results (10) have not received sufficient attention, partly because there's another 9000-person PRO 2000 trial by the Microbicides Development Programme, which will probably be presented this fall, and because people ate waiting for results of antiretroviral-based microbicide trials. [See page 14 of this issue for results of the first PRO 2000 trial.]

Mascolini: You're encouraged by the PRO 2000 results?

Cohen: I'm very encouraged because PRO 2000 is incredibly better than nothing. As a vehicle, it's incredibly better than nothing. And if the second trial supports the first trial, I can see making PRO 2000 available to adolescent girls in sub-Saharan Africa.

During the PRO 2000 trial (HPTN/MTN 035), women got pregnant and had healthy babies. That's a big deal. If you're an adolescent girl trying to have a baby and someone says a safe topical agent will lower your risk of acquiring HIV 30% or 50%, that's not trivial.

References and Notes

(1.) Occam's razor, simply put, means the explanation requiring the fewest assumptions is probably the correct explanation. In this case Occam's razor would mean that suppressing STDs like HSV-2 infection with an antiviral would lower the risk of HIV transmission.

(2.) Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371: 2109-2119.

(3.) Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med. 2008;358:1560-1571.

(4.) McMahon MA, Siliciano JD, Lai J, et al. The antiherpetic drug acyclovir inhibits HIV replication and selects the V751 reverse transcriptase multidrug resistance mutation. J Biol Chem. 2008;283:31289-3193.

(5.) Padian NS, Buve A, Balkus J, Serwadda D, Cates W Jr. Biomedical interventions to prevent HIV infection: evidence, challenges, and way forward. Lancet. 2008;372:585-599.

(6.) Gray RH, Wawer MJ. Reassessing the hypothesis on STI control for HIV prevention. Lancet. 2008;371:2064-2065.

(7.) Cohen MS, Kaleebu P, Coates T. Prevention of the sexual transmission of HIV-1: preparing for success. J Int AIDS Soc. 2008; 11 (1):4.

(8.) Garcia-Lerma JG, Otten RA, Qari SH, et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008; 5(2):e28.

(9.) Sabbarao S, Otten RA, Ramos A, et al. Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges. J Infect Dis. 2006;194:904-911.

(10.) Abdool Karim S, Coletti S, Richardson B, et al. Safety and effectiveness of vaginal microbicides BufferGel and 0.5% PRO 2000/5 gel for the prevention of HIV infection in women: results of the HPTN 035 trial. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 48LB.
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