Update on PrEP...

[rawTOP]

This is a pretty good overview of where things stand on PrEP for gay men...

Medscape: Day 2 of the IAPAC summit dealt with issues involving PrEP, so let's turn our attention to that strategy. If you could discuss, again, some of the key data regarding efficacy of PrEP that were either presented or reviewed at the summit?

Dr Mayer: PrEP is a concept of using antiretroviral medication that is already approved to treat HIV infection before a person is exposed to HIV. A protective effect of PrEP was previoiusly demonstrated in animal studies that also showed an increased benefit of PrEP vs postexposure prophylaxis (PEP).^[10-12] Given the data from animal studies and given that it is very difficult to predict when a person is going to be exposed to HIV, it made sense to develop HIV prevention strategies that would provide people with some ongoing protection in case of exposure. There is a 2-front approach to the field of chemoprophylaxis. Some studies have focused on topical agents, with the argument that, in many cultures, lubrication may be used during sexual intercourse; this is particularly true for individuals who engage in anal intercourse (eg, MSM).^[13] Other studies have focused on different agents for prevention of HIV transmission.^[2] Several of the early agents that were studied in microbicide research were nonspecific agents, detergent agents, such as nonoxynol-9. Although nonoxynol-9 is an effective contraceptive agent, studies found that it caused sufficient irritation when used for HIV prevention, raising the questions as to whether it actually enhanced HIV transmission.^[14] The field then moved from agents that were broad spectrum and that would disrupt the virus (but could also disrupt mucous membranes where intercourse was occurring) to using antiretroviral agents for prevention.

The first study on topical PrEP to show efficacy was the CAPRISA 004 study.^[15] The study data -- first presented at the International AIDS conference in Vienna 2 years ago -- showed a 39% reduction in the likelihood of becoming HIV-infected for the women assigned to use an investigational vaginal gel that contained tenofovir (TFV) immediately before and right after sexual intercourse. A subsequent analysis of other predictors of efficacy found that adherence was the single biggest predictor of protection; unless women were adherent to the gel and used at least 80% of their gel doses, they did not get protection. If they were adherent to the gel at least 80% of the time, there was a 54% reduction in the likelihood of becoming HIV infected.^[15]

The second trial to show the efficacy of PrEP was the iPrEx study. The study, which enrolled 2499 MSM and transgender women who have sex with men in the United States, Thailand and countries in South America, found that if the MSM took a pill containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) on a daily basis, there was a 44% reduction in the likelihood of them becoming HIV-infected.^[16] As with the CAPRISA 004 study, a subsequent analysis of individuals' drug levels found that only about one-half of the men were taking the medication with any consistency^[15,16]; of those who were taking the medication consistently, the protective value of the medication was over 90%. In other words, the likelihood of becoming HIV-infected was decreased by close to 90% if people were taking the medication on a consistent basis.^[16] Although iPrEx and CAPRISA studies used different approaches to PrEP and involved different study populations, both of these studies are extremely important because they show that chemoprophylaxis can work in diverse populations.^[15,16]

Not all PrEP studies have succeeded. Two studies of PrEP (ie, FEM-PrEP, VOICE) were stopped because the independent Data Safety Monitoring Boards thought that they were futile -- that they would not be able to detect an efficacy signal. Both studies enrolled African women at risk for HIV. For FEM-PrEP, the investigators found that medication adherence were quite low, providing some explanation as to why there was no perceived benefit.^[17] The VOICE trial, which was funded by the National Institutes of Health to be conducted in the Microbicide Trials Network (MTN), enrolled 5000 women.^[18] The participants were assigned to either a gel or pill formulation; for example, women assigned to the pill arm either were assigned to TDF alone, TDF/FTC, or placebo. The study therefore had 3 active comparisons: 2 different types of pills -- 1 with TDF alone, 1 with TDF/FTC -- or TFV gel. The women in the TFV-gel group were asked to use the gel on a daily basis, unlike the CAPRISA study which used pericoital dosing. Two of the arms in the VOICE study (ie, TFV-gel arm, oral TDF-alone arm) were subsequently stopped early, owing to a lack of efficacy. The oral TDF/FTC arm is ongoing. The data from this study raised concerns about the use of PrEP in women, whether gel or pill.^[18]

However, 2 other studies (Partners PrEP and TDF2) were quite robust in their findings.^[19,20] Partners PrEP study enrolled close to 5000 HIV discordant couples; the infected partners had high CD4 counts and therefore did not qualify for immediate treatment (at the beginning of the study). The uninfected partners were randomly assigned to 1 of 3 groups: an oral pill that contained TDF/FTC, TDF alone, or placebo. At the time that this study was stopped, both the TDF-alone and the TDF/FTC arms were highly efficacious with more than two-thirds of a rate of protection. When the research team checked drug levels they learned that there were very high levels of medication adherence and people who had medication on board in their system had in the range of a 90% protection rate -- very similar to the kind of findings seen in iPrEx.^[16,19] These findings were highly statistically significant. The question is: why are there such high rates of adherence and efficacy in this study, which had a large sample of women -- about 60% of the uninfected partners in this study were women. The suggestion certainly was that adherence really played a major role once again. There still are questions about whether there could be other cofactors in Partners PrEP because these were, for the most part, stable, monogamous couples^[19]; there might be less inflammation in the genital tract owing to less STIs and that also might lead to a higher level of efficacy of prophylaxis. In other words, if the women in FEM-PrEP and possibly the women in VOICE acquired other infections, would the benefit of prophylaxis not have been as strong? This question has not yet been answered.

Another study -- TDF2 -- that was conducted by the United States Centers for Disease Control and Prevention (CDC) in Botswana enrolled several thousand young heterosexual men and women. The participants did not have to be in a discordant couple. In Botswana, because HIV prevalence is seen in 30% of young heterosexual adults, if one changes partners, there is a high likelihood of coming into contact with HIV.^[20] The CDC study looked at TDF/FTC as an oral medication; again it was found to be protective overall. The number of women enrolled did not allow the study to achieve statistical power to make a separate statement about protection for women, but the results for the men and the women pooled together showed a strong protective benefit.^[20]

In summary, you have 2 studies involving women in sub-Saharan Africa looking at oral medication that did not show benefit, though one study used only TDF alone. You have 3 other studies, one of which showed a benefit of TFV gel for women, the other two which showed a benefit of TDF/FTC for women, and one which showed a benefit of oral TDF alone. All of the studies that enrolled men showed benefit of prophylaxis for these men.

The field is left with the sense that oral chemoprophylaxis seems to work quite clearly for men, possibly because of the higher HIV concentrations in rectal secretions (for MSM) or possibly because it is more difficult for heterosexual men who are only engaging in insertive sex to become HIV-infected. For women there are strong data that say that it works but that the threshold for protection may require higher levels of adherence.

Regarding the gel for prophylaxis (ie, a topical microbicide), there was 1 successful study and 1 unsuccessful study in terms of showing efficacy endpoint.^[15,18] A third study -- FACTS -- is now underway.^[21] It is being conducted in South Africa and that is looking at pericoital gel use and could certainly suggest the benefit of gel if it does achieve a positive result. If not, it may not be that TFV gel is the problem, per se, but it may be that there is something about how a gel interacts with the vagina, particularly if it is given more frequently, as in the case of VOICE.

The field now is left with some basic questions about what level of adherence is necessary to achieve optimal protection with pills and gels, particularly regarding the gels for women. The other major question is: could a gel be designed that would be protective for anal intercourse? A study conducted through the Microbicide Trials Network (MTN) looked to answer this question, using the investigational vaginal TFV gel. The research team found that the vaginal TFV gel could be irritating when applied rectally; this was very instructive for the research team, realizing that what you put in 1 part of the body may not work in another part of the body.^[22] The reason for the discomfort rectally was that there was glycerin in the vaginal gel which helps it spread in the vagina and may make it feel better internally, but when applied to the rectum or rectal and colonic mucosa, glycerin would stimulate peristalsis and defecation, which is not a characteristic one would want to have when contemplating anal intercourse. A subsequent study -- MTN-007 -- reformulated the vaginal gel to remove the glycerin and investigated additional ways for it to be tolerated rectally. MTN-007 was just completed; data were presented at the 2012 Conference on Retroviruses and Opportunistic Infections^[23] and discussed at the IAPAC 2012 Evidence Summit in London. The researchers found that the reformulated gel was quite well tolerated, without any significant symptomatology. A new study -- MTN-017 -- will now look at populations (eg, MSM) who would benefit most from a TFV gel formulation applied rectally; this study will be underway soon.^[24]

Given that all of the medications studied to date for PrEP contain TDF, the other big question is whether TDF should be used for PrEP, given that TDF is a mainstay of HIV treatment. In addition, TDF can cause significant side effects (eg, renal impairment [typically reversible], bone mineral density loss), though these effects are uncommon.^[25] In the aforementioned studies that looked at oral TDF, side effects were not a problem; so it is not an acute issue, but people are concerned that, for HIV-uninfected individuals, there should be the highest bar for safety. It was that concern that led to the research of other drugs for PrEP. There will be a study getting underway in late 2012 called HPTN 069; it will be looking at the drug maraviroc, which is an FDA-approved CCR5 receptor antagonist and functions as an entry inhibitor, to see whether it might be well tolerated and whether it might be a suitable candidate to study as an alternative to TDF-based regimens.^[26]

There also is a lot of ongoing work looking at other formulations of antiretrovirals. Two ring formulations have been developed: one containing dapivirine, an investigational non-nucleoside reverse transcriptase inhibitor, and the other containing maraviroc (which is being used offlabel in this context) . Both ring formulations are undergoing study now, in the United States and Africa.^[27,28] The advantage of a ring insertion is that with the flexible silastic technology, a very small ring can be made that can be impregnated with medication and only has to be changed once per month; it would get around some of the problems of adherence.

Even more dramatic is the idea of injectable antiretrovirals. Two injectable antiretrovirals are in early phase study. One is the previously FDA-approved non-nucleoside reverse transcriptase drug rilpivirine made into a long-acting formulation that appears to have drug levels available at least for 1 month. Another formulation is being developed that could potentially be given every 3 months. Another drug earlier in the developmental pathway is an integrase inhibitor; it is undergoing early phase studies in humans.

The field is very dynamic in the sense of having proof-of-concept for several TDF-based regimens, with a couple of studies that were not successful raising questions about what levels of adherence are necessary or what other local factors in the genital tract are necessary to understand. Scientists and clinical researchers now must think about other ways to deal with the concerns raised by substantial levels of nonadherence in these early phase studies.

Medscape: Let's return to the investigational rectal microbicide gel study for a moment. Is that formulation being investigated for intermittent use, or is it going to be more like the FEM-PrEP trial where it was going to be consistent use?

Dr Mayer: The rectal microbicide's developmental pathway is going to be looking at both approaches, so they will be looking at daily use and will also be looking at intermittent use. We honestly do not know what is best, and I think what we are learning early on is that the different tissues -- you may not have the same approach for both.

Medscape: Let's again turn our attention to implementation. What was discussed at the summit regarding the challenges of implementation of PrEP and how to overcome those challenges?

Dr Mayer: The implementation of PrEP is in a much earlier stage than the implementation of antiretrovirals for HIV treatment and the implementation of TasP. The US FDA reviewed an application by the manufacturer of TDF and FTC to expand the indication of the medication to be used for oral PrEP. The FDA advisory board voted in favor, though not unanimously, for approval for indications for MSM and heterosexuals at high risk, but the FDA has indicated that it wants further guidance in terms of a risk evaluation and mitigation strategy (REMS). The REMS could be everything from recommendations for specific types of monitoring for renal function to specific ways in which HIV status would be documented in real-world settings. [Editor's note: The FDA subsequently approved TDF/FTC for use in PrEP on July 16, 2012, with REMS.] With regard to PrEP, I anticipate that it will be quite variable across the world in terms of the implementation. Concerns were raised at the IAPAC summit that, because of limited resources, the priority should be to make sure that people living with HIV have access to medication -- not to delay getting them access to any medication. However, the modelers suggested that the combination of earlier treatment in and the use of PrEP in key populations could have an even more dramatic effect in curtailing the epidemic.^[29] The challenge, again, for policy people is how to get sufficient resources now to have an impact that can really save substantial resources later.

A variety of different new projects were presented at the summit in hopes of learning the best ways to provide PrEP to different populations. In France the IPERGAY study is focused on MSM and is looking at intermittent PrEP, based on initial findings that men who engage in risk-taking behaviors do not do so all of the time. The research team is trying to see how to use the medication parsimoniously, because clearly, if people have some sense of when they are going to engage in risk-taking behaviors -- they know that they work all week and they only go to a club on the weekends -- and that is the only chance that they would have to engage in a risk-taking behavior, then the pharmacology might suggest that as long as one has drug on board at a certain threshold, that it might be feasible to just take medication on say, Thursday or Friday, engage in risk, and then have a tail period. We do not know yet what the best approach is in terms of what is the least amount of drug closest to the risk event that makes sense to take, and then how much medication to take afterwards. Studies are underway; they may help the field in the sense of being able to use less medication may make it a lot cheaper and more accessible, and be less likely to result in side effects. Studies like this I think will inform the field a great deal.

Medscape: Was there any discussion about providers having concerns that patients who are offered PrEP and who start using PrEP are going to engage in more high-risk behavior? Current trial data do not bear this conclusion out, but is there still concern in the field that it may be the case?

Dr Mayer: There is concern in the field, and there was concern expressed at the IAPAC summit about risk compensation. If people knew that they were now protected, would they engage in more risks? Certainly, there are some very valid concerns with the focus on antiretrovirals for prevention. Part of the prevention package for people considering and then using PrEP would be to screen for other STIs to make sure that individuals are not acquiring and transmitting syphilis, gonorrhea, or chlamydia while using PrEP, since antiretrovirals do not protect against acquisition of STIs.

In clinical trials there was very little evidence of risk compensation, but it can be argued that clinical trials are not the real world. Participants in clinical trials receive intensive counseling, follow-up, and monitoring; participants are self-selected to be in the study so they knew that they might be getting placebo. So, demonstration projects are underway. Also, the iPrEx study has an open-label extension study that is being conducted at the iPrEx sites.^[30]

Additionally, the United States needs to deal with health disparities. We know that the HIV epidemic disproportionately affects black MSM^[31]; they are one-quarter of the new HIV infections, but less than 1% of the US population.^[32,33] Given that, there is a demonstration project that should be getting underway the next few months in the HIV Prevention Trials Network that will be focusing on culturally tailoring a PrEP support system for black MSM (ie, access and triage to appropriate social services).^[34] The reasons why people engage in behaviors that might put them at risk for HIV may have a lot to do with them being depressed, using substances, or having a social adversity (eg, unstable housing, being economically poor) so the more that programs are holistic and address some of these precipitants of risk, the more effective the use of PrEP.

The sense at the summit was that some people had significant concerns about PrEP, but the majority understood that for some individuals in some settings in some parts of the world, PrEP could be extremely beneficial, particularly if coupled with a risk-prevention program. Very few people at the meeting thought that the ideal was to get every person who is potentially at risk on PrEP to take pills for the rest of his or her life. With regard to PrEP, the first issue is to get the individuals who have some risk tested so as to make sure that they are not HIV infected. Second, their providers have to inquire about their HIV risk or work with them to understand what their risk might be for HIV. Then there has to be some assessment about whether this person is an appropriate candidate for PrEP. Then the provider has to be sufficiently knowledgeable to prescribe and monitor an individual on PrEP. Certainly the scaling up of PrEP in discrete settings is going to take a longer than that for HIV treatment for prevention.

For me the key take away is that PrEP can be 90% effective - about the same as a condom. BUT because guys taking the pills aren't actually sick, in some cases quite a few don't take their pills consistently. That leads to lower efficacy and drug resistance.

I still say that for the worried well PrEP can be a good idea. But if you really just want to be a cumdump who's ass up in bathhouses most weekends that 10% that PrEP isn't effective will catch up to you and you'll become poz anyway.

[bearbandit]

When the news broke about the licencing of Truvada (tenofovir/FTC) For PrEP, I was in hospital recovering from a bout of Tenovir poisoning that damn near killed me. I asked the HIV registrar her views on the breaking news and her reply was almost identical to rawTOP's: "lower efficacy and resistance". It's fascinating news because it proves that it can be done, it's just that its usefulness is really limited to highly motivated individuals, such as a sero-discordant straight couple wanting a baby. Best way to think of it is as a stepping stone to something better...

Edited August 27, 2012 by bearbandit
grammar and spelling errors