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GHDonline Expert Panel: PrEP: A promising, novel HIV prevention strategy

By Sarah Arnquist | 06 Mar, 2011 Last edited by Sarah Arnquist on 30 Mar 2011

GHDonline.org is pleased to host an online expert panel on the implications of PrEP as an emerging HIV prevention strategy.

Our panelists, Douglas Krakower, MD , and Andrew Mujugira, MBChB, MSc will offer some initial thoughts and then we look forward to a week-long virtual discussion.

Initial questions:

1. What are some potential barriers and facilitators to implementing PreP in clinical settings?

2. How can we encourage long-term adherence to PrEP outside the research setting?

3. What additional additional questions need to be answered with further research?

Replies

 

Andrew Mujugira Replied at 12:21 AM, 7 Mar 2011

Pre-exposure prophylaxis (PrEP) is a novel biomedical strategy being investigated for HIV prevention among diverse high-risk populations worldwide. Two completed clinical trials have demonstrated partial efficacy of PrEP in decreasing HIV acquisition risk by 39% and 44% respectively in heterosexual women and men who have sex with men (Abdool Karim et al 2010, Grant et al 2010). If safe and efficacious in ongoing trials, PrEP will likely be targeted to high-risk subpopulations. However, significant barriers will have to be overcome. Integrating PrEP into existing HIV prevention programs will require evaluation of cost-effectiveness, ongoing monitoring of HIV status, behavioral risk assessment, and provision of adherence counseling. High coverage will be required to achieve population-level reductions in HIV incidence.

Maintaining long-term medication adherence in healthy asymptomatic individuals in real-world settings will be challenging. We find that linking adherence to activities of daily living is useful. In our studies, participants use radio news bulletins as reminders, or take medications with meals or at bedtime. Using pillboxes, diaries or cell phone alarms and involving a spouse or family members are useful adherence strategies.

Further research is needed to evaluate long-term safety and efficacy, different formulations, plus alternative dosing and delivery strategies in HIV susceptible individuals, including those with chronic active hepatitis B infection and renal dysfunction, and in adolescents, pregnant and breastfeeding women. Monitoring rates of drug resistance and their impact on future treatment options will be important. Qualitative studies will help understand barriers to adherence, drug sharing with HIV infected persons and behavioral disinhibition. Finally, evaluating PrEP effectiveness in real-world conditions should be considered.

Nyende Ali Replied at 7:34 AM, 7 Mar 2011

This is a pretty interesting one. Well just out of curiosity, was thinking of us bringing something close to this on board. I mean what do you guys think of the effectiveness of HIV&AIDS counselling on behavioral change.
Is HIV&AIDS counseling an effective tool to Behavioral change?.
Just like in many HIV&AIDS service points, HIV counseling entails the development of a relationship between a counselor and client for the purpose of assessing risk for HIV infection or transmission, developing a plan to reduce risk, and assisting the client to cope with emotional and interpersonal issues related to HIV. The goal of client-centered HIV counseling is to conduct an individualized risk assessment, which may or may not include HIV antibody testing, and to develop an effective individualized risk reduction plan. Evaluation of the effectiveness of HIV counseling has been impeded by a lack of adequate outcome measurement instruments and concerns about the validity of self-reported behaviors.

I think Critical research needs include definition of the mechanisms that facilitate enduring behavioral change, assessment of the cost-effectiveness of counseling, and identification of the structural and environmental barriers to effective counseling interventions.Guys What do you have to say about this.I want to conduct a research to measure the effectiveness of HIV&AIDS counseling on behavioral change. So any one who wants to join me in this initiative to please join me. or Email me on

Douglas Krakower Replied at 9:39 AM, 7 Mar 2011

To the HIV prevention community: here is a post to help introduce the topic of PrEP:

Translating the promising results of PrEP trials into clinical practice will require attention to several potential barriers and facilitators.
Are people aware of PrEP and how to use it safely? Determining the most effective ways to educate potential PrEP consumers and healthcare providers in optimal PrEP use will be a priority. Innovative uses of existing public health infrastructure and media (e.g., the Internet) could facilitate dissemination of information on PrEP in some settings.
Who should use PrEP? Identifying individuals who are most likely to benefit from PrEP will entail patient-provider communication around high-risk behaviors, though current levels of risk assessment in clinical practice are generally low in many settings. Efforts to reduce stigma associated with high-risk behaviors could enhance communication.
Will PrEP be acceptable to high-risk individuals, providers, and other stakeholders? It is not known if asymptomatic individuals at high-risk of HIV acquisition will be willing to use prophylactic medications, or if providers will be willing to prescribe them given the potential unintended consequences of PrEP, such as adverse effects, increased risk behaviors , and the emergence of drug resistance. Further data on the safety, efficacy and behavioral implications of PrEP may influence acceptability.
What are the cost implications for PrEP? Given resource limitations, some stakeholders may feel that funds should not be diverted to PrEP from provision of antiretroviral therapy (ART) to people living with HIV. Refined cost-effectiveness estimates could facilitate decisions around PrEP use as further data on its effectiveness in public use become available. Decreasing the cost of antiretrovirals through generic production of current PrEP medications or the use of less expensive agents are likely to impact cost considerations.
Will patients adhere to PrEP regimens? Results from the CAPRISA and iPrEx studies suggest that adherence levels are likely to correlate strongly with prophylactic effect for PrEP. In these studies, adherence levels were suboptimal in substantial numbers of participants. Novel interventions to support adherence, such as the use of wireless technology (e.g., SMS messaging), could offer solutions.

There are many future questions for study, including:
How should PrEP be delivered? Oral and topical PrEP offer relative benefits and drawbacks, and understanding the most acceptable and effective way to deliver PrEP is likely to depend on the transmission dynamics of local HIV epidemics. Intermittent PrEP schedules may decrease cost and drug exposure and perhaps enhance adherence. Further studies to determine optimal delivery methods will be important.
Who will prescribe PrEP? Most potential PrEP consumers will be cared for by primary care providers (PCPs), yet PCPs are likely to have variable comfort prescribing antiretrovirals. Understanding ways to engage and train PCPs to provide PrEP is warranted.
Will PrEP increase high-risk behaviors? If individuals using PrEP increase risk taking, the net effect could be to increase the risk of HIV acquisition. Current studies do not suggest that this occurs, but assessing the behavioral impact of PrEP and testing interventions to decrease risk compensation will be essential.

Douglas Krakower Replied at 9:47 AM, 7 Mar 2011

To Nyende Ali,

I think your emphasis on behavioral counseling is justified. And I agree that measuring outcomes to assess effectiveness can be challenging, though some studies have measured proximate outcomes for HIV transmission. For example, studies may ask individuals about number of sexual partners or frequency of sex acts that involve barrier protection before and after counseling interventions to assess impact. But enduring change, as you point out, seems to be the key goal. Studies involving adaptation of new interview and counseling techniques, such as motivational interviewing, may offer insights into ways to create long-lasting behavioral changes. Finally, to join behavioral counseling and PrEP, the future of prevention is likely to involve tailored interventions that depend on local factors. As you say, individualized risk assessment may guide which prevention modality is most suitable for each person. The NIH is funding "prevention package" approaches to test these ideas, so we should have more data in the next few years.

I hope you are able to study these topics.

Douglas Krakower Replied at 11:24 AM, 8 Mar 2011

To the forum members:

We conducted the HOPE conference this morning, a video conference among several US and South African sites with additional participation from other regions of the world, and the topic was PrEP. Though it ended early due to technical issues (we will reschedule - please contact me for info on how to participate, as membership is open), we began a discussion of how implementation would occur in real-world settings. I would really like to hear from the members of this forum about how others feel that PrEP may or may not have an impact on clinical practice. Any thoughts about this open ended question would be very valuable.

Thank you,
Doug

Sarah Arnquist Replied at 1:50 PM, 8 Mar 2011

Dear Doug,

I'm sure we will all find your HOPE Conference presentation incredibly useful. Along those lines of introducing PrEP into clinical practice, Dr. Paul Sax recently posted a case study in JournalWatch asking: "A young man who repeatedly engages in high-risk sexual activity with other men requests pre-exposure prophylaxis to prevent HIV infection. Do you oblige?"

Here's the link: http://aids-clinical-care.jwatch.org/cgi/content/full/2011/228/1

One commenter said, "Prescribing pre-exposure prophylaxis for a high-risk behavior to an apathetic person is like purchasing ammunition for a repeat bank robber. This patient needs a counselor."

Another said: To justify prescription to one individual sets a precedent whereby this should be prescribed to all who seek it. This intervention would need further evidence of value from a population health point of view before it could be justified."

And another: " How is this different than prescribing a PPI for heartburn when a patient refuses to give up coffee or a statin for hypercholesterolemia when a patient will not make dietary modifications. Our business is to prescribe medicines to mitigate risk when people do not (for whatever reason) make healthy lifestyle choices."

What do you think?

Douglas Krakower Replied at 2:58 PM, 8 Mar 2011

Very good questions, and the answers from the other clinicians (I presume they are clinicians based on their access to Paul Sax's column) are informative about some of the potential barriers to PrEP provision. Many clinicians worry, appropriately so, that the use of PrEP will cause individuals to increase their risk taking behaviors, thereby causing a net increase in the risk of HIV acquisition when using a partially effective PrEP agent. Studies need to monitor for this phenomenon, so-called "risk compensation" or "behavioral disinhibiton." However, the data that are available from published PrEP studies do not support these concerns at this time. There were decreased number of sex partners and stable, high-levels of condom use among participants over the course of the CAPRISA 004 trial (by participant report). In oral PrEP trials, no evidence of risk compensation has been published to date. We will have to wait and see if this occurs outside of a trial setting, but for now, I think we should let the data guide us as we move forward, albeit cautiously. The context of PrEP is the unacceptably high globoal incidence of HIV at 2.6M new infections per year, and if PrEP can have a significant impact on the epidemic, we should consider using it where appropriate if ongoing studies confirm efficacy in trial and non-trial settings.

I agree that prescribing to a single individual means we should provide PrEP to all who may benefit from it. This could be different than "all who seek" PrEP, as there could be "worried well" who seek PrEP despite low risk of HIV acquisition. But for those who are at-risk, based on behavioral practices or demographics, and wish to take PrEP, clinicians should consider prescribing it if they and their patients believe the data demonstrate efficacy and safety. Guidelines could facilitate prescribing, and interim guidlines from CDC for oral PrEP provision exist (MMWR Jan 2011). But I can understand any clinician's reticence about prescribing PrEP given there are limited data to date, though much of the data come from well-designed studies (including gold-standard randomized trials).

I would agree with the author who writes about PPIs; ideally, people would minimize their risk of HIV acquisition through behavioral changes and not through biomedical ones. But there are structural factors and personal circumstances (poverty, gender inequalities, substance abuse disorders) that may place people at high risk for HIV acquisition despite their attempts to minimize risk behaviors. For these people, PrEP may be a safety net to help protect them. And even if we ascribe a person's high-risk behaviors to choice alone, I agree that we have a duty to protect people in whatever way we can, ideally as a bridge towards future behavioral change and discontinuation of PrEP.

I applaud those with the courage to write about reasons why PrEP should or should not be provided in the community, and I hope for more vigorous discussion this week.

What do others think?

Rishabh Phukan Replied at 3:41 PM, 8 Mar 2011

Sarah,

Thanks for linking the post by Dr. Sax.

I disagree with the analogy that compares giving PrEP to high risk-takers is analogous to giving a bank robber bullets. The reason for this being that the bank robber's bullets aren't likely to ricochet and hurt them, making them risk 'free'. However, for an MSM practicing high risk sex, the lack of condom use is a double edged sword where if they are seronegative, they can seroconvert if exposed.

I think a better analogy is that presented by clean needle exchange programs. If clean needles are given to the population, that doesn't mean that more people are going to become addicts. It deals with taking your health into your own hands and making your own choices, while those on the receiving end of the bank robbers bullets have no choice. (For an NYT article on the topic see: http://www.nytimes.com/2011/02/08/health/08vancouver.html)

In Africa, however, needle transmission is minuscule compared to that through sex. One does have to entertain gender politics on this front and note that women are often unable to lobby for safe sex and condom use. I think that the CAPRISA trial was notable not only because it showed the PrEP could lead to positive outcome, but MORE SO because it allowed women to have a bigger say in their own health. Just because women are at times powerless to ensure that their partners use a condom does not mean that they are powerless against HIV/AIDS.

The body belongs to the patient, at times the physicians role as an educator should be clear. One can only advise their patients to make the best decisions for themselves, but cannot force them to comply. No matter how much one wishes they were able to for these matters, especially those concerning adherence, right? I do agree with the last comment that PrEP should be provided if available, though this does not mean that education and counseling should not take place as well. These are not mutually exclusive.

By not providing medications for those when they are available we are judging certain practices as good or bad while we should be deeming them safe or unsafe. It is possible to have multiple partners safely, just as it is possible to have multiple partners unsafely.

Sarah Arnquist Replied at 8:00 AM, 9 Mar 2011

CROSS POSTED FROM THE ADHERENCE COMMUNITY:

SHANTA GHATAK replied to the discussion:

Reply contents:
"Changing risky behaviour in this young person may not be easy as he may be suffering from some sort of obsessive compulsive disorder as well and may not have access to counselling or treatment for various socio economic reasons. That he is asking for the medicines shows that he is willing to be treated. We can offer counselling repeatedly while asking him to attend the clinic frequently when he is being given the medicine supply? It is not a routine that we encounter such cases in large numbers but they are not uncommon. My only concern is that this patient should not run away to a provider who may not be knowledgable enough to tackle the complexity of the disorder.

Though this may not be in the course of the advisable optimal care that should be provided in such a case as this one but we may need to look at what we can achieve in the long run.

Thanks

###

Christopher Shaw replied to the discussion:

Reply contents:
"Hi Doug, thanks for presenting part of the PrEP talk this morning, looking forward to participating in the full presentation when it is rescheduled. This is an interesting topic of discussion. PrEP once thought of only as precautionary for potential accidental exposures has probably always been used on the down-low by savvy folks with knowledge of and access to it. Now with so much buzz about its expanding use the Journal Watch case focuses on an msm who has unprotected sex with reasonable awareness of risk.

I commend this 29 year old fellow . Much the way a patient traveling to an exotic destination might check in for a few vaccines or prophylaxis medications for malaria and anti-diarrheals so they can eat food cooked on the street, this guy knows his risk, he recognizes when it is greatest and he asks a health care provider for prophylaxis protection before going "to town." Sure there are other issues a health care provider would want to caution him about, the risk for other infections, the use of condoms for added protection and the risks the PrEP might have for him. But with this guy who clearly knows his risk the benefit of prescribing PrEP out weighs the costs.

I know there are a number of other issues to consider with prescribing PrEP; cost? who should have access to it?who should prescribe? how should people who have it prescribed be monitored? etc but for someone with risk factors I would strongly lean toward providing PrEP."

Andrew Mujugira Replied at 10:37 AM, 9 Mar 2011

This is an interesting discussion about PrEP provision to a young man with high-risk behavior. Intermittent PrEP could also be considered for another high risk subpopulation-serodiscordant couples.

In Africa, social, economic and cultural pressures to have children result in high pregnancy rates. HIV serodiscordant couples wanting to have children face the difficult choice between wanting to conceive and risking transmission of HIV. In resource limited settings, where assisted reproduction techniques are not available or feasible, often the only option is to tempt fate and practice unprotected sex. It is therefore not surprising that a substantial proportion of incident HIV infections occur within HIV serodiscordant couples. Ultimately, provision of ART to the HIV infected partner is the preferred option. But in situations where national guidelines limit provision of ART to those with CD4 counts <350 or <250 cells/ μL and viral load monitoring is not available, provision of PrEP to the HIV susceptible partner during peak fertility periods is a possible indication for PrEP.

This scenario could apply to couples with HIV infected males and susceptible females, since those with HIV susceptible males and infected females can be taught how to practice artificial insemination during her fertile window.

Sarah Arnquist Replied at 10:54 AM, 9 Mar 2011

CROSS POSTED FROM THE ADHERENCE COMMUNITY:

Jessica Haberer, MD, MS wrote:

Hi All,

Great discussion!

Along with Andrew Mujugira, I am also involved in the ancillary adherence study for the Partners PrEP clinical trial in East African heterosexual HIV serodiscordant couples. At the recent CROI conference, we presented early results on adherence to PrEP within the trial to date. We have been using two relatively robust, objective adherence measures (unannounced home-based pill counts and electronic monitoring caps, called MEMS) in addition to the clinic-based pill counts performed in the parent trial. We have found adherence to be near perfect with all these measures (i.e. 99-100%), which was quite surprising given the problems seen with adherence in iPrEX and CAPRISA. We are also checking random drug levels at 6, 12, and 24 months, but won't have those results until the trial is stopped and unblinded. They will be very important for validating (or not) our other objective measures.

We think the main difference between our results and those in the other PrEP trials is the nature of the study populations. That is, we are working with stable, serodiscordant couples in which the HIV+ index has disclosed to the HIV- partner, while the other studies have involved high-risk individuals who may not have as much support. As everyone knows, however, behavior among participants in a highly structured clinical trial who are counseled at least monthly to take their medications is unlikely to be replicated by participants outside of the trial.

I would be interested in hearing what the community thinks 1) about differences in adherence among potential target populations for PrEP and 2) how high levels of adherence can be practically supported outside of clinical trials. For instance, could support groups be helpful? Online chat rooms? SMS reminders?

Thanks!
Jessica

Jessica Haberer, MD, MS Replied at 9:21 AM, 10 Mar 2011

(Posted on behalf of Rivet Amico)

Excellent points regarding rates of adherence in different subpopulations. We just presented some sobering findings for the iPrEx trial in terms of how our measures of adherence (self-report and pharmacy based) can be quite discordant from drug concentration results, mirroring what has been found in ART adherence research where reports or classification (via pharmacy refill measures) of very low adherence appear to map well onto non-detection of study drug, but high adherence was not as predictive as needed to place a lot of confidence in our measures being able to accurately identify people who had drug detected from those who did not. Moreover, other presentations at CROI (Pete Anderson’s) suggested that overall rates of adherence at study visit week 24 were lower than desired and we are now looking into differences observed by research site for leads on why drug was detected at higher rates in different geographies.

To me, that these adherence rates are specific to “study drug” versus PrEP, per se, is an important factor- we were very clear to participants about the possibility that they were on a placebo and it is very possible that when trials move to open label that rates of adherence may be much higher. We should keep in mind the potential difference between adherence to ‘study drug’ in blinded RCTs and adherence to PrEP especially now that there is some data to point to added protective benefits….in addition to keeping in mind the population’s motivation for use (e.g., when your partner is known HIV-positive).

The rates of adherence in Partners PrEP is very exciting and we are all anxiously awaiting the evaluation of these measures (unannounced pill counts and EDM) to blood levels of drug.

This is a very exciting time with many future directions. I think many of us are hoping for PrEP to be one of many possible sexual health promotion strategies for those who choose to use it who are otherwise at high risk for HIV-infection. Not the only strategy, but one of many possible strategies that can be synergistic with other presently available approaches.

Rivet

K Rivet Amico, PhD
Research Scientist
Center for Health, Intervention and Prevention
University of Connecticut

Douglas Krakower Replied at 11:08 AM, 10 Mar 2011

Dear Rivet (as channeled through Jessica) and Jessica,

Thanks for explaining your recent work on adherence in iPrEx and clarifying some of the nuances about adherence within the trial setting versus the clinical setting. We are all looking forward to iPrEx OLE (i.e., open label extension - it's hard not to enjoy the acronymic title of the study) and your adherence work.

The potentially high adherence rates in Partners PrEP is excellent news. I am interested to hear your thoughts on adherence to intermittent PrEP, aka iPrEP. IPrEP may offer advantages to daily PrEP, such as lower costs and overall drug exposure, and some have speculated that adherence will be superior than seen with daily PrEP regimens. However, preliminary data from iPrEP trials (from IAVI) have shown surprisingly low rates of adherence among some sets of participants.

What are your thoughts on these early data and how they may impact future iPrEP studies?

Thanks very much for your thoughts. I would welcome others to comment as well.

Doug

Douglas Krakower Replied at 11:14 AM, 10 Mar 2011

I also want to thank Chris Shaw for his comments. Chris has great experience with the care of persons living with and affected by HIV as a provider, and I am encouraged to hear his positivity towards providing PrEP to a person who may benefit from this approach. The analogies of a traveler heading into an area where chemoprophylaxis may offer protection is a great way to show that "PrEP" as a strategy has existed in other areas of medicine for decades (malaria prophylaxis for those for whom it is feasible offers a well-known example).

Thanks so much, Chris.

Doug

Sophie Beauvais Replied at 5:27 PM, 12 May 2011

Dear all,

We have just published a peer-reviewed discussion brief on the promises and pitfalls of putting PrEP into practice with key points and references from this exchange. You can view and download it in the community. We invite you to provide feedback and continue the conversation on PrEP. Thank you.

This Community is Archived.

While this community is no longer active, we invite you to review and recommend past posts and resources. Membership for this community is closed, but we hope you'll join us in one of the many other communities on GHDonline.

Moderators of HIV Prevention and GHDonline staff