Frequently asked questions about PrEP and the iPrEx trial

The results of the iPrEx PrEP effectiveness trial of once-daily TDF/FTC (brand name Truvada) in gay men, transgender women and other men who have sex with men are a landmark in HIV prevention research. The results, released on November 23, showed that TDF/FTC reduced risk of HIV infection by an average of 43.8%. This was calculated by looking at rates of infections among participants who received TDF/FTC plus a standard prevention package compared to those in the placebo arm who received a look-alike pill with no active drug, along with the prevention package. All of the men in the trial received the same package of proven prevention services. This is the first proof that an oral antiretroviral can be used to reduce risk of HIV among HIV-negative people. It is cause for great excitement and also raises important questions. This FAQ looks at some of the most important questions we have about PrEP and the iPrEx trial at this time.

1. What do the iPrEX data on TDF/FTC for HIV prevention tell us?
2. What are the trial's statistical conclusions about the effectiveness of once-daily TDF/FTC for HIV prevention?
3. How does an HIV prevention trial like iPrEx measure protection against HIV infection?
4. What are the immediate implications of the iPrEx results for gay men and other men who have sex with men?
5. What might happen next, and who decides?
6. Aren't there concerns that people who take PrEP may develop drug resistance if they become HIV-infected? Did the iPrEx trial data provide any insight into how resistance to TDF/FTC may or may not develop in people who take PrEP?
7. How would a partially effective intervention like PrEP using daily TDF/FTC be used in the real world? Isn't there a concern that PrEP or other partially effective interventions could do more harm than good—by causing people to stop using more effective interventions like condoms?
8. Could the evidence that daily-dosing with TDF/FTC as PrEP reduces HIV risk encourage some men to take more risks than before?
9. How important is adherence to the daily pill-taking regimen in the iPrEx trial, and what does that mean for real world use?
10. Who would pay for PrEP using TDF/FTC? Isn't that drug expensive?
11. How can PrEP using TDF/FTC be used in countries where gay men and other men who sex with men are not recognized legally?
12. What does this result mean for the other ongoing PrEP trials?
13. What are the participants in other PrEP trials and other HIV prevention trials being told about this result and how it affects the trials they are in?
14. Will we need a confirmation trial of TDF/FTC as PrEP amongst men who have sex with men?
15. Given the partial effectiveness seen in this trial and the CAPRISA 004 microbicide trial, shouldn't participants in other trials be offered 1% tenofovir gel or TDF/FTC?
16. What is the status of follow up on the RV144 AIDS vaccine trial and the CAPRISA 004 microbicide trial?
17. What is treatment as prevention? Is it related to PrEP?
18. Which HIV prevention research results are expected next?

1) What do the iPrEX data on TDF/FTC for HIV prevention tell us?

• Provision of once-daily TDF/FTC (tenofovir disoproxil fumarate combined with emtricitabine, brand name Truvada) reduced risk of HIV infection among gay men, transgender women and other men who have sex with men who were also receiving intensive counseling about safer sex, HIV testing, condoms, treatment for sexually transmitted infections and other prevention services on a monthly basis (see question 2).
• The trial underscores the importance of providing a comprehensive prevention package. All of the iPrEx participants received a full prevention package, including condoms, safer sex counseling and treatment of sexually transmitted infections. At each monthly clinic visit, participants were tested for HIV and counseled about daily use of the trial drug, a level of counseling and testing not easily achieved outside of a clinical trial.
• The trial also demonstrates that PrEP using daily TDF/FTC is only safe in people with confirmed HIV-negative diagnoses. The two cases of drug resistance documented in iPrEx occurred among two men who started taking TDF/FTC while in the earliest phases of HIV infection, and therefore did not test positive for HIV using the trial's diagnostics.
• iPrEx shows that adherence to the drug regimen is essential. Participants who received TDF/FTC and had detectable levels of drug in their blood were at much lower risk of HIV compared to participants who received TDF/FTC and had no drug in their blood. The trial also analyzed risk of infection as it related to reported rates of pill taking. Participants who reported taking their pills correctly and consistently the majority of the time had significantly lower risk of HIV infection compared to those who reported taking the pills less frequently.
• PrEP using TDF/FTC is a promising prevention intervention for gay men, transgender women and other men who have sex with men. The effectiveness was found among participants reporting unprotected anal intercourse at the time they enrolled in the trial. It may prove to have similar benefits in the context of vaginal sex and penile exposure, but these data will come from other ongoing trials (see question 12).

2) What are the trial's statistical conclusions about the effectiveness of once-daily TDF/FTC for HIV prevention?

Simply put, what the iPrEx statistics say is that it is highly likely that once-daily TDF/FTC provides some protection against HIV. The level of protection could be anywhere from 15.4 to 62.6 percent.

In all, 64 of the 1,248 study participants who received a placebo became HIV infected during the study, while 36 of the 1,251 participants receiving the study drug became HIV infected. This translates into an average 43.8 percent fewer infections overall among participants who received the study drug plus the prevention package, compared to those who received a placebo plus the prevention package. This analysis included all trial participants, whether or not they remained in the study for the duration of the trial or reported taking their pills regularly. An analysis that includes this full range of participants is known as an "intention to treat" analysis (or ITT). More specifically, the iPrEx trial data are based on a "modified intention to treat" analysis. The term "modified" here refers to the fact that men who were later found to be HIV-positive at the time that they first enrolled in the trial were excluded from the final analysis.

3) How does an HIV prevention trial like iPrEx measure protection against HIV infection?

Biomedical HIV prevention trials enroll HIV-negative volunteers and all of the participants receive a standard HIV prevention package. The exact components of this package vary by trial. Participants are randomly assigned to one of two groups: One group of participants receives the experimental intervention—such as TDF/FTC—and the other group receives a placebo that is indistinguishable from the experimental product.

Participants are followed over time. Those who test positive for HIV are immediately taken off of the study product (this could be the placebo or experimental product since trial site staff and participants do not know which arm each participant is in). At the end of the trial, the research team compares rates of HIV infections in the group of participants who received the experimental product plus the prevention package to HIV rates in those who received the placebo plus the prevention package. A finding of lower rates of infection among participants using the experimental product could indicate that the product has an HIV prevention benefit.

In the case of iPrEx, the standard prevention package included monthly HIV testing, risk reduction counseling, condom promotion, and sexually transmitted infection (STI) screening and treatment. Neither the participants nor the research team knew who had received the TDF/FTC tablets or the placebo tablets. All participants were counseled during their regular study visits that they should not assume that they had received the experimental product; that there was no guarantee that the product would provide any protection; and that they should continue using proven HIV prevention methods such as condoms.

4) What are the immediate implications of the iPrEx results for gay men and other men who have sex with men?

This study is of critical importance since it is the first to show that the drugs that treat HIV can be used to prevent infection in HIV-negative people. A PrEP strategy based on once-daily dosing with TDF/FTC has the potential to change HIV risk for gay men and other men who have sex with men. There's reason for enthusiasm that there is a new potential prevention tool for these communities that have been so hard hit by HIV. There's also reason for caution. Gay men and all other high-risk groups should discuss these results with their health providers to evaluate their implications. There is a need for immediate guidance from relevant public health authorities.

It is unrealistic to ignore the potential that some men may want to begin using PrEP immediately. Since the drug used in the study is licensed and available for use for HIV treatment, there is a need to act quickly to share clear, accurate information about the some of the trial's key conclusions among gay men and other men who have sex with men and their health providers. These include: PrEP using daily TDF/FTC was found to be safe and effective in the context of rigorous monitoring and HIV testing. Resistance emerged among two participants who started TDF/FTC without a confirmed HIV-negative diagnosis and were subsequently found to be HIV-positive. Side effects do occur and may affect the tolerability of TDF/FTC as a prevention strategy.

In addition, it is critical to stress that the trial evaluated once-daily dosing. There is no evidence for "disco dosing" or other strategies that use TDF/FTC or any other drug on other schedules. Obtaining drug from HIV-positive individuals will place those individuals at risk and should not be pursued.

We anticipate that in the coming weeks and months, national and international public health agencies, such as UNAIDS, the World Health Organization (WHO) and the US Centers for Disease Control and Prevention, will be issuing guidance to gay men and other men who have sex with men and to their health providers about off-label use of PrEP and the context in which it might be responsibly used.

5) What might happen next, and who decides?

At AVAC, we believe that there are roles for many stakeholders:

• WHO/UNAIDS should move without delay to issue a statement clarifying the implications of the results for gay men and other men who have sex with men. They should also use this opportunity to stress that gays and lesbians are part of communities in each country around the world and therefore these results are relevant in all settings. In addition, this statement should address the broader timeline for results from other PrEP trials, providing a normative agency perspective on how countries with predominantly heterosexual epidemics might plan for and assess PrEP using TDF/FTC or other medications as a potential strategy.
• National authorities, especially those in the countries where iPrEx took place, need to urgently review the data and issue guidance on what is now known and not.
• Gilead (the manufacturer of TDF/FTC under the brand name Truvada) should provide updates on its conversations with the US Food and Drug Administration (FDA) and other regulatory bodies about the possibility of seeking a supplemental prevention indication for TDF/FTC.
• Civil society groups including (and especially) communities of gay and bisexual men and transgender women, AIDS treatment and prevention advocates and many others must work to understand what the iPrEx data do and do not show about daily use of TDF/FTC as PrEP. We must work together to help communities understand these findings and discuss, develop and disseminate advocacy agendas for the way forward.

6) Aren't there concerns that people who take PrEP may develop drug resistance if they become HIV-infected? Did the iPrEx trial data provide any insight into how resistance to TDF/FTC may or may not develop in people who take PrEP?

If someone becomes infected with HIV while using an ARV-based prevention strategy, then his or her virus will be exposed to whatever ARV drug or drugs are being used in that strategy. As a result, resistance to that drug could emerge. (Use of an antiretroviral in someone who is not infected with HIV cannot cause resistance.)

iPrEx trial participants were tested for HIV at every monthly study visit. Any participant who tested positive for HIV was asked to immediately stop taking their pills and to return all remaining medication (neither participants nor trial staff knew who had received TDF/FTC and who had received the placebo pill). By minimizing the time that any participant was taking TDF/FTC after becoming HIV infected, the risk of acquiring resistance was reduced.

All of the men who did become HIV-infected during the trial received HIV drug resistance testing. Among these men, no tenofovir resistance was detected. Three of the participants had HIV that was resistant to FTC. One of these participants was in the placebo arm and two in the TDF/FTC arm. After obtaining these results, the trial team went back to the earliest blood samples from these participants and determined that all three individuals were in the early stages of HIV infection at the time of enrollment. The infections were not detected because the men were not yet antibody positive to HIV.

Therefore, in this trial setting, resistance was only seen in men who were already infected with HIV when they started taking the study drug. This underscores the need to incorporate regular HIV testing into any program implementing ARV-based prevention in HIV-negative people. It is also essential to ensure that there are immediate public health messages directed to gay men, their health providers, and the general public, that the iPrEx data show the risk of drug resistance was only minimized when the strategy was used by men who were confirmed to be HIV-negative.

7) How would a partially effective intervention like PrEP using daily TDF/FTC be used in the real world? Isn't there a concern that PrEP or other partially effective interventions could do more harm than good—by causing people to stop using more effective interventions like condoms?

An intervention is only effective when it is used correctly and consistently. A condom, which reduces risk of HIV infection to nearly zero, is not effective at all if it remains in its wrapper. A strategy such as PrEP using daily TDF/FTC, which is less effective than a condom, may be easier for some people to use for a variety of reasons, including that the pill does not need to be taken during or just before intercourse. More consistent use of a partially effective product may therefore have a significant impact on both individual risk of HIV and incidence (the rate of new HIV infections in a community) and could provide some protection to those who are not able to consistently use condoms.

It is also important to remember that, in the iPrEx trial, daily TDF/FTC reduced risk of HIV infection among men who were also receiving sexually transmitted infection (STI) diagnosis and treatment, counseling, condoms and behavior change support in a medical setting that catered to and was accepting of gay men and other men who have sex with men. All of the elements of the package are important. What this shows is that a partially effective strategy can have a major impact when added to other existing interventions.

8) Could the evidence that daily-dosing with TDF/FTC as PrEP reduces HIV risk encourage some men to take more risks than before?

PrEP, or any other new prevention strategy, has the potential to change people's perception of their risk of HIV and, therefore, their risk-related behaviors. In the context of this trial, participants actually reported reduced risk behaviors: increased condom use and decreased number of sexual partners. This trend towards decreased risk taking has been observed in most biomedical prevention trials, but clinical trials do not necessarily predict what will happen in the real world.

It is possible that the introduction of PrEP might lead some gay men and other men who have sex with men to feel that they are now well-protected against HIV; some men might increase their numbers of partners or rates of unprotected sex. Other men might not change their behaviors or might start taking fewer risks as a result of the counseling and testing they receive before starting PrEP. It is impossible to know how behaviors would change without close monitoring and follow-up research. This information must be gathered—starting with the iPrEx follow-up trial (see question 14).

9) How important is adherence to the daily pill-taking regimen in the iPrEx trial, and what does that mean for real world use?

In the iPrEx trial, participants were instructed to take one of the pills provided by the trial every day. The trial team conducted a small substudy that looked at whether participants in the active drug arm (receiving TDF/FTC) had detectable levels of the drug in their blood. This substudy found that participants receiving TDF/FTC who had detectable drug levels were at significantly lower HIV risk compared to those who had no detectable levels. Put another way: Detectable drug level in the blood strongly correlated with protection.

There were additional data on adherence collected on the basis of what participants reported about their pill-taking behavior. In this analysis, participants who reported higher levels of adherence had a lower risk of HIV infection, compared to those who reported lower levels of adherence.

In real world settings, the effectiveness of this strategy will depend on correct and consistent use. Should PrEP be introduced, men who use it will need to be supported with effective and supportive adherence strategies. Alternative dosing regimens (i.e., intermittent PrEP, which could be before and after sex or on a less-than daily basis) also need to be evaluated for effectiveness and feasibility.

10) Who would pay for PrEP using TDF/FTC? Isn't that drug expensive?

The cost of TDF/FTC (brand name Truvada) varies by country. Truvada, the drug manufactured by Gilead, costs an estimated US$17 per day in the US. The generic formulation made by various companies including Matrix, Hetero, Cipla and Aurobindo and used in many developing countries costs from 39 cents to 45 cents per tablet. Cost will obviously be an issue and must be at the top of the agenda as we move toward potential use of PrEP in different communities around the world.

But the drug cost would be just one part of any future PrEP intervention using TDF/FTC; such a program would have to have comprehensive prevention services, counseling and testing. Moreover, it is vitally important that implementation of new prevention programs using ARVs in HIV-negative people not take resources away from treatment programs.

11) How can PrEP using TDF/FTC be used in countries where gay men and other men who sex with men are not recognized legally?

There are gay men and other men who have sex with men worldwide—every country should consider this a relevant issue. That said, it will be challenging to develop programs for gay men in countries where homosexuality is illegal or where men who have sex with men lack basic human rights—but there is a great need for new prevention interventions for these men. PrEP programs in these settings will need to be developed on a foundation of a human rights based approach to providing health care and broader civil liberties to gay men, lesbians, transgender people and other sexual minorities.

12) What does this result mean for the other ongoing PrEP trials?

iPrEx is the only trial that has looked at daily TDF/FTC in the context of anal sex as the primary risk factor for HIV (i.e., among gay men and other men who have sex with men). Other ongoing trials are looking at PrEP in the context of penile-vaginal intercourse (i.e., women and heterosexual men) and/or injection drug use. (These trials also collect data on anal sex practices, but it is not the predominant mode of exposure as reported by participants.) Because of biological differences between anal and vaginal tissue, and between sexual and parenteral (via injection) exposure, these other PrEP trials must continue—with the following steps:

• The Data and Safety Monitoring boards, or equivalent bodies, monitoring each of the ongoing trials should be informed of the iPrEx results.
• Trial teams in each of the countries where trials are ongoing should discuss the iPrEx results and their implications for current research and future planning with policy makers, civil society and other key stakeholders, as well as providing targeted updates to their participants (see below). Informed consent documents for all ongoing trials should be updated to include information about iPrEx and CAPRISA 004 (see question 13) so that prospective participants have a clear understanding of available data and the rationale for a placebo-controlled trial in their context.

13) What are the participants in other PrEP trials and other HIV prevention trials being told about this result and how it affects the trials they are in?

AVAC believes that trial participants should always be informed of relevant data in a manner reviewed and approved by the trial's Institutional Review Board. This may in some instances involve a revision to the informed consent process. In the case of iPrEx, the data are relevant to all ongoing studies of ARV-based prevention including both oral and topical strategies, and to planned and ongoing biomedical prevention trials in gay men and other MSM, including HVTN 505 (a Phase II vaccine trial among gay men in the US).

14) Will we need a confirmation trial of daily TDF/FTC as PrEP amongst men who have sex with men?

Additional data can be gathered in a range of studies, including demonstration projects, follow-up trials—such as the one the iPrEx team is planning—and others. Given the iPrEx data, additional placebo-controlled trials of this strategy in gay men and other men who have sex with men are not warranted. As mentioned, one important source of additional information will be a follow-up trial, which will begin in early 2011 and be open to all participants from the original iPrEx trial. All HIV-negative participants who choose to join this open-label trial will receive the active TDF/FTC pill along with an HIV prevention package and will be counseled on daily use of the drug. However, monitoring and HIV testing will be less frequent, with the goal of learning about PrEP safety and effectiveness in a "real world" context.

Other questions include: Would a PrEP strategy containing a single drug—tenofovir alone, or a different single ARV—be more or as effective as TDF/FTC? How can adherence be supported? What is effectiveness in the context of less frequent monitoring and HIV testing?

15) Given the data from iPrEx and CAPRISA 004, what are the ethical implications of continuing placebo-controlled trials of 1% tenofovir gel or TDF/FTC?

To answer this question, it can help to look at what existing relevant ethical guidance documents say on the matter. For example, the WHO/UNAIDS Ethical Guidance for Biomedical Prevention Trials (online at http://data.unaids.org/pub/Report/2007/JC1399_ethical_considerations_en....) states, "Researchers, research staff, and trial sponsors should ensure, as an integral component of the research protocol, that appropriate counselling and access to all state of the art HIV risk reduction methods are provided to participants throughout the duration of the biomedical HIV prevention trial. New HIV-risk-reduction methods should be added, based on consultation among all research stakeholders including the community, as they are scientifically validated or as they are approved by relevant authorities."

In this instance, the question is whether the new interventions, including oral TDF/FTC and 1% tenofovir gel have been "scientifically validated" on the basis of the data from a single trial. There are still many important questions that iPrEx leaves unanswered. These data can't be extrapolated to people at risk of HIV via heterosexual sex or injection drug use. Differences in biology of the vagina and rectum, and between HIV risk in sexual versus injection exposure make it essential that ongoing placebo-controlled trials looking at PrEP in these contexts must continue. More information is also needed for 1% tenofovir gel.

16) What is the status of follow up on the RV144 AIDS vaccine trial and the CAPRISA 004 microbicide trial?

The RV144 trial sponsors and other researchers are working to confirm and extend the observations of RV144 through laboratory research on samples collected from the more 16,000 trial volunteers. Additional small trials are already underway, and additional vaccine efficacy trials that build on the RV144 result are being designed and are likely to begin in 2013.

The CAPRISA team is now designing two studies to follow the 004 trial participants to answer key operational research questions that would help design future implementation programs should tenofovir gel get licensed. In October, the FDA indicated that it would consider both CAPRISA 004 and VOICE as pivotal trials despite the different dosing strategies. (The NIH-funded VOICE trial is currently evaluating the same 1% tenofovir vaginal gel used in CAPRISA 004 but inserted once daily, rather than before and after sex as in the 004 regimen. VOICE is also testing the effectiveness of two forms of oral pre-exposure prophylaxis (PrEP) to reduce the risk of HIV infection.) The FDA also indicated that it would want to see additional safety data, including in younger women and post-menopausal women.

In addition, there is ongoing discussion about two additional effectiveness trials of 1% tenofovir gel, which are currently being designed, but not yet approved or funded, including:

• Follow-on African Consortium of Tenofovir Studies (FACTS consortium) 001 trial in South Africa would test the same dosing strategy as CAPRISA 004 in women from a variety of settings, include sexually active 16- and 17-year-olds, and it would gather more information on 1% tenofovir gel as a tool for HSV-2 prevention.
• The UK MRC's Microbicide Development Programme (MDP) 302 study would be conducted in other African countries and would compare two different dosing strategies—the CAPRISA 004 dosing regimen and use of a single coitally dependent dose.

17) What is treatment as prevention? Is it related to PrEP?

"Treatment as prevention" is a term describing the use of antiretroviral drugs that are used to reduce the risk of passing HIV to others. The strategy would function as a secondary benefit of antiretroviral treatment after its primary purpose of improving an individual's health. The rationale for this approach is that ARVs reduce viral load. Higher viral loads have been linked to increased risk of passing HIV to sexual partners. Treatment as prevention is an emerging area and there are different terms and phrases used to describe this approach, including "test and treat" and "testing and linkage to care plus," which recognizes that voluntary HIV testing and diagnosis is the first step to accessing care.

Treatment as prevention involves giving ARV drugs to HIV-positive people, while PrEP is for HIV-negative people. Find more information about treatment as prevention at www.avac.org/treatmentasprevention.

18) Which HIV prevention research results are expected next?

You can find more information about ongoing trials and expected results from AVAC's HIV prevention research timeline, available at www.avac.org/timeline.

For more in-depth information about these and other issues, visit www.avac.org/iprex.

Stay tuned for Cascade of Hope and Questions, Volume 3: Understanding the Results of iPrEx which will be available in the coming weeks.

More information from iPrEx is available at www.globaliprex.net.

Source: AIDS Vaccine Advocacy Coalition (AVAC)