FREQUENTLY ASKED QUESTIONS

According to UNAIDS, about 2.7 million people became infected with HIV in 2008, more than 50,000 new infections each week. Here in San Francisco, we see 8-10 new HIV infections every week. While HIV risk reduction counseling, condoms, male circumcision and other methods have been shown to reduce HIV infections, by themselves they are not enough; thousands of people still become infected with HIV every day. The need for effective new prevention methods is urgent.

PrEP stands for Pre-Exposure Prophylaxis, an experimental approach to HIV prevention where HIV negative people take HIV drugs to try to prevent HIV infection. PrEP is started before being exposed to HIV and continued during periods of risk. This is different from post-exposure prophylaxis (PEP) where the medication is started soon after exposure to HIV and continued for 28 days. PrEP can be in the form of a pill taken by mouth or a gel applied in the vagina or rectum. Current studies of oral PrEP (pills) have tested the HIV drug tenofovir (also known as Viread®) alone or in combination with emtricitabine (the combined drug is also known as Truvada®) as a daily pill. Both tenofovir and Truvada® are approved for the treatment of HIV infection in HIV- positive people.

Preventing an infection by giving a drug that is also used to treat that infection has been a successful approach against other diseases such as malaria.

Prepare is the San Francisco Department of Public Health HIV Research Section's site of the Global iPrEx trial, testing whether the use of daily Truvada® could reduce the risk of HIV infection among gay men, male to female transgendered women and other men who have sex with men (MSM). In this study, participants were randomly assigned to receive daily Truvada® or a placebo (dummy pill). The study was "blinded" meaning that neither the participants nor the staff at the study sites knew who was getting Truvada® and who was getting placebo. All participants received HIV prevention services including monthly HIV testing, risk reduction counseling, condoms and lube, and testing and treatment of sexually transmitted infections (STIs).

In San Francisco, 140 participants enrolled in the study. Globally, 2,499 volunteers participated at 11 sites in the United States, Ecuador, Peru, Brazil, South Africa and Thailand. This was the first large-scale clinical trial conducted among MSM in Asia and Africa.

In addition to studying whether Truvada® can prevent HIV infection, Prepare looked at the safety of HIV negative people taking Truvada® daily. The study was looking for any side effects of the drug, along with whether people taking the drug changed their sexual risk behavior. The study was also measuring how well study participants were able to take a daily pill.

This study was funded by the National Institutes of Health (NIH), with additional support from the Bill and Melinda Gates Foundation. Truvada® is made by Gilead, who donated the drug for this study, but did not provide additional funding to the sites.

The iPrEx study found that HIV infection rates were high among men enrolled in the study (over 2% per year), but that the rate of HIV infection was 44% lower in men who were receiving Truvada® as PrEP. This is a statistically significant level of efficacy, meaning it is highly unlikely these results are due to chance. This is an important advance in HIV prevention research, as it is the first biomedical strategy that has been shown to reduce the risk of HIV infection in MSM and transgender women. It is important to note that all study participants received comprehensive HIV risk reduction services, and so we don't know how effective PrEP might be in the absence of those services.

Unfortunately, despite giving all participants comprehensive HIV prevention services, one hundred (100) HIV infections occurred among 2,499 participants during the study. Of these, 36 infections occurred in the study group that received Truvada®, while 64 occurred in the group that received placebo. We know that even if Truvada® had no effect, we might see a difference in the number of infections between the two groups. However, this big a difference would only be expected to be seen 5 times out of 1000 if it were due to chance alone (a p value of 0.005), making it almost certain that Truvada® did provide protection against HIV infection in this population of MSM and transgender women.

First, 44% is just an estimate of how much being given Truvada® reduced the risk of HIV infection. The 95% confidence intervals (95% CI) for this study was 15% - 63%, meaning that it can be determined with 95% confidence that the true efficacy in this trial falls somewhere between 15 and 63%.

These results apply to the overall population of participants being given Truvada® compared to placebo, not to individual people. So, it is not accurate to say that one person taking PrEP has a 44% less chance of becoming HIV infected than a person who is not taking PrEP. Rather, among the 2,499 participants enrolled in this study, those in the group given PrEP were 44% less likely to become HIV infected than those in the group given the placebo.

What this protection means for HIV prevention in general or for individual people will require further analyses of these data, in addition to further studies of participants' ability to take the pills, how best to provide them in the context of other HIV prevention services, and other considerations.

Many study participants found it challenging to take the study pills on a daily basis. The data also shows, however, that those participants who were able to take the pill more often might have been more likely to be protected from HIV infection than those who took the pills less frequently.

It is difficult to measure exactly how many pills participants took. We measured pill taking in 4 different ways: asking the participants monthly how many pills they took, counting the number of pills we gave to participants each month, counting the number of pills participants brought back to us each month, and measuring the levels of study drug in the blood. None of these measures is perfect, and in this and other studies, we often find that the information we get from different measures of pill taking don't agree with each other. There are likely many reasons for this including people not remembering exactly how many pills they take; losing, forgetting, or discarding pills, and differences in how much study drug is absorbed into the blood.

Even understanding these limitations, participants who reported taking the drug more often experienced more protection:

• Study participants who reported taking Truvada® on 50% or more of days had 50% fewer HIV infections (95% CI 18-70%; P=0.006).
• Those who reported using PrEP on 90% or more of the days had 73% fewer HIV infections (95% CI 41-88%; P=0.001)

In this study, blood levels of study drug were compared in 34 people who became HIV- infected and a matching group of 43 people who remained HIV-negative. Among those given Truvada®, study drug was detected in less than 10% of people who became HIV infected and about half of those who remained HIV-negative. This finding suggests that participants who had drug detected in their blood were more likely to be protected from HIV than those who didn't. It is important to realize that samples were only tested in a small number of people and at only one snapshot in time. Therefore, drug level testing in many more samples is being planned for this study.

Further studies will also be required to understand how to help people take the pills more consistently, and to what extent doing so will increase protection against HIV.

The iPrEx study demonstrated that PrEP with Truvada® was generally safe and well tolerated. There were no differences in serious side effects between the group who received Truvada® and those who received placebo.

Other side effects related to use of the PrEP tablet in the study were infrequent and mild:

• Nine percent (9%) of individuals who received PrEP reported nausea in the first month of the study, compared to 5% of those who received placebo; after the first month there was no excess nausea among those who received the active pill.
• A small number of participants who received PrEP experienced increases in creatinine, which marks a decrease in kidney function; 2% in the group receiving Truvada® vs. 1.1% in the placebo group. All creatinine elevations stopped when study drug was discontinued. Investigators monitored kidney function throughout the study and found no serious problems.
• Unintentional weight loss of more than 5% was reported in 2.2% of people receiving PrEP compared with 1.1% of placebo users (P=0.04).

These side effects mirror those found in previous PrEP studies conducted by Family Health International among women in West Africa and by the U.S. CDC among MSM in the United States. They are also consistent with the experience of HIV-positive people taking Truvada® for treatment of HIV infection.

Because it appears that many participants may not have been taking a daily pill throughout the study, and because participants were seen in the study only for an average of one year, these estimates of side effects may not reflect what would be seen if the pill is taken daily or for a longer period of time. More information on the safety of Truvada® will come from additional data from iPrEx and from other studies in the field.

The Prepare study is a clear and important step forward for HIV prevention research. These results mean that PrEP may be an additional tool for HIV prevention for MSM and transgender women when used in combination with standard HIV prevention tools such as HIV testing and counseling, provision of condoms and lube, and STI testing and treatment.

Besides being the first study to report on and demonstrate the efficacy of oral PrEP in people, Prepare is the first randomized clinical trial to demonstrate a protective effect for a biomedical intervention against HIV in MSM. These data address an important unmet need in public health, as HIV infection rates are higher in MSM than among other groups in almost all countries.

It is unknown how a partially effective intervention such as PrEP might be best used. For MSM who cannot consistently use condoms however -- especially those living in settings with high rates of HIV -- even a partially protective intervention such as PrEP might be beneficial.

These study results do not answer questions about:

• Whether PrEP drugs other than Truvada® are safe and effective
• Whether PrEP is safe and effective in populations other than MSM and transgender women who have sex with men
• The safety and potential protective effect of alternative dosing regimens, (e.g., intermittent PrEP)
• How to best implement a PrEP program or the cost-benefit of doing so
• The potential public health impact of providing broad access to PrEP for HIV prevention
• The patterns of risk behavior and pill taking that may occur now that more information is available about PrEP safety and efficacy

One concern about PrEP use is the possibility that if a person unknowingly becomes HIV infected while taking the pills, they may develop a drug-resistant strain of the virus. HIV-infected people are treated with several HIV drugs at a time in order to avoid thisrisk.

There was very little drug resistance seen in the Prepare study. No one in the study developed resistance to the tenofovir component of Truvada®. Two cases of resistance to emtricitabine occurred among participants taking study drug.

Both of the participants with emtricitabine resistance were already HIV-infected at the time of enrollment in iPrEx, but their infection was too recent to be detected by HIV antibody tests at enrollment. They were found to be HIV antibody positive at their next visit, one month later. Stored blood specimens from their enrollment visit were found to have HIV present by viral load testing.

While many effective treatments remain available for people with emtricitabine resistance, it will still be important, if PrEP is made widely available, to do everything possible to minimize the chances of drug resistance for anyone using PrEP.

In order to minimize the chance for resistance, it will be important to ensure regular HIV testing of anyone using PrEP, and to stop PrEP immediately if a person becomes HIV- infected. Additionally, PrEP providers would need to perform both HIV testing and a health screen for viral symptoms before starting a patient on PrEP, to decrease the chances of giving PrEP to someone already HIV infected.

Overall, participants in the Prepare study decreased their risk for HIV during the study, whether they received Truvada® or placebo. This is likely due to the consistent HIV risk reduction counseling offered as part of the study procedures.

Additionally, participants were reminded that it was unknown whether Truvada® could decrease their risk for HIV transmission, and that they may be receiving a placebo, which would not offer any protection against HIV.

These results are an exciting step forward for HIV prevention. San Francisco has been at the forefront of HIV prevention and treatment since the beginning of the HIV epidemic. Extensive discussions with clinicians, prevention providers, and community partners will be needed to determine how PrEP might be added to current prevention efforts. Additional studies will be required to determine who should use PrEP and in what situations, how to deliver PrEP safely and effectively in different settings, and whether findings from the iPrEx study can be adapted to reduce new HIV infections at the community level.

At the national level, it is likely that the US Centers for Disease Control and Prevention (CDC) will seek expert advice from researchers, clinicians, prevention providers, and community members on whether the evidence is sufficient to recommend daily Truvada® for PrEP, and to whom these recommendations would apply. Public health programs will also want an opportunity to evaluate these data and get expert input, including CDC recommendations, before deciding whether and how to provide PrEP through their programs. Funders, including insurance agencies, are also likely to need time to make decisions about whether, and in what circumstances, they would provide PrEP. Cost will be an important consideration in these discussions, as in the U.S. the average price for Truvada® could be as high as $800 - $1000 per month, excluding the cost of clinical visits and laboratory monitoring.

In the meantime, HIV uninfected persons at risk of HIV infection may choose to consult with their primary care providers about what these results may mean for their specific situation. We strongly recommend that people NOT take PrEP on their own, without close monitoring from a medical provider.

Many additional studies are underway that may ultimately help to determine how and in whom PrEP is best used. These are described in Question 19.

MSM and transgender women who have sex with men are among the groups most affected by HIV in the United States, much of South America, and in some other countries. Across different societies, where data are available, rates of HIV infections are generally far higher among MSM than in the population at large. Studies indicate that the proportion of MSM who are HIV infected is 10 percent or higher in each of the countries in which Prepare was conducted. Worldwide, MSM are in urgent need of improved HIV prevention, treatment and care.

Other studies are looking at PrEP for HIV prevention in other populations at increased risk for HIV in other countries - including injection drug users in Thailand and heterosexual women and men in Africa.

Most PrEP studies to date have either used tenofovir, or Truvada®, which is a combination of tenofovir and emtricitabine. The reason these drugs were chosen is that they can be taken once a day, they have fewer side effects compared to many other HIV drugs, and they do not easily create HIV resistance.

The HIV Research Section in the SF Department of Public Health (SFDPH) is committed to conducting innovative research in collaboration with communities most affected by HIV. In San Francisco, the Prepare study was carefully reviewed with input from our long-standing Community Advisory Group, a group of community members who provide input into all levels of research being conducted by the SFDPH HIV Research Section.

In addition, the SFDPH held several community consultations and educational forums in San Francisco to gain further feedback and educate the community about Prepare before the study began, and continued to actively offer educational workshops and forums throughout the course of the study. SFDPH also partnered with community based organizations for recruitment into the study, and plans to do so to share results of the study broadly.

Other study sites around the world engaged community in similar ways. Because the iPrEx study began in the Andes, the Community Advisory Boards in Peru and Ecuador had particular influence over the study design.

The safety of study participants is of utmost concern in any research study. Before joining the study, all Prepare study participants went through an extensive informed consent process where they learned in detail about the study, including all the risks and benefits of participating, and that they could leave the study at any time. That process included understanding and signing a written informed consent document, as well as multiple one-on-one meetings with counselors and study staff to answer any questions. After enrolling in the study, participants had access to a study clinician at all times to address any questions or concerns they might have.

All participants received monthly HIV testing and risk reduction counseling as well as condoms and lube during the study. Participants recruited into this study were at risk for HIV, and some became HIV positive during their participation. At that point, study staff provided linkages to appropriate care for their mental and physical health and well- being, including medical treatment for HIV infection. Those participants were also asked to stop taking the study drug, but to continue coming in for visits. The study medication itself did not contain HIV virus and could not cause HIV infection.

In addition to multiple community consultations, the Prepare Study was reviewed and approved by institutional review boards in each of the study cities, who considered the medical importance of the study and that the study procedures were ethically sound. In addition, a Data and Safety Monitoring Board (DSMB) was formed of investigators not involved in the trial. This group met two times per year throughout the trial to monitor safety data during the study.

As with all HIV prevention studies conducted by the San Francisco Department of Public Health, Prepare study participants were given a comprehensive risk reduction package including the provision of condoms and lube, ongoing HIV risk reduction counseling and testing, and testing and treatment for other sexually transmitted infections, all designed to help them reduce their risk of HIV infection while in the study. Study results showed that participants did in fact decrease their risk for HIV during their study participation.

Researchers offer this package of prevention services because they are ethically compelled to offer the best available HIV prevention services in the trial. Additionally, it is critically important that study participants understand that it is unknown whether the study drug can prevent HIV infection, and that they may be receiving a placebo, which affords no protection.

Although these measures often work to reduce HIV-risk taking behavior, many participants are still not able to use condoms 100 percent of the time, for any number of reasons. At the end of the study, researchers compared the group who were given Truvada® with the group who received placebo to see whether PrEP provided additional benefit, over and above the comprehensive prevention package, in lowering the rate of becoming infected with HIV.

The first round of PrEP studies are testing whether daily dosing of PrEP is safe and effective for HIV prevention. This dosing regimen was selected because it is the same used for HIV treatment. The iPrEx study showed protection with PrEP taken on a daily basis; it is not known what PrEP taken less frequently is safe or effective in preventing HIV. Additional studies are planned to look at whether intermittent PrEP (e.g. taking PrEP either before and after sex, or on a regular schedule several times a week) can be safely taken.

These study results are a very exciting signal about a potential new tool in the fight against HIV, yet they also raise new questions. Further analyses will be done on these data, and other studies are needed to find out more about how to encourage people to take the pill, and how to deliver PrEP within a context of a comprehensive prevention program. There are additional questions to be answered about whether and how PrEP may be adopted as a public health intervention, and who might pay for the costs.

Furthermore, the data from the Prepare study is limited to MSM and transgender women who may become exposed to HIV through sex. It is unknown what the results may be for different populations at risk for HIV, including women and IV drug users. Several different studies are happening around the world in these populations, and data from those studies will enhance our understanding of PrEP's efficacy. Other studies are evaluating different drugs to be used for PrEP, different methods for delivering these drugs (e.g., rectal and vaginal gels, vaginal rings), and less frequent dosing. The goal of all of these studies is to learn how to deliver the safest, most effective, and most cost efficient strategy to have the biggest public health impact in different populations around the world.