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.