iPrEx Study - Questions and Answers: iPrEx

QUESTIONS AND ANSWERS
The iPrEx Study: Pre-Exposure Prophylaxis as HIV Prevention Among Men who Have Sex with Men


1. What is the iPrEx study?

The Chemoprophylaxis for HIV Prevention in Men study, also known as iPrEx, is a Phase III clinical study designed to determine whether a daily tablet containing a combination of two antiretroviral drugs used for HIV treatment can safely and effectively prevent HIV infection among men who have sex with men and transgendered women who have sex with men. The iPrEx study, which began in July 2007, is the National Institute of Allergy and Infectious Diseases’ (NIAID’s) first large-scale study to evaluate the investigational HIV prevention research approach known as pre-exposure prophylaxis, or PrEP.

2. What is pre-exposure prophylaxis?

Pre-exposure prophylaxis, or PrEP, is an investigational approach to HIV prevention in which antiretroviral medicines currently approved to treat HIV infection are given to people who are not infected with HIV in an attempt to reduce their risk of infection. The concept behind PrEP is not a new one. Drugs are taken to prevent malaria during periods of increased risk and can also be used to reduce the risk of developing tuberculosis and certain types of meningitis.

With HIV, scientists theorize that taking an antiretroviral drug before exposure to HIV could potentially inhibit HIV replication immediately after exposure to the virus, thereby preventing the establishment of permanent infection. There is scientific evidence to support this theory in animal models and humans. Antiretroviral drugs have been successfully used to prevent HIV transmission from infected mothers to their newborns.

3. How many participants were involved in the iPrEx study, and where was the study conducted?

The iPrEx study enrolled 2,499 sexually active men who have sex with men and transgendered women who have sex with men. All participants were at least 18 years old and HIV-negative at the time of enrollment. All participants were born male (1.2% of participants reported their current gender identity as female).

The study was conducted at 11 sites in nine cities in Brazil, Ecuador, Peru, South Africa, Thailand and the United States.

4. Who funded, sponsored and conducted iPrEx?

NIAID sponsored the iPrEx study through a grant to the J. David Gladstone Institutes, a non-profit independent research organization affiliated with the University of California at San Francisco. Additional study funding was provided by the Bill and Melinda Gates Foundation. Gilead Sciences, based in Foster City, Calif., donated the study drug.

The study was conducted under the leadership of protocol chair Robert M. Grant, M.D., M.P.H., of the Gladstone Institute of Virology and Immunology, and protocol co-chair Javier R. Lama, M.D., M.P.H., of Investigaciones Medicas en Salud, a Peruvian-based research organization.

5. What was the design of the iPrEx study?

The iPrEx study was a randomized, double-blind, placebo-controlled Phase III clinical trial. Participants were randomly assigned to receive on a daily basis an antiretroviral tablet containing combination emtricitabine (FTC 200 milligrams) and tenofovir (TDF 300 milligrams)—a combination known by the brand name Truvada—or a placebo pill. The study was designed to determine whether the daily combination antiretroviral pill could safely and effectively prevent HIV infection among sexually active men who have sex with men and transgendered women who have sex with men, all of whom were routinely counseled about safe sex practices, provided condoms and treated other sexually transmitted infections. Once enrolled, all study participants were evaluated for HIV infection monthly for the duration of their participation in the study (average enrollment was 1.2 years)

6. What were the results of the iPrEx study?

Investigators found that study participants who took the daily dose of oral antiretrovirals experienced an average of 43.8 percent fewer HIV infections than those who received a placebo pill (95% CI 15.4 to 62.6%; P=0.005). In all, 100 cases of HIV infection occurred among participants in the iPrEx study. Of those, 36 HIV infections occurred among the 1,251 participants who were randomized to receive the study drug compared with 64 HIV infections among the 1,248 participants who were randomized to receive the placebo. The average reduction in HIV infection risk of 43.8 percent includes all study participants—even those who did not take the daily pill consistently. However, the drug’s ability to reduce the risk of HIV acquisition was greater among those volunteers who were more adherent to the daily drug regimen. Participants who took the drug on 50 percent or more days as measured by pill count, bottle count and self reporting experienced 50.2 percent fewer HIV infections (95% CI 17.9-69.7%; P=0.006). Those who took the drug on 90 percent or more days had 72.8 percent fewer HIV infections (95% CI 40.7-87.5%; P=0.001).

Overall, efficacy was greatest, 58 percent, among participants at particularly high risk for HIV, as measured by self-reports of unprotected receptive anal intercourse (URAI) at the time of enrollment in the study (95% CI 32-74%; P=add value).

The researchers found that consistent with earlier, smaller studies that led up to the iPrEx study, the antiretroviral drug proved to be safe and well-tolerated as a prophylaxis method. Side effects were mild and infrequent and included a small number of reports of transient nausea that dissipated after several weeks. Additionally, some participants who received the active drug experienced mild elevations of creatinine, a naturally occurring molecule filtered by the kidneys, but these elevations resolved spontaneously or with discontinuation of the pill.

Additionally, no HIV drug resistance occurred among individuals who became HIV-infected during the course of the study. There were three cases of emtricitabine resistance (one participant in the placebo group; two participants in the active drug group), but these cases occurred among individuals who were HIV-infected at the time of enrollment. Their HIV infections were so recent that they were not detected by standard HIV antibody testing.

Although there was concern at the launch of the study that the PrEP approach could cause study participants to relax their use of condoms and safe sex practices, this was not the case during the iPrEx study. Rather, participants reported a decrease in the number of sexual partners and increased use of condoms.

7. Why was the iPrEx study conducted in men who have sex with men and transgendered women
who have sex with men?

Men who have sex with men are among the groups disproportionately affected by HIV/AIDS. An article published on HIV and men who have sex with men in the December 2007 PLoS Medicine reported that men who have sex with men have a markedly greater risk of being infected with HIV than the general population in low and middle-income countries in the Americas, Asia, and Africa. Studies indicate that HIV prevalence among men who have sex with men is 10 percent or higher in each of the countries in which the iPrEx study was conducted. In the United States, 53 percent of new HIV infections occur in this population, according to 2006 HIV incidence estimates from the Centers for Disease Control and Prevention.

8. How was participant safety monitored during the trial?

Study participants were extensively counseled prior to enrolling in iPrEx about the purpose and design of the study, were encouraged to ask questions, and were required to pass a comprehension test to demonstrate that they understood the study and their rights as potential study volunteers to give their informed consent. Participants were free to leave the study at any time and for any reason without repercussions.

All study participants received intensive HIV risk-reduction counseling throughout the study, including free condoms and treatment for other sexually transmitted infections. HIV testing was provided on a monthly basis.

Participant safety was closely monitored throughout the trial by a data and safety monitoring board (DSMB), an independent committee composed of clinical research experts, statisticians and other representatives of the international academic research community, including representatives from the United States, Peru, South Africa, Brazil and Thailand.

9. Why was FTC/TDF (Truvada) selected as the study drug?

FTC/TDF was chosen for use in the iPrEx study because it has been shown to be safe and effective with few side effects as an HIV treatment for HIV-infected individuals. The drug, which is approved by the Food and Drug Administration (FDA) as an HIV treatment for HIV-infected individuals, is taken orally once daily and remains in the bloodstream for many hours. Currently, 1.5 million people worldwide are using tenofovir-based drug regimens, including FTC/TDF.

Truvada also has prevented infection when tested in nonhuman primate models of HIV infection, and it was thought that a two-drug antiretroviral combination would be more effective than a pill containing only one antiretroviral.

Truvada is not approved by the FDA for PrEP.

10. What is the next step for iPrEx study participants?

Beginning in 2011, investigators will conduct an 18-month follow-on study to iPrEx designed to provide additional information about the antiretroviral drug’s long-term effectiveness and safety, as well as participant risk behavior and pill-taking practices. All HIV-negative iPrEx participants will be eligible to participate and will receive the study drug.

11. What additional information is being provided to study participants?

During the course of the trial, study participants who later became HIV-infected were contacted by their individual clinical sites and referred for appropriate medical care. Now that the iPrEx study has ended, participants are being informed as to whether they received the FTC/TDF study drug or the placebo and provided with additional information, including information about the upcoming follow-on study.

The clinical sites have made a concerted effort to reach study participants in advance of the public announcement of the iPrEx results. However, some participants may be first learning of the study’s findings through this announcement. Participants are encouraged to contact their study sites for more information.

12. Will PrEP now become widely available as an HIV prevention method?

It is important to note that the iPrEx results are from one study only. These results pertain solely to the effectiveness of PrEP among men who have sex with men and cannot be extrapolated to other populations. That is why ongoing PrEP research among other study populations is critical to providing a comprehensive view of the potential utility of PrEP as an HIV prevention method.

Now that the iPrEx results are available, the U.S. Centers for Disease Control and Prevention will continue working with a variety of experts and stakeholders at the federal, state and local levels are looking closely at the study data and will move forward in the coming months to determine whether and how these findings should be incorporated into ongoing HIV prevention programs.

13. What other PrEP research is NIAID conducting?

NIAID launched a clinical trial in September 2009 known as the VOICE study (“Vaginal and Oral Interventions to Control the Epidemic”), or MTN 003, that is exploring both PrEP and a vaginal microbicide gel as prevention for male-to-female HIV transmission. Specifically, the Phase IIB study among 5,000 heterosexual women in South Africa, Uganda and Zimbabwe is comparing three different, once-daily HIV prevention strategies—a daily oral FTC/TDF pill, a daily oral pill containing tenofovir only, and a tenofovir-based vaginal gel—to a placebo pill and a placebo vaginal gel.

In 2011, NIAID will launch the ADAPT study (“Alternative Dosing to Augment PrEP Pill-Taking”), or HPTN 067, a Phase II behavioral study to evaluate the feasibility of using FTC/TDF intermittently as pre-exposure prophylaxis against HIV infection. The study, which will be conducted in South Africa and Thailand, will involve 360 men who have sex with men and women who have sex with men at high risk for HIV infection.

Other federal agencies and organizations are also conducting PrEP research in other study populations, including intravenous drug users, heterosexual men and women, and heterosexual couples in which one partner is infected with HIV and the other is not.



For additional information about the iPrEx study, see http://www.iprexnews.comExternal Web Site Policy.

Media inquiries can be directed to the NIAID Office of Communications at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Questions and Answers: iPrEx