RE: Timing the Review and Approval of Pre-exposure Prophylaxis for HIV Prevention

We, the undersigned, are non-profit organizations and coalitions who support the development of and access to new safe and effective HIV prevention options in the United States and globally. Data from multiple clinical trials in different populations showing that antiretroviral drugs for HIV treatment can also prevent HIV infection have accumulated to the point where FDA approval decisions could be made for this intervention. The approval issues for the different populations are not identical. For the reasons outlined below, we urge the FDA and Gilead Sciences to reconsider plans to combine the approval for a prevention indication for both men who have sex with men, including transgender populations (MSM) and heterosexuals into a single filing. The combination could unnecessarily delay approval for MSM, the group at greatest risk of HIV infection in the United States.

FDA has a duty to move forward on beneficial products by setting out best terms of use, and, by law, to “promote the public health by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner.” This duty is what’s in question today.

Results from three large clinical trials show that oral pre-exposure prophylaxis (oral PrEP) has the potential to prevent new HIV infections. Last year the iPrEx trial found that daily TDF/FTC (marketed as Truvada by Gilead) along with standard prevention reduced HIV infection risk by 42% in at-risk gay/bisexual men and transgender women who have sex with men (MSM).

The results preceded release of important infection data for MSM in the U.S. The U.S. Centers for Disease Control (CDC) estimates that MSM account for more than half of all new HIV infections in the U. S. For many MSM the HIV risk is growing. CDC found an estimated 34% increase in HIV infections in young MSM between 2006 and 2009, and a 48% increase in HIV among young black/African American MSM over the same period. MSM represent a population with demonstrable need for effective prevention tools.

Two additional trials have shown that oral TDF/FTC (or TDF alone as in one of the trials) as PrEP also reduces HIV infection risk by 62-73% in at-risk heterosexual men and women. But a fourth study of oral TDF/FTC as PrEP, which was conducted in a population of heterosexual women, was stopped before its anticipated end date after an interim data review found equal numbers of infections in the experimental and placebo arms. More recently, the oversight board of an ongoing PrEP trial comparing oral TDF alone to oral TDF/FTC and a gel containing TDF recommended discontinuing the use of oral TDF alone in a single arm of the study. That approach was deemed unable to show efficacy in the population of heterosexual women being studied. The other arms of the study continue to evaluate the other PrEP modalities. We do not yet know why this pattern emerged in these trials. Nevertheless, combined data show oral PrEP may be a vitally important prevention tool for some heterosexual populations.

Separate safety and effectiveness questions in data collected in heterosexual groups may unduly lengthen FDA review for MSM if the two approvals are bundled together. In addition to clarity surrounding the one trial that was stopped, FDA may have questions about:

• Offering oral PrEP to women who use hormonal contraceptives concurrently;
• Balancing risks to unborn children exposed to drugs in the absence of a known risk of exposure to HIV from an uninfected pregnant mother;
• The basis of using two-drug combinations vs single drugs in heterosexual populations.

The US DHHS perinatal guidelines for HIV recently withheld recommendations for oral PrEP based on these concerns. If approval for both MSM and heterosexuals is bundled together, it may take many months to answer the questions affecting one group more than the other.

Harms result when the benefits of FDA approval are delayed for a safe and effective intervention:

• Patients do not have the benefit of the safety and control measures that come with proper labeling, study- and FDA-regulated risk management;
• FDA regulatory requirements are not able to be integrated with or to facilitate other efforts to demonstrate real world effectiveness in a cohesive organized manner;
• FDA approval spurs insurance coverage from private and public sources needed to secure equitable access for disadvantaged populations;
• The drug manufacturer will be restricted from communicating important data to clinics because of restraints on unauthorized marketing;
• While PrEP should only be given to those who can truly benefit, a delayed approval means many of them will simply not get it at all. Whichever infections could have been averted will unfortunately occur.

These harms should not be imposed on either MSM or heterosexuals. FDA’s duty also requires the Agency to safeguard patients from uncertainty, and today, unfortunately, that uncertainty possibly weighs more heavily with one group more than the other. We must shore up that uncertainty promptly but not delay access to risk-reducing tools for MSM sooner if we can. Approval delayed, like justice, is approval denied.

FDA approval also influences the availability of PrEP in other countries hardest-hit by HIV/AIDS that look to the FDA for assurance that a new therapy is safe and effective. The largest international program for HIV treatment and prevention in developing countries, PEPFAR, considers FDA approval an important step in providing programming/access to PrEP.

Before the results of heterosexual PrEP studies were announced, the FDA and Gilead were reported to be ready to move forward on a review of PrEP for MSM. Now it looks like action on PrEP for MSM may take longer. Even six months of further delay could result in many preventable new HIV infections.

The FDA and Gilead should move quickly to ensure a thorough review of PrEP for MSM. It’s time. We also urge no delay to clear up data that will help heterosexual populations in need. Useful interventions often go through sequential approvals as was the case for Gardasil to prevent HPV related cancers and lesions in young women and men. Oral PrEP is not a magic pill but it adds to the available arsenal we have to prevent HIV.

Sincerely yours,

AIDS Action Committee of Massachusetts
AIDS Foundation of Chicago
AIDS Research Consortium of Atlanta
AIDS United
AVAC
Black AIDS Institute
Fenway Health
GMHC
Harlem United
International Rectal Microbicides Advocates
National Minority AIDS Council
Project Inform
San Francisco AIDS Foundation

A PDF version of this document is available here.

Close to 100 openly HIV-positive gay and bisexual men from across the United States and around the world have signed a new letter (http://tinyurl.com/pozPrEPletter) calling for an open discussion, “based on facts rather than on fear or misinformation,” of the challenges and opportunities presented by pre-exposure prophylaxis (PrEP) for HIV prevention in gay and bisexual men and transgender women. The new open letter is designed in part to urge FDA review of PrEP and to clarify facts about important PrEP research that advocates say have been misrepresented in a paid ad campaign sponsored by the AIDS Healthcare Foundation (AHF).

Pre-exposure prophylaxis, or PrEP, is a new HIV prevention method in which an uninfected person takes a daily HIV medication to reduce HIV infection risk. Data from an international study released in November, 2010 called iPrEx found that men and transgender women who have sex with men who received a daily single-tablet dose of the HIV drugs tenofovir and emtricitabine along with condoms and safe sex counseling had an average of 42% fewer HIV infections than those who received condoms and counseling alone. Much higher rates of protection were achieved among participants who took PrEP consistently.

Most of the HIV prevention community welcomed the news of a new tool that could significantly reduce infections in the populations at highest risk for HIV in many parts of the world. One HIV treatment provider, however, the AIDS Healthcare Foundation, has taken out an extensive series of full-page advertisements in gay papers around the country claiming that gay and bisexual men will act recklessly and will spread HIV if they are allowed to use PrEP. The AHF ad campaign claims that it is supporting gay and bisexual health by urging the U.S. FDA to ignore the PrEP study.

Today’s open letter challenges both the tone and content of the AHF communications and encourages “a full and factual discussion of the pros and cons of PrEP… based on facts, not misinformation.” Reminding the world that “gay and bisexual men invented safer sex…and have worked tirelessly to prevent new HIV infections,” the letter also points out that gay and bisexual men account for more than half of new HIV infections in the United States and are in particular need of new HIV prevention approaches.

“As an HIV positive gay man I signed this letter because I learned from experience we need all credible options to stop this epidemic. I owe my life to the fact that advocates and activists have pushed hard for decades to make effective AIDS drugs available to HIV-positive people,” said Kali Lindsey. “Now we know that AIDS drugs can also play an important role in the health and well-being of HIV-negative gay men, how could we not move forward to reap the benefits of this research. It is not an option to ignore these findings.”

In July of this year the results of two addition studies, Partners PrEP (led by the University of Washington Department of Global Health) and TDF2 (led by the U.S. Centers for Disease Control and Prevention) demonstrated that PrEP is also safe and effective in heterosexual women and men. The Partners study found that participants who received PrEP experienced an average of 62-73% fewer HIV infections than those who received placebo. The TDF2 trial, conducted by the U.S. Centers for Disease Control found that the risk of HIV infection dropped by an average of 63% among those who received PrEP in addition to condoms and counseling. Data expected from the FEM-PrEP trial, which was stopped in April after it was determined that the trial would not be able to provide an efficacy result, will also provide additional information about PrEP use among women.

The new letter acknowledges that the PrEP, “is no magic solution to the HIV crisis,” and that research, “raises important questions…includ(ing) how to best support regular PrEP use; how to ensure the continued use of condoms and other precautions for those who decide to take PrEP; how to target PrEP to those who will benefit most; and how to pay for this new HIV prevention tool.” Its signers express their commitment “to promoting safer sex and the open exchange of accurate information on HIV prevention,” and to “clarify the facts about PrEP, open up community discussion and make clear our belief that we are entitled to respect, accurate information and new HIV prevention tools.” The letter concludes by calling on all interested parties to “get the facts about PrEP, seek information, and express opinions…but to do so based on real information, not fear of the scientific process or prejudice against gay/bi men.”

The letter was coordinated by a group of U.S.-based AIDS advocacy organizations, including AIDS Foundation of Chicago, AVAC, International Rectal Microbicide Advocates (IRMA), and Project Inform.

A copy of the sign-on letter supporting an informed debate on PrEP for gay and bisexual men is below. Openly HIV-positive gay and bisexual men who wish to add their name to the letter can do so at: http://tinyurl.com/pozPrEPletter.

Contact:
Kay Marshall (AVAC), [email protected], +1-347-249-6375

New York, 18 April 2011 – At a scheduled, interim data review, the Independent Data Monitoring Committee (IDMC) for the FEM-PrEP study of oral pre-exposure prophylaxis (PrEP) using daily TDF/FTC (brand-name Truvada) determined that the trial would not be able to answer the question of whether the study drug decreased risk of HIV infection among HIV-negative women at risk via sexual transmission. The IDMC has, therefore, recommended that the study be discontinued.

“Today’s announcement about the FEM-PrEP study is disappointing,” said Mitchell Warren, AVAC executive director. “However, it must be seen as what it is – the closure of a single trial in a field that has generated exciting results in the recent past. Even with this finding, there is still a strong rationale for continuing other trials, including those in women, in hopes of obtaining better results in the future.”

The FEM-PrEP trial tested the same drug and daily dosage of TDF/FTC (also known as Truvada) as the landmark iPrEx PrEP trial among gay and bisexual men and transgender women. Last November, results of the iPrEx trial showed a 44 percent reduction in HIV risk overall in participants who received TDF/FTC compared to those who received the placebo. In July 2010, results of the CAPRISA 004 study showed a 39 percent reduction in HIV risk among women who used a 1% tenofovir gel microbicide compared to those who received a placebo gel. In both trials, there was evidence that adherence matters – that participants who used the intervention most consistently had the highest levels of protection.

Two other ongoing trials in sub-Saharan Africa are evaluating oral TDF/FTC and/or TDF alone among heterosexuals. The VOICE trial is evaluating oral TDF and TDF/FTC as well as 1% tenofovir gel in 5,000 women in sub-Saharan Africa. Partners PrEP is evaluating oral TDF and TDF/FTC in the HIV-negative member of couples in which one partner is HIV-infected.

“The premature closing from FEM-PrEP does not predict the findings from either VOICE or Partners PrEP,” Warren said. “It is too soon to tell whether the differences observed between iPrEx and FEM-PrEP are due to the route of exposure, pill-taking behavior, biological differences in drug activity, or some other factor. Along with further analysis of FEM-PrEP data, VOICE, Partners PrEP and other ongoing trials will add critical pieces to the puzzle of if and how to deploy PrEP as an effective prevention tool.”

“We commend the FEM-PrEP trial team, the members of the IDMC and especially the nearly 2,000 women who participated in the trial. Despite the inability of the trial to answer the question of whether TDF/FTC reduces women’s risk of HIV infection, FEM-PrEP has provided and will continue to provide key information that will help move the PrEP research agenda forward,” Warren said.

Further analysis of the FEM-PrEP data will provide a better of understanding of the observation that there was a higher pregnancy rate among women in the active drug arm of the trial, compared to those in placebo arm.

In addition to VOICE and Partners PrEP, there is an ongoing PrEP efficacy trial among injection drug users and a soon-to-be-launched follow-on to iPrEx known as the iPrEx Open Label Extension study, or iPrEx OLE. There are still close to 20,000 participants involved in PrEP trials around the world.

“Medical research is often complicated, and we must expect setbacks along the way. But with 2.6 million new HIV infections every year, it is imperative that we continue to look for new ways to curb the epidemic,” Warren added. “The success of the iPrEx and the CAPRISA 004 trials have shown the promise of ARV- based prevention options as part of a comprehensive prevention package that includes condoms behavioral counseling and treatment of other sexually transmitted diseases. There will never be a silver bullet for HIV prevention, so we must continue to seek a variety of new options to protect those at risk through different routes of transmission and throughout their lives.”

More information about ongoing PrEP research is available at avac.org/prep.

Contact:
Mitchell Warren, [email protected], +1-914-661-1536
Kay Marshall, [email protected], +1-347-249-6375

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About AVAC: Founded in 1995, AVAC is an international non-profit organization that uses education, policy analysis, advocacy, and community mobilization to accelerate the ethical development and eventual global delivery of AIDS vaccines and other new HIV prevention options as part of a comprehensive response to the pandemic.