New York, NY — The announcement today that the 1% tenofovir gel arm of a large-scale HIV prevention trial known as VOICE will stop early is disappointing but is not the end of the road for tenofovir gel or antiretroviral (ARV)-based microbicides.

“This is a blow to the HIV prevention field but is not the definitive answer about whether 1% tenofovir gel is an effective HIV prevention product for women,” said Mitchell Warren, AVAC Executive Director. “New interventions are studied in multiple effectiveness trials for exactly this reason. CAPRISA 004, the first trial of 1% tenofovir gel, found effectiveness in women. VOICE found no effect. The FACTS 001 safety and effectiveness trial of tenofovir gel, which has just begun in South Africa and uses a different dosing strategy from VOICE, will provide additional information and hopefully clarity about the effectiveness of tenofovir gel.”

“One immediate priority is ensuring that communities directly connected to planned and ongoing trials of tenofovir gel are informed and engaged with discussions about the way forward. Finding prevention options that work for women must remain a top priority, and there is still crucial investigation of tenofovir gel as both a rectal and a vaginal microbicide, which must continue,” Warren said.

After a recent, scheduled interim review of trial data, the independent Data Safety and Monitoring Board (DSMB) for VOICE—a five-arm proof-of-concept trial that has enrolled more than 5,000 women in South Africa, Uganda and Zimbabwe—recommended that the 1% tenofovir gel arm of the study be stopped and that the women in that arm exit the trial in a structured process. The DSMB concluded that there was no possibility that daily use of tenofovir gel would show efficacy in preventing HIV in the context of the VOICE trial. Importantly, the DSMB found no safety issues in any arm of the trial. No other data from the trial have been released at this time.

In September, the VOICE trial DSMB met and recommended stopping the oral tenofovir (TDF, brand-name Viread) arm of the trial after it was determined that oral TDF could not be shown effective in the context of this trial.

VOICE will continue to evaluate oral TDF/FTC (a combination of TDF and emtricitabine (FTC), brand-name Truvada) with final results expected in late 2012.

In July 2010, results from the CAPRISA 004 trial showed that 1% tenofovir gel reduced the risk of HIV infection by 39 percent overall among the women in that trial. At this time, it is impossible to know why the results of VOICE and CAPRISA 004 were different. The differences could be related to the dosing schedule—women in CAPRISA 004 were counseled to use the gel before and after sex, while women in VOICE were counseled to use it daily—or it could be related to how frequently women used the gel or other variables. VOICE launched in 2009 with a five-arm trial design to evaluate the safety and effectiveness of oral TDF, oral TDF/FTC and 1% tenofovir gel, each used daily, compared to a placebo gel or placebo pill.

“Based on the limited information available at this time, we simply don’t know whether the lack of effect was due to biology, adherence, both, or something else. This is one reason why the ongoing FACTS 001 trial, which is evaluating a different dosing strategy, with different adherence requirements, should continue,” Warren said. “The concept of ARV-based prevention has been proven, but to meet the prevention needs of different populations we need the right drug at the right time in the right place. We hope that further research with tenofovir- and other ARV-based options will provide a range of new prevention options.”

The FACTS 001 trial of 1% tenofovir gel, which began enrolling in October and will include 2,200 HIV-negative women in South Africa counseled to follow the same dosing schedule as CAPRISA 004, should provide more information about how and if tenofovir gel might reduce risk of HIV infection in women. Results from FACTS 001 are expected in 2014. In addition, follow-on studies among women who participated in the CAPRISA 004 study will provide more critical information about the effectiveness and acceptability of tenofovir gel under different circumstances.

“We commend the VOICE trial team, the members of the DSMB and especially the more than 5,000 women who are participating in the trial,” said Warren. “VOICE has and will continue to provide critical information about both tenofovir-based PrEP and microbicides that will help move the HIV prevention research agenda forward,” Warren said.

The disappointing news from the VOICE trial is the latest development in a complex picture of what ARV-based prevention means for HIV-negative women. The Partners PrEP trial provided evidence of benefit that both daily oral TDF/FTC or daily oral TDF reduced HIV-negative women’s risk of acquiring HIV from an HIV-positive male spouse or stable partner. (The same benefit was observed for HIV-negative men with HIV-positive female partners.) The trial enrolled serodiscordant couples, in which one partner was HIV- negative and one was HIV-positive. The smaller TDF2 expanded safety study, which enrolled young men and women, also showed a reduction in risk for both men and women who took daily TDF/FTC. However, the VOICE oral TDF arm and the FEM-PrEP study of oral TDF/FTC in women found flat results.

“We must, without any delay, accelerate the development of prevention strategies for HIV-negative women that address possible adherence issues. While we do not yet know the role that adherence to the drug regimen might have played in the FEM-PrEP and VOICE trial data to-date, we know that, for some women, strategies that require less-frequent dosing, such as a vaginal ring inserted monthly, and long-acting injectables, will be simpler to use from an adherence stand point,” Warren said.

“Simultaneously, we must make good on the promise made to all trial participants to extract every bit of valuable data that we can from the ongoing trials. We have much to learn from analyses of FEM-PrEP and VOICE as well as from FACTS 001 and the ongoing Partners PrEP trial. The prevention field must be prepared to act on emerging findings from these trials with clear plans and processes for accelerating or shelving approaches.”

“Medical research is often complicated, and we know to expect setbacks along the way. But with 2.7 million new HIV infections every year, it is imperative that we continue to look for new ways to curb the epidemic,” Warren added. “It is especially important that we focus on interventions that will help young women—who so often bear the brunt of the epidemic—protect themselves.”

“There will never be a silver bullet for HIV prevention, so we must continue to rapidly expand testing, treatment and voluntary medical male circumcision, amongst the array of evidence-based interventions, while also accelerating the research and development of additional new options, notably a range of ARV- and non-ARV-based prevention methods and vaccines to protect against HIV.”

A table of ongoing and planned ARV-based microbicide and PrEP trials is below. For more information visit www.avac.org.

A PDF version of this press release is available here.

Contact:
Mitchell Warren, mitchell@avac.org, +1-914-661-1536
Kay Marshall, kay@avac.org, +1-347-249-6375

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About AVAC: Founded in 1995, AVAC is a non-profit organization that uses education, policy analysis, advocacy and a network of global collaborations to accelerate the ethical development and global delivery of AIDS vaccines, male circumcision, microbicides, PrEP and other emerging HIV prevention options as part of a comprehensive response to the pandemic.

New York, NY — Thirteen prominent U.S. HIV/AIDS organizations have issued an open letter to the U.S. Food and Drug Administration and Gilead Sciences calling for prompt regulatory review of pre-exposure prophylaxis (PrEP) for HIV prevention in gay and bisexual men and transgender women (men who have sex with men, or MSM). The letter urges FDA and Gilead to start the review process that could allow safe and appropriate approved PrEP use as a public health intervention, and not to delay review because of distinct questions about the safety and efficacy of PrEP in heterosexual populations. The letter is available online at: www.avac.org/letters/fda-gilead

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.

Advocates assert that the need for new HIV prevention strategies for MSM is urgent. The U.S. Centers for Disease Control (CDC) estimates that MSM account for more than half of all new HIV infections in the United States. CDC logged an estimated 34% increase in HIV infections in young gay men between 2006 and 2009, and a 48% HIV increase among young black/African American gay men over the same period.

“We desperately need new strategies and tools to reduce the rapidly increasing rates of HIV infection in black gay and bisexual men,” said Phill Wilson, executive director of the Black AIDS Institute. “We’ve had evidence of PrEP’s effectiveness in MSM for almost a year now. It’s time to use every tool at our disposal to reduce the 50,000 new HIV infections that occur each year in this country. Prompt FDA review will help ensure that appropriate guidelines for PrEP use are established that can reduce HIV infections and safeguard public health.”

Data on PrEP in heterosexuals raise important but unique questions that may require further study. Two major trials in Africa found that PrEP reduces HIV infection risk in heterosexual men and women substantially. But two other studies present conflicting information about how PrEP works in heterosexuals. Critical and necessary efforts to understand how PrEP interacts with hormonal contraception, or how PrEP may impact pregnancy, however, should not delay access to a potentially lifesaving form of HIV prevention for MSM.

Before the results of the heterosexual PrEP studies were announced, the FDA and Gilead Sciences, the maker of the drugs, were reported to be ready to move quickly to consider approval of PrEP for those MSM who could benefit from the approach. Recent signs indicate, however, that FDA review of PrEP for this population may not start until the agency acquires more data on PrEP among heterosexuals—despite the urgent need for new HIV prevention strategies for MSM, and the fact that PrEP data in MSM were announced nearly one year ago.

“The FDA and Gilead Sciences should move quickly to ensure a thorough review of PrEP for MSM now, while they both work simultaneously and swiftly to thoroughly address questions and concerns about PrEP among heterosexual populations,” said Mitchell Warren, executive director of AVAC “Prompt FDA review of PrEP in MSM is the right thing to do for public health. In the midst of a growing HIV epidemic, HIV prevention delayed is HIV prevention denied.”

Contact:
Kay Marshall, kay@avac.org, +1-347-249-6375
Robert Reinhard, rjreinhard@gmail.com, +1-415-570-1010

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A PDF version of this document is available here.

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), kay@avac.org, +1-347-249-6375