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HIV prevention trial with Truvada halted prematurely for lack of efficacy
  A study in three African countries where women were given an AIDS drug to prevent HIV infection is being stopped because the project is not working, researchers said Monday.
There are four possible explanations for the failure of the study, which enrolled 1,951 women in Kenya, South Africa and Tanzania starting in June 2009.
One is that the women weren't taking the medicines as instructed, despite assertions they were. Another is that the pill's active ingredients didn't get into cervical and vaginal tissues in sufficient concentrations to have an effect. The third is that the strategy doesn't work. The final explanation is that it works but by chance didn't in that experiment.
"These findings by no means suggest we should not do further PrEP trials in women," Fenton said. "This really underscores the complexity of HIV prevention and the importance of doing multiple trials in different populations."
There are four possible explanations for the failure of the study, which enrolled 1,951 women in Kenya, South Africa and Tanzania starting in June 2009.
One is that the women weren't taking the medicines as instructed, despite assertions they were. Another is that the pill's active ingredients didn't get into cervical and vaginal tissues in sufficient concentrations to have an effect. The third is that the strategy doesn't work. The final explanation is that it works but by chance didn't in that experiment.
It is possible the women who had been randomly assigned to Truvada missed an unusually large number of both birth control and Truvada pills. Blood samples drawn every four weeks will be tested to determine the drug levels of the women randomly assigned to Truvada.
Alternatively, the drugs might be less effective at preventing infection through vaginal intercourse than anal intercourse, the method in the study that showed protection last year, said Mastro of FHI, which was formerly known as Family Health International.
LA Times By Thomas H. Maugh II, Los Angeles Times
April 18, 2011, 1:02 p.m.
A major clinical trial attempting to show that daily use of the anti-HIV drug Truvada could prevent new HIV infections in heterosexual women was halted prematurely Monday when preliminary results indicated that the study "will be highly unlikely to be able to demonstrate the effectiveness of Truvada in preventing HIV infection in the study population, even if it continued to its originally planned conclusion," according to a statement released by Family Health International, which is overseeing the trial. The "surprising and disappointing" results came only six months after the release of data showing that the drug could reduce the infection rate by at least 44% in gay men, and by as much as 70% in those who used it consistently. That finding was hailed as a major breakthrough in AIDS prevention and researchers speculated that similar results would be obtained in ongoing studies in other population groups. But it was not to be.
In a "Dear Colleague" letter sent to physicians Monday by HIV experts at the Centers for Disease Control and Prevention, the experts cautioned women against using the drug for prevention. Some women have been using the drug off-label for that purpose, despite the lack of evidence of its efficacy.
Researchers are at a loss to explain the results. Possibilities include: low adherence to the drug regimen; a true lack of effect of the drug in women, as opposed to the effect in gay men; or some other as-yet-unknown reason.
All of the women in the study were using contraception. The overall pregnancy rate was 9%, with the greatest incidence of pregnancies in the group of women taking oral contraceptives and receiving Truvada. That, some experts said, suggests that the lack of effectiveness of the drug may be due to lack of adherence, although it is possible that there is some previously unobserved interaction between the AIDS drug and contraceptives.
Side effects in the drug group were similar to those observed among people taking Truvada for HIV treatment, and included diarrhea, nausea, fatigue, headache, dizziness and rash.
April 18, 2011
Results of FEM-PrEP Clinical Trial Examining Pre-Exposure Prophylaxis (PrEP) for HIV Prevention Among Heterosexual Women
Dear Colleague,
Today, FHI announced that it will stop the FEM-PrEP study of pre-exposure prophylaxis (PrEP) for HIV prevention among heterosexual women. The decision was made after a regularly scheduled interim review of data by the trial's independent data monitoring committee determined that the trial could not demonstrate efficacy even if it continued to its originally-planned conclusion. These preliminary results are disappointing, especially given that this approach has already been shown to be effective in reducing HIV infection among men who have sex with men (MSM). The well-conducted study included nearly 2,000 women at high risk for HIV infection in three African nations and sought to determine if a once-daily pill containing oral tenofovir and emtricitabine (FTC/TDF or TruvadaĻ) could protect women from HIV infection.
While PrEP with FTC/TDF was not shown to be effective in preliminary analyses of these study results, it cannot yet be definitely determined whether this drug combination works, or does not work, to prevent HIV among women. FEM-PrEP study investigators will be conducting additional analyses in the coming months to better assess potential reasons for the results in this study - including examining factors such as adherence and differential risk behavior between the two trial arms -- that may account for the lack of demonstrated efficacy in this trial. Investigators from other PrEP trials, including CDC, will be working closely with FHI to review all available data and determine any implications for ongoing research.
Given today's results, CDC cautions against women using PrEP for HIV prevention at this time. We will not know if PrEP is effective for women, couples, or injection drug users until the conclusive results of this and other trials are reported.
In the interim, CDC reiterates that daily PrEP with FTC/TDF has only been shown to be effective for HIV prevention among MSM. Interim CDC guidance on use among MSM is available here:
Lack of Success Terminates Study in Africa of AIDS Prevention in Women
Published: April 18, 2011
In an unexpected setback for a new form of AIDS prevention, scientists on Monday halted a study in Africa intended to find out whether a daily antiretroviral pill can prevent women from becoming infected with the AIDS virus.
Early data showed no evidence that the pill was working.
Women taking the medication, Truvada, were just as likely as those taking a placebo to become infected, according to an independent panel that analyzed the results after the study had enrolled about half the 4,000 women researchers had hoped to enlist.
Of the 1,900 women taking Truvada or a placebo, 28 in each group had become infected as of last week, according to FHI, formerly Family Health International, the nonprofit group that was conducting the study in South Africa, Kenya and Tanzania.
"It's surprising, disappointing and frustrating," said Mitchell Warren, executive director of AVAC, an advocacy group for AIDS prevention in New York. "But there's a strong rationale for continuing other trials in women in hopes of obtaining better results in the future."
Two other studies of what is called "pre-exposure prophylaxis" in women are still under way in Africa. The results are expected over the next two years.
The inconclusive results of the latest trial are a surprise to many experts. A study published last November found that Truvada protected gay men against infection. Men who took their pills faithfully were shown to have better than 90 percent protection, a result hailed as a breakthrough for AIDS prevention.
And results published last summer from a trial in South Africa showed that a vaginal gel containing tenofovir, one of the two antiretroviral drugs in Truvada, reduced the chances of infection by 54 percent in the women who used it faithfully before and after sex.
Because the current study - known as FEM-PReP on the list of catchy acronyms scientists use to distinguish many similar trials from one another - was stopped early and abruptly, many questions about it remain.
One is whether there was any difference in how often the women given Truvada and those given a placebo actually took their pills. More women taking Truvada complained of unpleasant side effects, and therefore a greater number might have failed to adhere to the program.
The researchers asked the women every month how often they took their pills, but preferred to confirm those answers through blood samples. The samples are in storage and have not yet been analyzed.
After that is done, "we might be able to get a better handle on the adherence," said Dr. Timothy Mastro, vice president for health and development sciences of FHI.
Any woman who became pregnant was removed from the study, because Truvada has not been proved safe for pregnant women; for unknown reasons, more women taking the medication became pregnant, which may also have skewed the early results.
Another question is how much Truvada infused the walls of the vagina, where the initial infection takes place.
According to Dr. Robert M. Grant, a California AIDS researcher who led the study of Truvada in gay men, other research has shown that vaginal gels are as much as 100 times more effective than pills at getting protective antiretroviral drugs into the vaginal walls. Pills and gels are about equally effective in getting them into rectal tissue, he said.
FHI Statement on the FEM-PrEP HIV Prevention Study
FHI to Initiate Orderly Closure of FEM-PrEP
Monday, April 18, 2011
Following a scheduled interim review of the FEM-PrEP study data, the Independent Data Monitoring Committee (IDMC) advised that the FEM-PrEP study will be highly unlikely to be able to demonstrate the effectiveness of Truvada [emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] in preventing HIV infection in the study population, even if it continued to its originally planned conclusion. FHI subsequently concurred and has therefore decided to initiate an orderly closure of the study over the next few months. The final analyses have not yet been conducted. At this time, it cannot be determined whether or not Truvada works to prevent HIV infection in women.
The FEM-PrEP clinical trial-implemented by FHI in partnership with research centers in Africa-is designed to study whether HIV-negative women who are at higher risk of being exposed to HIV can safely use a daily dose of a pill called Truvada to prevent infection. This study was funded by the United States Agency for International Development (USAID), with early funding from the Bill & Melinda Gates Foundation.
The FEM-PrEP outcome is surprising and disappointing, given a number of earlier studies suggesting the promise of pre-exposure prophylaxis (PrEP) using antiretrovirals. Most recently, the iPrEX study showed that use of Truvada can prevent infection in men who have sex with men at risk of HIV.
There are a number of possible reasons for the study findings, including low adherence to study regimen, a true lack of effect of the product among women (versus men who have sex with men), or other factors still to be determined. FHI will be conducting further analyses and will share additional findings in the coming months. The IDMC commended the trial team on a study conducted to a high standard with good follow-up and careful attention to good clinical practice and ethical standards.
Only preliminary FEM-PrEP data are available at this time:
* As of February 18, 2011, the study had screened 3,752 women and enrolled 1,951: 739 in Bondo, Kenya; 764 in Pretoria, South Africa; 432 in Bloemfontein, South Africa; and 16 in Arusha, Tanzania. The most common reason for women not being enrolled was existing HIV infection. The overall HIV prevalence was 21 percent among women screened for enrollment across the sites.
* Preliminary data indicate about 90 percent of the participants were retained in the study.
* Adherence to study product was approximately 95 percent when the study product was available for use.
* Women reported an average of 3.7 vaginal sex acts in the 7 days prior to enrollment, consistent with the average of 3.6 acts reported during follow-up.
* As of February 18, the approximate rate of new HIV infections among trial participants was 5 percent per year. A total of 56 new HIV infections had occurred, with an equal number of infections in those participants assigned to Truvada and those assigned to a placebo pill.
* Women participating in FEM-PrEP used an effective method of contraception at the time of enrollment-66 percent were using injectables and 30 percent were using oral contraceptives. The overall pregnancy rate was 9 percent; the highest pregnancy rates were among women using oral contraceptives.
* The use of Truvada in FEM-PrEP was associated with some known side effects that were not serious.
Among study participants randomly assigned to the Truvada arm, observed pregnancy rates were higher than among women randomly assigned to the placebo arm. This is unexpected and inconsistent with known drug interactions involving tenofovir (TDF) and contraceptive hormones, and with known metabolic effects of emtricitabine (FTC). Possible explanations include differential pill adherence by group, previously undefined drug-drug interactions, chance, or a combination of factors (including yet unknown factors). FHI will conduct further analyses of these data.
FHI and its partners are especially grateful to the women whose willingness to participate and commitment to the study were essential. To the extent possible, all participants have been notified of the decision and are being asked to come to the study clinics for final visits. Study participants who became infected with HIV during the study are being followed by the study team for an additional year and are referred for appropriate medical care and treatment in their community.
When the follow-up of the HIV-uninfected women is complete in a few months' time, FHI will be conducting in-depth analyses of study data and blood specimens collected during the study to examine the factors contributing to the observed outcomes. FHI will also collaborate with scientists conducting other PrEP studies to compare findings and to better understand the results.
When available, the final results from FEM-PrEP will make a strong contribution to our understanding of the use of antiretrovirals for HIV prevention. FHI, USAID, and research partners in Africa are committed to finding new technologies and developing new strategies to protect women from HIV.
About FEM-PrEP
FEM-PrEP is a randomized, placebo-controlled, clinical trial of the effectiveness of daily, oral Truvada for HIV prevention among HIV-uninfected women in Kenya, South Africa and Tanzania. Truvada combines two antiretroviral drugs-emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)-in a single pill that is taken once a day. Truvada has been proven safe and effective as a treatment for HIV-positive people. FEM-PrEP has a strong socio-behavioral and community engagement component. The study is funded by the U.S. Agency for International Development (USAID), and received early support from the Bill & Melinda Gates Foundation.
About FHI
FHI is a global health and development organization whose science-based programs bring lasting change to the world's most vulnerable people. Since 1971, FHI has worked with 1,400 partners in 125 countries, forging strong relationships with governments, diverse organizations, the private sector and communities. By applying science to healthcare programs and clinical research, FHI is helping countries make measurable progress against disease, poverty, and inequity-improving lives for millions.
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