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78% Prevention HIV-Infection...97% Adherence-Explains Success
 
 
  "In the Botswana study...a big reason his experiment showed promising results is that the subjects took their pills 97 percent of the time. (In the CDC study in Botswana, people took them 84 percent of the time)...FEM-PrEP failed to show protection because its participants simply skipped too many doses..."I think adherence is the biggest driver of the difference between our study and theirs," Jared Baeten says....Adherence-the ability to take PrEP as prescribed by the trial protocol-is a critical component of efficacy. Initial findings from the Partners PrEP study showed high reported adherence for the once-daily regimen. It will be important to learn why and how adherence was high in this study and what lessons can be learned for eventual rollout of PrEP. At the same time, research into intermittent dosing (e.g., weekly, semi-weekly or around the time of sex), which may be easier from some people to adhere to, is needed. Moreover, additional research is still urgently needed for other methods where adherence is less important, such as vaginal rings with monthly release, periodic injectable forms of ARVs and vaccines."

"This study demonstrates that antiretrovirals are a highly potent and fundamental cornerstone for HIV prevention and should become an integral part of global efforts for HIV prevention," said Connie Celum.

"HIV serodiscordant couples, where one partner has HIV and the other does not have HIV infection, are in urgent need of prevention strategies. In sub-Saharan Africa, a substantial fraction of new HIV infections occur among HIV serodiscordant couples. The Partners PrEP Study is the first to show that PrEP reduces HIV risk in heterosexual men and women; the results are critically important for Africa, where the majority of new HIV infections occur. Over the past year, studies of PrEP have suggested great promise for this emerging HIV prevention strategy, and important studies of TDF, FTC/TDF, and a vaginal microbicide gel containing tenofovir are ongoing. Results from the full panel of completed and ongoing studies of PrEP will together provide key information about the ultimate prevention benefits of PrEP in different populations."

"The CDC study findings were scheduled to be released next week at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (www.ias2011.org) in Rome by the CDC principal investigator Michael C. Thigpen, M.D. However, due to the unexpected release of the Partners PrEP data today, CDC is releasing the TDF2 results now, to ensure that all emerging trial data are concurrently available to fully inform public health and policy discussions moving forward. The results will still be presented and discussed at the IAS 2011 conference on Wednesday, July 20."

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CDC Press Release

CDC Trial and Another Major Study Find PrEP Can Reduce Risk of HIV Infection among Heterosexuals

CDC Assessing Data from All Heterosexual Trials to Develop Interim Guidance for Use


A new CDC study called the TDF2 study, along with a separate trial released today, provide the first evidence that a daily oral dose of antiretroviral drugs used to treat HIV infection can reduce HIV acquisition among uninfected individuals exposed to the virus through heterosexual sex.

The CDC TDF2 study, conducted in partnership with the Botswana Ministry of Health, found that a once-daily tablet containing tenofovir disoproxil fumarate and emtricitabine (TDF/FTC, known by the brand name Truvada) reduced the risk of acquiring HIV infection by roughly 63 percent overall in the study population of uninfected heterosexual men and women. The strategy of providing daily oral antiretroviral drugs to uninfected individuals prior to HIV exposure is called pre-exposure prophylaxis, or PrEP.

In a separate announcement, the University of Washington (UW) released preliminary results of the Partners PrEP study, which also found that daily PrEP reduced HIV transmission among heterosexual couples in Kenya and Uganda. CDC co-managed two of the nine sites for this study. The Partners PrEP study found that two separate antiretroviral regimens - tenofovir (known by the brand name Viread) and TDF/FTC - significantly reduced HIV transmission among serodiscordant couples, in which one partner is infected with HIV and the other is not. The findings were released after the trial's independent data safety monitoring board conducted an interim review of the trial data and recommended that the study be stopped early due to strong evidence of effectiveness. For more information on this study, visit http://www.uwicrc.org.

The CDC study findings were scheduled to be released next week at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (www.ias2011.org) in Rome by the CDC principal investigator Michael C. Thigpen, M.D. However, due to the unexpected release of the Partners PrEP data today, CDC is releasing the TDF2 results now, to ensure that all emerging trial data are concurrently available to fully inform public health and policy discussions moving forward. The results will still be presented and discussed at the IAS 2011 conference on Wednesday, July 20.

"These are exciting results for global HIV prevention. We now have findings from two studies showing that PrEP can work for heterosexuals, the population hardest hit by HIV worldwide," said Kevin Fenton, M.D., director of CDC's National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. "Taken together, these studies provide strong evidence of the power of this prevention strategy."

A previous study (iPrEx) had already shown PrEP reduced HIV transmission among men who have sex with men (MSM) last fall, but it was not previously known if the strategy could prevent HIV infection among heterosexuals.

The CDC and UW study results follow preliminary findings from another PrEP study earlier this year, the FEM-PrEP trial, which did not demonstrate a protective effect of PrEP among heterosexual women. Researchers from that study are conducting additional analyses, including a close examination of adherence among women in the trial, to better understand the potential reasons for the interim outcome of that study.

More Information on CDC TDF2 Study and Results

In addition to finding PrEP reduced the risk of HIV infection by roughly 63 percent in the study population overall, researchers from CDC's TDF2 study also conducted a separate analysis to better understand the level of effectiveness among trial participants believed to be taking study medications. This analysis excludes any HIV infections that occurred more than 30 days after a participant's last reported drug dose, because those individuals could not have been taking study pills at the time of infection. These results indicate that TDF/FTC reduced the risk of HIV infection by 78 percent.

Overall, a total of 1,219 HIV-uninfected heterosexual male and female participants (aged 18-39) in Botswana were enrolled in the TDF2 trial and randomly assigned to take a daily TDF/FTC pill or a placebo pill. All participants in the study were provided comprehensive HIV prevention services, including male and female condoms, intensive risk-reduction behavioral counseling, and testing and treatment for sexually transmitted infections. Three participants were determined to be HIV-infected at the time of enrollment, and 16 of the participants randomized never began study medication. Those individuals were excluded from these analyses, which include data on the remaining 1,200 participants who were HIV-negative at the time of enrollment and began study medication (54.7 percent male, 45.3 percent female).

In the primary analysis, among the 601 participants who received TDF/FTC, there were nine who became infected with HIV during the study. Among the 599 individuals who received a placebo, 24 became infected with HIV during the study. This translates into a statistically significant overall reduction in risk of 62.6 percent.

Among participants known to have a supply of study drugs (the separate analysis described above), protection was even greater, with a statistically significant risk reduction of 77.9 percent. Additional analyses of the level of effectiveness based on the level of adherence to the study regimen, as well as an examination of the level of protection provided by detectable drugs in the blood, are under way but are not yet complete.

Consistent with other PrEP studies, preliminary analyses did not identify any significant safety concerns associated with daily use of TDF/FTC. Participants assigned to receive the study drug were more likely than those assigned to the placebo arm to report nausea, vomiting, and dizziness.

All participants infected during the study were immediately referred to medical care. All uninfected participants will be offered the study drug for a year as part of a CDC follow-up study.

CDC officials note that the trial would not have been possible without the dedication of the more than 1,200 participants and the strong collaboration between the Botswana Ministry of Health and CDC. Additional study funding was also provided by the National Institutes of Health, and Gilead Sciences, based in Foster City, Calif., donated the study drug.

"Given the severity of the HIV epidemic among heterosexual men and women globally - and the critical need for female-controlled prevention methods - this study provides exciting and welcome news," said Jonathan Mermin, M.D., director of CDC's Division of HIV/AIDS Prevention. "The next important step is to fully review the data and assess when and how PrEP should best be used for HIV prevention among heterosexuals."

TDF/FTC is FDA-approved and marketed for use in the United States under the name Truvada, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. It is not FDA-approved for PrEP.

Next steps

In the wake of today's announcements, CDC will fully review the data from all of the heterosexual trials and will begin working with a range of stakeholders and with established guidelines development working groups to develop guidance specific to the use of PrEP among heterosexual men and women in the United States.

CDC urges heterosexual men and women and their health care providers in the United States to await that guidance before considering PrEP. However, if providers have patients for whom they believe the initiation of PrEP is urgent, CDC recommends following the cautions and procedures previously published for PrEP use in MSM (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6003a1.htm?s_cid=mm6003a1_w). The Partners PrEP finding that TDF alone was as effective as TDF/FTC in studies for prevention of heterosexual transmission suggests that providers may consider daily doses of either regimen in this population. However, for MSM, the interim guidance remains that only TDF/FTC should be prescribed, because there are no data on effectiveness for TDF alone to prevent HIV acquisition by MSM.

It will also be critical for providers to consider factors unique to heterosexuals, including concerns related to the use of PrEP among women who may become pregnant.

Importantly, anyone considering using PrEP should know:

· PrEP should only be used among individuals who have been confirmed to be HIV-negative. Initial and regular HIV testing is critical for anyone considering using PrEP. All individuals considering PrEP must also be evaluated for other health conditions that may impact PrEP use.

· PrEP should never be seen as the first line of defense against HIV. It was only shown to be effective in clinical trials when provided in combination with regular HIV testing, condoms, and other proven prevention methods.

· Taking PrEP daily is critical. No other dosing regimen was evaluated in these studies.

· PrEP must be obtained and used in close collaboration with health care providers to ensure regular HIV testing, risk reduction and adherence counseling, and careful safety monitoring. Anyone considering using PrEP should speak with his or her doctor.

· PrEP has only been shown in clinical trials to reduce HIV infection among heterosexual men and women and among men who have sex with men. At this time, there are no data on its benefits or risks among injection drug users.

· Because pregnant and breastfeeding women were excluded from participation in PrEP trials, further evaluation of available data will be needed before any recommendations can be made regarding the use of PrEP for women during conception, pregnancy, or breastfeeding.

For more information on efforts to evaluate and plan for PrEP implementation in the United States, visit www.cdc.gov/hiv/prep.

For a complete list of PrEP trials being conducted, see http://www.avac.org/ht/a/GetDocumentAction/i/3113.

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University of Washington

Partners PrEP Study

EMBARGOED UNTIL RELEASE Wednesday July 13, 2011, 2:00 a.m. Pacific Daylight Time

PIVOTAL STUDY FINDS THAT HIV MEDICATIONS ARE HIGHLY EFFECTIVE AS PROPHYLAXIS AGAINST HIV INFECTION IN MEN AND WOMEN IN AFRICA

Seattle, WA - In a result that will fundamentally change approaches to HIV prevention in Africa, an international study has demonstrated that individuals at high risk for HIV infection who took a daily tablet containing an HIV medication - either the antiretroviral medication tenofovir or tenofovir in combination with emtricitabine - experienced significantly fewer HIV infections than those who received a placebo pill. These findings are clear evidence that this new HIV prevention strategy, called pre-exposure prophylaxis (or PrEP), substantially reduces HIV infection risk.

The study is led by the University of Washington's International Clinical Research Center and involves 4,758 HIV serodiscordant couples, in which one partner has HIV and the other does not, from nine research sites in Kenya and Uganda. "This study is the largest study to date looking at the effectiveness of PrEP," said Dr. Connie Celum, a UW professor of global health and medicine and the principal investigator of the study, known as the Partners PrEP Study. The study is funded by the Bill & Melinda Gates Foundation.

"This study demonstrates that antiretrovirals are a highly potent and fundamental cornerstone for HIV prevention and should become an integral part of global efforts for HIV prevention," said Celum.

Study results through May 31, 2011 were reviewed on July 10, 2011 by the Partners PrEP Study Data and Safety Monitoring Board (DSMB), an independent group of experts that monitored the study's conduct, safety, and effect of PrEP on preventing HIV infections on an ongoing basis. Due to the strong HIV prevention effect seen, the DSMB recommended that the Partners PrEP Study results be made public and the placebo arm of the study be discontinued. The DSMB also recommended that the study continue: those receiving tenofovir (TDF) and tenofovir combined with emtricitabine (FTC/TDF) PrEP will remain on those medications and those receiving placebo will start receiving TDF or FTC/TDF PrEP.

Through May 31, 2011, a total of 78 HIV infections occurred in the study: 18 among those assigned TDF, 13 among those assigned to FTC/TDF, and 47 among those assigned placebo. Thus, those who received TDF had an average of 62% fewer HIV infections (95% CI 34 to 78%, p=0.0003) and those who received FTC/TDF had 73% fewer HIV infections (95% CI 49 to 85%, p<0.0001) than those who received placebo.

"This is an extremely exciting finding for the field of HIV prevention. Now, more than ever, the priority for HIV prevention research must be on how to deliver successful prevention strategies, like PrEP, to populations in greatest need," said Dr. Jared Baeten, co-chair of the study and a

more --UW associate professor of global health and medicine. "We are incredibly grateful to the investigators, site teams, participants, and communities for their dedication to this research and to HIV prevention. The level of investment and motivation from each of these groups was tremendous."

TDF and FTC/TDF were statistically similar in their levels of protection against HIV and reduced HIV risk in both women and men. Importantly, PrEP was found to be safe: the rate of serious medical events was similar for those assigned to TDF, FTC/TDF, and placebo. Ten percent of women annually became pregnant during the study and they were discontinued from the study medication during pregnancy; pregnancy rates were similar across the three arms and there was no evidence that TDF or FTC/TDF was associated with pregnancy complications.

The study was designed to find out whether TDF or FTC/TDF would reduce the risk of acquiring HIV for persons who had an HIV infected sexual partner. Of the 4,758 couples enrolled in the study, one-third of the HIV uninfected partners were randomly allocated to receive TDF, one- third FTC/TDF, and one-third a matching placebo. The study was double-blinded, meaning that both study participants and the researchers who interacted with them did not know which treatment the participants were receiving. All study participants received a comprehensive package of HIV prevention services, which included intensive safer sex counseling (both individually and as a couple), HIV testing, free condoms, testing and treatment for sexually transmitted infections, and monitoring and care for HIV infection.

In the study, adherence to the daily PrEP medication was very high - more than 97% of dispensed doses of the study medications were taken. More than 95% of participants were retained in study follow-up.

The medications used in the Partners PrEP Study, TDF (300 mg) and combination FTC (200 mg) / TDF (300 mg), are marketed by Gilead Sciences, Inc. under the brand names Viread® and Truvada®. They are available generically in many countries at prices as low as approximately 25 cents (U.S.) per tablet. Gilead Sciences donated study medication for, but did not provide funding or otherwise participate in the design, implementation, or analysis of the Partners PrEP Study.

HIV serodiscordant couples, where one partner has HIV and the other does not have HIV infection, are in urgent need of prevention strategies. In sub-Saharan Africa, a substantial fraction of new HIV infections occur among HIV serodiscordant couples. The Partners PrEP Study is the first to show that PrEP reduces HIV risk in heterosexual men and women; the results are critically important for Africa, where the majority of new HIV infections occur. Over the past year, studies of PrEP have suggested great promise for this emerging HIV prevention strategy, and important studies of TDF, FTC/TDF, and a vaginal microbicide gel containing tenofovir are ongoing. Results from the full panel of completed and ongoing studies of PrEP will together provide key information about the ultimate prevention benefits of PrEP in different populations.

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Partners PrEP and TDF2 pre-exposure prophylaxis trials both demonstrate effectiveness in preventing HIV infection among heterosexuals

FHI 360 congratulates the Partners PrEP and TDF2 teams while continuing to analyze FEM-PrEP results

RESEARCH TRIANGLE PARK, NC, JULY 13, 2011-
Results announced today by the two clinical trial teams, Partners PrEP and TDF2, provide the first evidence that HIV infection among heterosexuals can be prevented by taking an oral, once-daily tablet. Pre-exposure prophylaxis (PrEP) is an HIV-prevention strategy in which HIV-negative people take an antiretroviral drug, commonly used to treat HIV, on a daily basis to reduce their risk of acquiring HIV.

Researchers at the University of Washington announced today that its Partners PrEP trial demonstrated effectiveness in preventing heterosexual HIV transmission among men and women in Kenya and Uganda. In a second announcement today, the U.S. Centers for Disease Control and Prevention (CDC) revealed that its TDF2 trial also demonstrated effectiveness in preventing heterosexual HIV transmission among men and women in Botswana.

FHI 360 congratulates the Partners PrEP and TDF2 teams and study volunteers for their landmark contributions to HIV prevention research.

The Partners PrEP Trial

Partners PrEP trial participants were HIV-discordant, heterosexual couples where one person was HIV-infected and the partner was HIV-negative. In some couples, the man was HIV-infected, while in some the woman was HIV-infected. The trial had three arms; the HIV-negative person was randomized to either a placebo, a daily, oral dose of tenofovir disoproxil fumarate (TDF, 300 mg; Viread®) or a daily, oral dose of Truvada®, which contains a combination of the antiretroviral drugs TDF (300 mg) and emtricitabine (FTC, 200 mg) in a single pill. TDF and TDF/FTC have been proven safe and effective as a treatment by preventing HIV from reproducing itself in individuals who are already infected with the virus. The study findings indicate that both TDF alone and TDF/FTC were effective in preventing HIV infection and that both men and women were protected.

The TDF2 Trial

In TDF2, study participants were given either a placebo or a daily, oral dose of Truvada, one of the same drugs used in the Partners PrEP trial. Overall, Truvada was found to be effective at preventing HIV infection in the TDF2 study population. The size of the TDF2 trial was not large enough, however, to determine conclusively the levels of HIV protection afforded to men and women separately.

These two results provide exciting and strong evidence that a strategy including daily, oral PrEP can prevent HIV infections in persons at risk of heterosexual infection. PrEP with Truvada was already proven effective among men who have sex with men in the iPrEx trial reported in late 2010.

The FEM-PrEP Trial

FHI 360 is closing its PrEP trial, FEM-PrEP, which is a Phase III, randomized, placebo-controlled clinical trial designed to assess the safety and effectiveness of a daily oral dose of Truvada (TDF/FTC) for HIV prevention among women in sub-Saharan Africa.

Following a scheduled interim review of the FEM-PrEP study data in April 2011, the trial's Independent Data Monitoring Committee (IDMC) advised that the FEM-PrEP study will be highly unlikely to demonstrate Truvada's effectiveness in preventing HIV infection in the study population, even if it continued to its originally planned conclusion. FHI subsequently concurred and initiated an orderly closure of the study over the subsequent few months.

Screening and enrollment stopped on April 18, 2011, a total of 4,054 women had been screened for the FEM-PrEP trial, and 2,119 had been enrolled. As of May 25, 2011, 602 had completed their follow-up and study exit visits. As of that date, there were a total of 66 incident HIV infections, still balanced between the two arms-those assigned to Truvada and those assigned to placebo. The total number of HIV infections will likely increase between now and the end of the study.

We previously reported that as of February 18, 2011, a total of 56 new HIV infections had occurred; an equal number of infections occurred in participants assigned to Truvada and those assigned to a placebo pill. In addition, observed pregnancy rates among study participants randomly assigned to the Truvada arm were higher than among the women randomly assigned to the placebo arm. This is unexpected and inconsistent with known drug interactions involving tenofovir and contraceptive hormones and with known metabolic effects of emtricitabine. The use of Truvada was associated with some known side effects, none of which were considered serious.

Possible Explanations for Preliminary FEM-PrEP Findings; Continued FEM-PrEP Analyses

Possible explanations for the preliminary HIV infection outcome of the trial include low adherence to the study pill, study pill sharing between the participants in the Truvada and placebo groups, biological factors, chance or a combination of factors. FHI 360 is conducting additional analyses to help understand the potential reasons for the interim findings. These analyses include a close examination of adherence through several mechanisms among women in the trial, including an assessment of antiretroviral drug levels in the blood, in-depth-interviews, pill counts and monthly structured interviews. Also, HIV strains from women who became infected during the trial are being examined for evidence of antiretroviral drug resistance.

Next Steps

Closing of the FEM-PrEP trial was initiated in April 2011 and is expected to be complete for the HIV-negative participants by August 2011. Follow up of women who became HIV-infected during the trial will continue for another year as per protocol.

As the trial is still ongoing, data analyses from FEM-PrEP are not yet complete. Ongoing data cleaning will be completed by the end of October 2011. Confirmation of all HIV infections, resistance testing and tenofovir and emtricitabine drug level testing will be conducted during August-December 2011, contingent upon receipt of the necessary approvals in each country for export of specimens. The primary statistical analysis will be conducted in November 2011. Publication of the main findings, along with dissemination of final results to site communities, is expected between late 2011 and early 2012. Secondary analyses and associated paper writing will occur in late 2011 and 2012. Follow-up of participants who seroconverted during the trial will be completed in August 2012, per protocol.

Comparison with Partners PrEP and TDF2

In light of the Partners PrEP and TDF2 results, there is a need to explore why FEM-PrEP and the other trials had different findings. In addition to possible differences in adherence to the study pills, it is possible that there may have been important differences in the study populations related to sexual activity, other sexually transmitted infections or levels of inflammation that can affect HIV susceptibility. FHI 360 will be working with scientists from the University of Washington and CDC to compare data from the three studies to better understand differences and similarities.

Continued Hope

The HIV epidemic continues to ravage many communities in the world. While we work to understand better why the outcome differed among participants in the Partners PrEP and TDF2 trials vs. the FEM-PrEP trial, the results of both Partners PrEP and TDF2 provide evidence that PrEP can play an important role in HIV prevention among heterosexuals.

 
 
 
 
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