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.orgExternal Web Site Icon.
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.orgExternal Web Site Icon) 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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TDF2 STUDY OF PRE-EXPOSURE PROPHYLAXIS (PrEP)AMONG HETEROSEXUAL MEN AND WOMEN IN BOTSWANA: KEY FACTS
Overview
• Daily oral PrEP with a tablet containing tenofovir disoproxil fumarate and emtricitabine (TDF/FTC, known by the brand name Truvada®) was found to reduce the risk of acquiring HIV infection by roughly 63 percent in the study population overall.
• In addition, researchers conducted a separate analysis to better understand the level of efficacy 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.
Trial Design and Study Population
• Overview: The TDF2 study examined use of a once-daily antiretroviral pill containing tenofovir disoproxil fumarate and emtricitabine (TDF/FTC, brand name Truvada®) as PrEP for HIV infection among young adult heterosexual men and women in Botswana at two sites in Gaborone and Francistown. The CDC study was conducted in partnership with the Botswana Ministry of Health. Additional funding was provided by the National Institutes of Health, and the study drug was donated by Gilead Sciences.
CDC researchers had anticipated that results from the TDF2 study would only include safety and adherence findings. However, because PrEP was highly effective in this population, the study was able to draw conclusions about overall efficacy, even with a relatively small number of infections occurring in the study population.
• Study Population: A total of 1,219 HIV-uninfected, sexually active, healthy male and female volunteers between the ages of 18-39 in Botswana were enrolled in the trial and randomly assigned to take a daily TDF/FTC pill or a placebo pill. Three participants were determined to be HIV-infected at time of enrollment, and sixteen of the participants randomized never began study medication. Those individuals were excluded from the efficacy analysis, which includes data on the 1,200 HIV-negative participants who were randomized and received study medication.
Participants were randomly assigned to one of two arms: 601 were assigned to take a daily TDF/FTC pill, and 599 were assigned to receive a placebo (overall in the study, 54.7 percent were male, 45.3 percent female). Neither researchers nor participants knew an individual’s group assignment.
• Informed Consent: To make sure that participants fully understood all aspects of their participation in the trial, all volunteers were required to pass a comprehension test prior to providing written informed consent. Study participants were free to withdraw from the trial at any time and for any reason.
• Prevention Services: To assist participants in eliminating or reducing HIV risk behaviors, extensive risk reduction counseling was provided at each study visit, and more often if needed. Participants were offered free male and female condoms and STD testing and treatment to reduce their risk for HIV infection. The health of participants was closely monitored throughout the trial, and participants were linked to any necessary medical care. All participants who became HIV-infected during the trial were immediately referred to care.
• Scientific and Ethical Review: To ensure that the study remained on a solid scientific and ethical foundation, all procedures and plans were reviewed and approved by scientific and ethical review committees at CDC (called institutional review boards, or IRBs) and the Botswana Ministry of Health (called the Health Research and Development Committee, or HRDC) prior to trial launch. Additionally, trial data were reviewed regularly by an independent data safety and monitoring board (DSMB) to ensure that continuing the trial was safe and scientifically appropriate. CDC worked closely with community partners at each research site to ensure active community participation throughout the course of the trial.
• Retention: While the study experienced challenges with retention in this highly mobile population of young Botswana adults, researchers were ultimately able to secure final data on HIV infection and safety for more than 90 percent of study participants (i.e. only 10 percent of the participants were completely lost to follow-up).
Study Results
Efficacy
• In the primary trial analysis of all 1,200 participants who began the trial, there were nine HIV infections among the 601 participants who received TDF/FTC, compared to 24 infections among the 599 assigned to receive placebo. This translates to a 62.6 percent (95% CI, 21.5 to 83.4; p= 0.0133) reduction in the risk of HIV infection among those receiving TDF/FTC.
• Among participants known to have a supply of study drugs , protection was even greater, with an efficacy of 77.9 percent (95% CI 41.2 to 93.6, p=0.0053). There were 4 infections in the TDF/FTC group, and 19 in the placebo group.
• Additional analyses of efficacy based on the level of adherence to the study regimen, as well analyses of the level of protection associated with measurable levels of TDF/FTC in the blood, are underway and will be published in the coming months.
• By gender, the CDC TDF2 data suggest efficacy for both men and women, but not all of these analyses reach statistical significance. This trial cannot alone draw conclusions for heterosexual men and women separately. These data will need to be considered in conjunction with data from other heterosexual trials. Preliminary results from the Partners PrEP trial found that daily PrEP was highly effective for both men and women (see http://www.uwicrc.org). Earlier this year, interim results from another PrEP trial (FEM-PrEP) did not demonstrate a protective effect among heterosexual women (see http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm).
The TDF2 results by gender were:
o Among all 1,200 participants who began the trial, the point estimates suggest efficacy for both men and women, but the results were only statistically significant for men:
• For women: There were 7 infections among women receiving TDF/FTC, and 14 infections among women receiving a placebo. This translates to an estimated risk reduction of 49.4 percent, but the finding is not statistically significant (95% CI -21.7 to 80.8; p=0.107).
• For men: There were 2 infections among men receiving TDF/FTC and 10 among those receiving placebo. This translates into a statistically significant HIV risk reduction of 80.1 percent (CI 24.6 to 96.9; p=0.026).
o Among participants known to have a supply of study drugs2, point estimates again suggest efficacy for both men and women, but the results only reach statistical significance for women:
• For women: There were 3 infections among women receiving TDF/FTC, and 13 infections among women receiving placebo. This translates into a statistically significant HIV risk reduction of 75.5 percent (CI 23.8 to 94.4; p=0.021).
• For men: Among men receiving TDF/FTC, there was only one infection, and 6 infections occurred among men receiving placebo. This translates into an estimated risk reduction of 82.4 percent, but the finding is not statistically significant (CI -2.8 to 99.1; p=0.065).
Adherence and Risk Behavior
• There were no significant differences in overall adherence (based on pill count) or reported sexual risk behavior between the two study arms. Analyses of trends in adherence and risk behavior over time are underway and will be published in the coming months.
o Adherence (as measured by pill count) was high, both among those receiving TDF/FTC and those receiving placebo (84.1 percent and 83.7 percent, respectively).
o Reported sexual risk behavior was similar between the two study arms:
• Roughly 14 percent of participants in both study arms reported more than one sexual partner in the prior month.
• The percent of reported vaginal sex episodes with condom use was also similar between the two groups (81.9 percent TDF/FTC vs. 79.7 percent placebo).
Safety and Resistance
• Consistent with other PrEP studies, preliminary analyses did not identify any significant safety concerns associated with daily use of TDF/FTC.
• The only difference between the two groups was an increase in minor side effects – nausea, vomiting, and dizziness – among participants assigned to receive TDF/FTC. Analyses are underway to determine if these effects alleviated over time.
• There was no difference in pregnancy rates between the two study arms.
• Consistent with the previous PrEP trial among MSM, there were no cases of drug resistance among participants taking TDF/FTC who became infected after enrollment.
• One case of TDF and FTC drug resistance occurred in a participant who had unrecognized HIV infection at the time of enrollment and several false negative HIV tests in the months following enrollment. This case underscores the need to ensure PrEP is only used among HIV-negative individuals. Further analyses are underway to examine potential reasons for the false negative test results. Those results will be published when available in the coming months. The participant was immediately referred to care once diagnosed and is currently responding well to HIV treatment.
Resources
• 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, visit http://www.avac.org/ht/a/GetDocumentAction/i/3113.
• For information on the available results of other heterosexual PrEP trials, visit:
o Partners PrEP: http://www.uwicrc.org
o FEM-PrEP: http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm
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