Recognizing the importance of microbicides research to HIV/AIDS prevention, the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), established the Microbicide Trials Network (MTN) in 2006, with co-funding from the NIH’s National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The MTN brings together international investigators and community and industry partners devoted to reducing the sexual transmission of HIV through the development and evaluation of products used orally or applied topically. MTN-affiliated researchers and partners work within a unique infrastructure specifically designed to facilitate the research required to support licensure of these products for widespread use.
The MTN is based in the U.S. at the University of Pittsburgh and Magee-Womens Research Institute and led by co-principal investigators Sharon Hillier, Ph.D., and Ian McGowan, M.D., Ph.D. MTN’s core operations are supported by a network laboratory at the University of Pittsburgh; a statistical and data management center housed within the Statistical Center for HIV/AIDS Research & Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center; and FHI 360, a global organization with expertise conducting clinical protocols. Charlene Dezzutti, Ph.D. is the principal investigator of the MTN Network Laboratory, while the MTN Statistical and Data Management Center principal investigator is Elizabeth Brown, Sc.D., from SCHARP. Principal investigator for FHI 360 is Ward Cates, M.D.
The MTN relies on three working groups to ensure scientific quality and community perspectives are the hallmarks of every MTN study. The Biomedical Science Working Group provides input and innovative ideas to enhance understanding or monitoring of patient safety (e.g., biomarkers) and specimen collection. The Behavioral Research Working Group provides expertise and perspective in the design of studies to better understand and address the complex interplay between human behavior and HIV risk and HIV prevention. The Community Working Group (CWG) ensures the successful conduct of studies through community and researcher partnerships and engagement and participation of the community at the site level. Specifically, the CWG engages community advisory boards at each site to provide input on MTN protocols and feedback concerning community experiences, best practices and lessons learned.
More than 25 clinical research sites are affiliated with the MTN. Trial sites currently are located in seven countries – Malawi, South Africa, Uganda, Zambia, Zimbabwe, India and the United States, with MTN-affiliated sites being added in Peru and Thailand.
Protocol teams are created for each MTN study and include investigators from clinical trial sites and representation from different specialty areas and disciplines. Protocol team members are held to the highest scientific and ethical standards in both designing and implementing MTN clinical trials.
The MTN Scientific Agenda
The MTN is guided by an agenda that aims to complement rather than duplicate the research programs of its global research partners. It also seeks collaborations with representatives of diverse scientific disciplines, as well as from the lay communities in which MTN trials are being conducted. Whether serving as a leader or a participant in the global effort, the MTN strives to make scientifically meaningful contributions that will enable progress toward its ultimate goal: A world without HIV/AIDS.
MTN’s research portfolio is designed to face the global urgency of the HIV/AIDS epidemic head-on by evaluating the safety and effectiveness of promising products for prevention of HIV. During the current funding period, 2006 to 2013, the MTN will have implemented a broad spectrum of clinical trials, including studies considered among the most critically important for advancing the field of HIV prevention. To date, MTN researchers have completed nine studies, and 20 trials are ongoing or planned. Emphasis has been on the evaluation of antiretroviral (ARV)-based prevention strategies, looking at whether some of the same ARVs commonly used to treat HIV can also be used for prevention, as either a vaginal microbicide or an oral tablet, an approach called pre-exposure prophylaxis (PrEP).
As MTN’s flagship study, VOICE – Vaginal and Oral Interventions to Control the Epidemic is a major HIV prevention trial designed to evaluate the safety and effectiveness of two different antiretroviral (ARV)-based approaches for preventing sexual transmission of HIV in women: daily use of an ARV tablet (tenofovir or Truvada) and daily use of an ARV-based vaginal gel (tenofovir gel). The study began in September 2009 and enrolled 5,029 women in Uganda, South Africa and Zimbabwe. Researchers stopped testing tenofovir tablets following an independent review of study data that took place in September 2011 determined that although the tablets were safe they were no more effective than placebo in preventing HIV. A November 2011 routine review drew the same conclusions about tenofovir gel, finding it safe but not effective among the women in the study. VOICE continues to evaluate Truvada. Final results, due in early 2013, will determine whether its daily use is safe and effective in preventing HIV in the women who remain in the study as well as help to understand why the tenofovir tablets and tenofovir gel were not.
In addition to microbicides in the form of a gel, the MTN is exploring other types of formulations, including vaginal rings. The MTN will be conducting the first Phase III trial of a vaginal ring containing the ARV dapivirine. ASPIRE – A Study to Prevent Infection with a Ring for Extended Use – is the first Phase III trial of a vaginal ring for HIV prevention and the first study powered to evaluate the effectiveness of a long-acting product intended for extended use. It is also the first Phase III trial of an ARV-based HIV prevention product using an ARV other than tenofovir or tenofovir combined with the ARV emtricitabine (Truvada). Unlike a vaginal gel that must be used every day or at the time of sex, rings under study are inserted monthly and release the active ingredient slowly over time so that feasibly a woman would have long-lasting protection against HIV. ASPIRE is expected to begin enrolling women mid-2012.
MTN researchers are conducting the only studies involving the use of HIV prevention products during pregnancy and breastfeeding to understand their safety in both women and their babies. These studies are critical because women need a product that will be safe and effective to use in all stages of life, including during pregnancy, when the risk of acquiring HIV from an infected partner is particularly high. Because women often continue to use medications when they are pregnant or breastfeeding, knowing whether microbicides are safe to use in this population before they become readily available also is vitally important.
Although the majority of microbicide research has focused on products to prevent HIV during vaginal sex, anal sex is common among men who have sex with men, and practiced by women around the world. According to some estimates, the risk of becoming infected with HIV during unprotected anal sex is 20 times greater than through vaginal sex. The MTN is making significant contributions in the area of rectal microbicide research, leading studies that are important steps toward eventually developing a microbicide to protect against HIV that is transmitted through receptive anal sex. In a study called MTN-017, researchers plan to evaluate the safety and acceptability of a rectal formulation of tenofovir gel at sites in Peru, South Africa, Thailand and the U.S. The study, which will involve men who have sex with men and transgendered women, will be the first Phase II trial of a rectal microbicide.
All MTN studies are designed according to the most rigorous international scientific and ethical standards and with utmost concern for participant safety and well-being. A detailed informed consent process ensures that participants understand the procedures, risks and benefits of any study, and that they were not obliged to participate and may leave the study, without consequence, at any time. During the trial’s conduct, strict national and international procedures for monitoring and reporting are followed, including regular reviews by a Protocol Safety Review Team and/or an independent Data and Safety Monitoring Board. A multi-tiered safety review process involves clinicians evaluating participants at the trial sites; a team at the MTN statistical and data management center (SDMC) that assesses incoming reports on a daily basis; three MTN physicians – two specializing in infectious diseases and HIV and one in obstetrics and gynecology – who review summary reports and any concerns raised by site clinicians or the SDMC; and monthly reviews by a protocol safety review team.
Particularly in sub-Saharan Africa, where both the VOICE and ASPIRE studies are being conducted, a woman’s risk for acquiring HIV through sexual intercourse is greater than in any other part of the world. To reduce the risk of HIV for both the women and men participating in its trials, MTN researchers provide trial participants free condoms, frequent HIV testing and HIV risk-reduction counseling, including on the use of condoms, and routine testing and treatment for sexually transmitted diseases (STIs). Despite these intensive, ongoing efforts, a research participant could acquire HIV if she or she has unprotected sex with a partner who is infected with the virus. Participants who become infected are taken off study product immediately and counseled and referred by study staff to local HIV care and support services. Providers and programs to which participants are referred offer psychosocial services and medical care, including antiretroviral therapy.
MTN researchers believe significant attention to safety should be paid even before a trial begins. Using a unique tissue explant model that very closely mimics how HIV infects cells of the cervix or rectum, researchers are able to test different products for their safety and effectiveness. These and other studies are designed to streamline product selection and move only the most effective and safest microbicides to testing in humans. In addition, researchers are looking at whether findings in the lab can be validated with clinical findings of early-phase clinical trials, which could help accelerate the research and development of better microbicides.