Recognizing the critical need for safe and effective HIV prevention approaches, the National Institute of Allergy and Infectious Diseases (NIAID) established the Microbicide Trials Network (MTN) in 2006, with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health, all part of the U.S. National Institutes of Health (NIH). The MTN brings together international investigators and community and industry partners whose work is focused on the development and rigorous evaluation of promising microbicides – products applied inside the vagina or rectum that are intended to prevent the sexual transmission of HIV – from the earliest phases of clinical study to large-scale trials that support potential licensure of these products for widespread use. From the outset, the MTN has worked to meet the needs of key populations at risk of HIV, including women in sub-Saharan Africa, adolescents, pregnant and breastfeeding women and men who have sex with men (MSM). Different formulations are being evaluated, including vaginal and rectal microbicide gels and intravaginal rings.
MTN’s unique research portfolio integrates both biomedical and behavioral science in the design and implementation of studies that whether in the earliest phases of clinical investigation or a large-scale multi-center trial are meant to support potential licensure of products for different high-risk populations.
MTN Organization and Structure
The MTN is based 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. Its core operations are supported by a network laboratory at the University of Pittsburgh with Charlene Dezzutti, Ph.D. serving as Network Laboratory principal investigator; a statistical and data management center (SDMC) housed within the Statistical Center for HIV/AIDS Research & Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center under the direction of SDMC principal investigator Elizabeth Brown, Sc.D.; and FHI 360, a global organization with expertise conducting clinical protocols, which has as its MTN principal investigator 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 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, spanning nine countries across Africa, Asia and the Americas: Malawi, South Africa, Uganda, Zambia, Zimbabwe, India, Thailand, Peru and the United States, including Puerto Rico. Protocol teams are created for each MTN study and include investigators from clinical trial sites and representation from different specialty areas and disciplines as well as community members.
The MTN Scientific Agenda
MTN’s unique research portfolio integrates both biomedical and behavioral science in the design and implementation of scientifically rigorous and ethically sound clinical trials, looking at the safety, effectiveness, acceptability and adherence involving a range of different vaginal and rectal microbicide products. During the current funding period, 2006-2013, 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 11 studies, and 12 trials are ongoing or planned.
MTN studies include the only trials 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, a time when the risk of acquiring HIV from an infected partner is particularly high. Moreover, while the field generally has focused on products for preventing HIV through vaginal sex, the MTN has played a significant role in advancing a scientific agenda that recognizes the need for products to prevent HIV transmission through anal sex. The MTN continues to lead pioneering studies evaluating the safety of vaginal gels reformulated for rectal use, an important step toward eventually developing a rectal-specific product for both men and women who practice in anal sex.
Three flagship trials form the centerpiece of the MTN’s research agenda: the recently completed VOICE study (MTN-003); ASPIRE (MTN-020), which is ongoing; and MTN-017, expected to launch later in 2013.
VOICE – Vaginal and Oral Interventions to Control the Epidemic – a Phase IIb study tested that the safety and effectiveness of two different approaches among 5,029 women in Uganda, South Africa and Zimbabwe: daily use of an antiretroviral (ARV) tablet (tenofovir or Truvada®) or daily use of a vaginal gel (tenofovir gel). The study’s primary results, which were reported in March 2013, found none of the products effective; most participants did not use them daily as recommended. Young, unmarried women were least likely to use their assigned product and the most likely to acquire HIV, indicating an urgent need for safe, effective and practical HIV prevention methods women like those in VOICE will actually use. Results of two qualitative behavioral studies, VOICE C and VOICE D, which are expected in the coming months, should help to better understand the reasons why so many women did not use the products in VOICE.
ASPIRE – A Study to Prevent Infection with a Ring for Extended Use – a Phase III study that seeks to determine whether a vaginal ring containing the ARV drug dapivirine is a safe and effective method for protecting against the sexual transmission of HIV when used by women for a month at a time. The study, which was launched in August 2012, will enroll approximately 3,476 women at several sites in Africa and take approximately two years to conduct, with results anticipated late 2014 or early 2015. ASPIRE and The Ring Study, which is being conducted by the International Partnership for Microbicides (IPM), represent a major step forward in the evaluation of a promising female-controlled HIV prevention method that potentially could provide women with discreet, long-acting protection. The dapivirine ring is the first ARV-based product to enter efficacy testing that is intended for monthly use and the first involving an ARV other than tenofovir or a tenofovir combination. As the product developer and regulatory sponsor, IPM will seek regulatory approval for the dapivirine ring based on the results from a package of studies of which ASPIRE and The Ring Study are the centerpiece
In MTN-017, researchers plan to evaluate the rectal safety, drug absorption and acceptability of a reduced glycerin formulation of tenofovir gel, as well as oral Truvada, at sites in Peru, South Africa, Thailand and the U.S., including Puerto Rico. The study, which will enroll 186 men who have sex with men (MSM) and transgender women, is 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 are 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.
Most of the clinical trials being conducted by the MTN involve particularly high-risk populations. To reduce trial participants’ risk of acquiring HIV, MTN researchers provide 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 in the laboratory. These and other studies are designed to streamline product selection and move only the most effective and safest microbicides to testing in people. 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.
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More information about HIV can be found in the UNAIDS Report on the Global AIDS Epidemic 2012, the current U.S. Centers for Disease Control and Prevention HIV Surveillance Report, and Kaiser Family Foundation fact sheets on HIV/AIDS: http://www.kff.org/hivaids/factsheets.cfm. To learn more about the Microbicide Trials Network go to www.mtnstopshiv.org.