MTN: Microbicide Trials Network

Recognizing the development of microbicides as an important priority in HIV/AIDS research, 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 as its newest of six NIAID-funded HIV/AIDS clinical trials networks. The MTN brings together international investigators and community and industry partners who are devoted to reducing the sexual transmission of HIV through the development and evaluation of products applied topically or administered orally, working within a unique infrastructure specifically designed to facilitate research required to support licensure of these products for widespread use.

MTN is guided by an agenda that aims to complement rather than duplicate the research programs of its global research partners. It also seeks participation by and collaborations with representatives of diverse scientific disciplines related to HIV prevention, 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, 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. It includes studies considered among the most critically important for advancing the field of HIV prevention. Many of these trials are focused on assessing antiretroviral (ARV)-based microbicides and include studies designed to evaluate microbicides along with other promising HIV prevention approaches, such as the daily use of ARVs as pre-exposure prophylaxis (PrEP). MTN is the first research group that plans to evaluate in parallel a vaginal microbicide gel and PrEP in the same trial. Notably, the MTN is leading the first microbicide studies involving pregnant women and also conducting studies to evaluate the rectal safety of vaginal microbicides, an important step toward eventually developing a microbicide specifically formulated for rectal use.

Based at the University of Pittsburgh and Magee-Womens Research Institute in Pittsburgh, Pennsylvania, U.S., 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 Family Health International, a global organization with expertise conducting clinical protocols. In addition, MTN comprises 13 clinical trial units with 24 clinical research sites located in seven countries. MTN receives its funding from three NIH institutes: NIAID, the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The MTN is led by Sharon Hillier, Ph.D. [1], of the University of Pittsburgh School of Medicine and Magee-Womens Research Institute, who serves as its principal investigator. Co-principal investigators are Ian McGowan, M.D., Ph.D. [2], also of the University of Pittsburgh; and Connie Celum, M.D., M.P.H. [3], from the University of Washington, Seattle. The Network Laboratory principal investigator is Charlene Dezzutti, Ph.D. [4], of the University of Pittsburgh School of Medicine and Magee-Womens Research Institute, while the MTN Statistical and Data Management Center principal investigator is Benoit Masse, Ph.D. [5], from SCHARP. Principal investigator for Family Health International is Ward Cates, M.D. [6] 

The MTN structure is also supported by three working groups that provide scientific and community input for all MTN protocols, ensuring the research being carried out by the network is forward thinking, cutting edge and scientifically meaningful. The Biomedical Science Working Group provides input and innovative ideas for patient safety (e.g., biomarkers) and specimen collection, whereas the Behavioral Research Working Group provides expertise that informs studies of behavior before, during, and after microbicide use and on the collection of behavioral data. The Community Working Group engages the community advisory boards at each site to provide input on MTN protocols and to provide feedback concerning community experiences, best practices, and lessons learned.

MTN Clinical Trials

The MTN currently has 17 clinical trials in progress or in various stages of planning. Some of these studies are highlighted below:

• The VOICE Study – Vaginal and Oral Interventions to Control the Epidemic – is a major HIV prevention trial evaluating the safety and effectiveness of two different approaches for preventing sexual transmission of HIV in women as well as determining which of these women are more likely to follow: taking an ARV tablet once a day (PrEP) or applying an ARV-based vaginal microbicide daily. Also known as MTN-003, VOICE will enroll 5,000 sexually active HIV-negative women at sites in southern Africa and help answer critical questions key to advancing HIV prevention efforts, including questions about adherence and acceptability of oral and topical strategies in sub-Saharan African heterosexual women, a population that has long remained at the very center of the epidemic.

• MTN-002 is the first study of a candidate topical microbicide in pregnant women. The Phase I trial aimed to understand if and to what extent pregnancy affects how the body absorbs the active drug in the ARV-based candidate microbicide tenofovir gel and whether the drug can be transferred to the fetus. The study involved 16 pregnant women who received a single dose of tenofovir gel prior to scheduled caesarean delivery. Results are expected in late May at the 2010 International Microbicides Conference.

• MTN-015 is a long-term, observational study that seeks to understand the nature of HIV progression and treatment response in HIV-positive women who become infected incidental to their participation in an HIV prevention trial of either a topical microbicide or oral PrEP. The study will help better understand the impact of these agents on the natural history and clinical course of HIV. Importantly, MTN-015 will help address theoretical questions about HIV drug resistance in the context of ARV-based prevention.

• MTN-016 is a first-of-its-kind registry of women who become pregnant while participating in an HIV prevention trial of either a microbicide or an oral antiretroviral drug as well as women who participated in trials of pregnant women, such as MTN-002. The registry, which is in development, will help determine the effects, if any, that early exposure to these products may have on fetal and/or neonatal development.

• MTN-007 is a Phase I trial involving both men and women that will evaluate safety and acceptability of tenofovir topical gel when applied rectally. A related study, MTN-006, is looking at safety, acceptability and drug absorption of both tenofovir vaginal gel applied rectally and tenofovir tablets taken orally. MTN-006 is being conducted in collaboration with the NIH-funded University of California, Los Angeles Integrated Pre-clinical Clinical Program.

More information about these and other studies can be found in the Studies [7] and News Room [8] sections of this site.

MTN Research Sites

The MTN conducts its multi-center studies through 13 NIH-funded clinical trial units (CTUs) at 24 locations in India, Malawi, Uganda, South Africa, Zambia, Zimbabwe and the United States. The MTN has also worked with study sites in Tampa, Florida and San Juan, Puerto Rico, through a collaboration with the NICHD-funded Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN).  A complete list of MTN research sites can be found under Sites [9].

Safety

Every MTN study is 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, for several studies, 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.

Researchers do their best to reduce participants’ risk for acquiring HIV, which includes providing condoms and ongoing HIV prevention counseling. Still, some women may become infected during participation in a study. Women who become infected (or who test positive for HIV during eligibility screening) are counseled and referred by study staff to services at local facilities that provide medical care and treatment, including antiretroviral therapy, and psychological and social support. These services may be available within the same health care facility that houses the research site or at another health care provider.

Importantly, 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 obtain preliminary information about different products' 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.

Community

The MTN is guided by an agenda that fosters participation by and collaborations with representatives of diverse scientific disciplines related to HIV prevention, as well as from the lay communities in which MTN trials are being conducted. MTN’s community advisory boards (CABs) play an essential role, as do community and advocacy groups, in every stage of protocol development and implementation. The MTN established the Community Working Group, comprising one CAB member and one community educator from each site, to ensure the successful conduct of studies through community and researcher partnerships and the engagement and participation of the community at the site level.

As part of its effort to be more responsive to the needs and perspectives of local communities, the MTN also has adopted the Regional Physician Model, a successful component of the Bill & Melinda Gates Foundation-funded Partners in Prevention. The Regional Physician is MTN’s local ambassador in Africa, and provides support to clinical sites, helps address their concerns, and educates local providers and community groups about microbicide research, MTN-specific trials and safety measures designed to protect all trial participants.