About the Microbicide Trials Network

The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID), with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), all components of the U.S. National Institutes of Health. 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 the research required to support licensure for these products for widespread use.

Based at the University of Pittsburgh and Magee-Womens Research Institute in Pittsburgh, Pennsylvania, USA, 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 at the Fred Hutchinson Cancer Research Center, and Family Health International, a global organization with expertise conducting clinical protocols.

The principal investigator of the MTN is Sharon Hillier, Ph.D., of the University of Pittsburgh School of Medicine and Magee-Womens Research Institute. Co-principal investigators are Ian McGowan, M.D., Ph.D., University of Pittsburgh School of Medicine; and Connie Celum, M.D., M.P.H., University of Washington, Seattle. Charlene Dezzutti, Ph.D., from the University of Pittsburgh School of Medicine and Magee-Womens Research Institute, is principal investigator of the network laboratory; while principal investigator for the statistical and data management center is Benoît Mâsse, Ph.D., from the Statistical Center for HIV/AIDS Research & Prevention at the Fred Hutchinson Cancer Research Center, Seattle, Washington. Principal investigator for Family Health International is Ward Cates, M.D.

MTN Clinical Trials

MTN plans to implement a broad spectrum of clinical trials in Africa, India and the United States between 2006 and 2013, including trials focused on assessing antiretroviral (ARV)-based microbicides, a newer class of candidate microbicides that differ from early types because they have specific action against HIV. In addition, because ARV-based microbicides are longer acting, their use may not be required before each act of sex, which is not always practical or desirable for some women. Many of MTN’s current and planned trials are breaking new ground. These pioneering studies include the first to evaluate microbicides along with other promising HIV prevention approaches, such as pre-exposure prophylaxis (PrEP), which involves taking an ARV pill every day; the first trial involving pregnant women; and among the first to evaluate the rectal safety and drug absorption of different products. Some of MTN’s studies are summarized below:

• The VOICE Study –Vaginal and Oral Interventions to Control the Epidemic – is a major HIV prevention trial that will evaluate the safety and effectiveness of two different approaches for preventing sexual transmission of HIV in women as well as determine which of these routines women are more apt to follow: an ARV pill once a day or the ARV-based vaginal microbicide tenofovir gel applied daily. Researchers will enroll 4,200 sexually active HIV-negative women at sites in Africa beginning early 2009. The study, also known as MTN-003, will 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 seeks 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 will involve 16 pregnant women who receive a single dose of tenofovir gel prior to scheduled caesarean delivery.

• 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 a 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.

• 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 or who participated in trial involving 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.

Also included in MTN’s research portfolio are two trials that prior to 2006 were led by NIAID’s HIV Prevention Trials Network (HPTN):

• HPTN 035 is a multi-center clinical trial that aims to determine the safety and effectiveness of two different candidate microbicides, BufferGel® and PRO 2000, in 3,100 sexually active HIV-negative women at seven sites in Malawi, South Africa, Zambia, Zimbabwe and the United States. Enrollment of the trial has been completed and results are due in 2009.

• HPTN 059 was the first study of a candidate microbicide looking at both daily use and use just prior to sex. In this Phase II (expanded safety) trial that assessed the safety and acceptability of tenofovir gel in 200 HIV-negative women, researchers found both approaches equally safe and women’s adherence to product use similar. Initial results were reported in February 2008 and a final analysis of study findings is in progress.

MTN Clinical Research Sites

The MTN conducts its multi-center studies through 13 NIH-funded clinical trial units (CTUs) at 18 locations in seven countries. CTUs based outside the United States are the National AIDS Research Institute in Pune, India; the South African Medical Research Council in Durban, South Africa (with four sites); Centre for the AIDS Programme of Research of South Africa (CAPRISA) in Durban, South Africa; and the University of Cape Town, South Africa.

Other international sites participate in MTN trials through collaborations with U.S.-based CTUs. These include two sites each in Zimbabwe (University of California, San Francisco) and Malawi (Johns Hopkins Bloomberg School of Public Health); and one site each in Uganda (Johns Hopkins School of Medicine) and Zambia (University of Alabama at Birmingham). The remaining U.S.-based CTUs are Case Western Reserve University in Cleveland; Columbia University in New York City, the University of Pittsburgh; the University of Pennsylvania, Philadelphia; and the University of Alabama at Birmingham, which is separate from its international site.

MTN also conducts studies at the University of South Florida in Tampa and the University of Puerto Rico in San Juan through a collaboration with the NICHD’s Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN).

Safety

Every MTN study is designed according to the most rigorous international medical practices and ethical standards, and includes every possible measure to protect the wellbeing of participants. A detailed informed consent process ensures that participants understand the procedures, risks and benefits of the 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 statistical and data management center (SDMC) that assesses incoming reports on a daily basis; two MTN physicians – one specializing in infectious diseases and HIV and the other 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 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.

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 (CAB) 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 the safety measures in place to protect all trial participants.

About Microbicides

Microbicides are substances that are designed to reduce or prevent the sexual transmission of HIV and other sexually transmitted infections when applied topically to the inside of the vagina or rectum. A microbicide could be produced in many forms, including gels, creams, suppositories, films, or as a sponge or ring that would release the active ingredient over time. Some microbicides are also being developed for rectal use. Several microbicide products are being tested in clinical trials, although none is yet approved or available for widespread use. If proven effective, microbicides could be an inexpensive and readily available approach for many women, especially women in developing countries who bear the brunt of the global epidemic.

According to statistics from the U.S. Centers for Disease Control and Prevention and UNAIDS:

• Nearly half, or 46 percent, of the 33.2 million people living with HIV/AIDS worldwide are women. In sub-Saharan Africa, women account for 61 percent of all infected adults.

• Young women are especially vulnerable, especially in sub-Saharan Africa, where it has been estimated that women aged 15 to 24 with HIV represent 76 percent of the total cases in that age group, outnumbering their male peers by three to one.

• In 2007, 2.1 million people died from AIDS and an estimated 2.5 million people became newly infected with HIV, including 420,000 under the age of 15. Every day, 6,800 people contract HIV.

• Between 70 and 90 percent of all HIV infections in women are due to heterosexual intercourse. Moreover, women are twice as likely as their male partners to acquire HIV during sex, due in part to biological factors that make women more vulnerable.

• Particularly in developing countries, educational efforts promoting abstinence, monogamy and condoms have not been completely effective.

For more information about MTN, go to www.mtnstopshiv.org.

# # #

5/30/08