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 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health, all 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. Whether a small Phase I study testing a product’s safety and acceptability or a large-scale Phase III trial evaluating its effectiveness, every MTN trial is designed to collect the kind of data regulatory agencies require for determining whether to approve a product for widespread use. Because the effectiveness of a product is also dependent on its use, behavioral and social science is embedded within each study to gain understanding of the needs and desires of different high-risk groups. MTN’s research agenda includes populations considered among those at highest risk, including women in Sub-Saharan Africa, adolescents, pregnant and breastfeeding women, transgender women and men who have sex with men (MSM). More than 25 clinical research sites on four continents partner with the MTN in the conduct of its clinical trials.
By the end of 2013, when its first funding period had come to a close, the MTN had completed 13 trials, including VOICE, a major effectiveness study involving more than 5,000 women; and 11 more trials were planned or in progress, including MTN’s current flagship studies, ASPIRE and MTN-017. With its funding renewed for another seven years, the MTN will see these studies to their completion as well as look to evaluate different formulations of rectal microbicides, new classes of antiretroviral (ARV) drugs formulated as either vaginal or rectal products – or that can be used as both, and vaginal rings with the dual purpose of preventing both HIV and unwanted pregnancy.
MTN Organization and Structure
The MTN is led by Sharon Hillier, Ph.D., of the University of Pittsburgh and Magee-Womens Research Institute (MWRI). The MTN is comprised of a Leadership and Operations Center, a Laboratory Center (LC) and a Statistical and Data Management Center (SDMC). Dr. Hillier directs the activities of the LOC. Charlene Dezzutti, Ph.D., serves as principal investigator of the LC, also based at the University of Pittsburgh and MWRI, while the SDMC, which is housed within the Statistical Center for HIV/AIDS Research & Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center, is under the direction of SDMC principal investigator Elizabeth Brown, Sc.D.
The MTN relies on three working groups to ensure scientific quality, innovation and community perspectives are the hallmarks of every MTN study. The Biomedical Science Working Group brings new ideas and innovative methods into the design of protocols to allow for greater insight in the areas of immunology, microbiology and virology and deeper understanding of clinical trial results overall. The Behavioral Research Working Group provides expertise and perspective in the design of studies to both understand and characterize how an individual’s social context, sexual behaviors, perceptions of risk, and other factors may influence whether or not a product is used. The Community Working Group (CWG) facilitates community engagement and advocates for inclusion of community perspectives throughout all stages of the research process, from concept development to study implementation and results dissemination.
MTN’s Unique Contributions
VOICE: Trial results sound loud and clear
VOICE – Vaginal and Oral Interventions to Control the Epidemic – was a Phase IIB trial conducted between 2009 and 2012 that tested the safety and effectiveness of two different approaches for preventing the sexual transmission of HIV among 5,029 women in South Africa, Uganda and Zimbabwe: daily use of an ARV tablet (tenofovir or Truvada®) or daily use of a vaginal gel (tenofovir gel). The study’s primary results, presented in 2013, found none of the products was effective. Although most participants reported regular use of their assigned product during the study, an analysis of blood samples at the end of the trial indicated that only 25 percent actually had. Young, unmarried women were least likely to use the study products and the most likely to acquire HIV, a revelation that speaks to the urgent need for safe, effective and practical HIV prevention methods that this most vulnerable of populations will actually use. Although the results of VOICE are disappointing, VOICE did in fact provide a clear answer: daily use of a product – whether a vaginal gel or an oral tablet – was not the right HIV prevention approach for the women in VOICE. Results of sub-studies and secondary analyses of VOICE data are expected to provide additional insight and build on the important contributions that VOICE has already made in the field of HIV prevention.
VOICE has been a catalyst for the research community to reevaluate methods for monitoring and enhancing product adherence in clinical trials, including in helping current and prospective participants and local communities better understand the importance of correct and consistent product use and the impact that non-adherence can have on the findings of a research study. Several trials have already incorporated ways to better understand product adherence while the trial is underway so that researchers can be made aware of and address challenges as they occur. For instance, in ASPIRE, MTN’s Phase III trial of the dapivirine ring, participant blood samples are being tested on a routine basis to determine the presence of active drug, but in a way that preserves the blinded, placebo-controlled nature of the study. The implications of VOICE will be even greater as more is understood about the reasons why women joined VOICE and why most (91 percent) stayed in the trial, yet, so few used the study products, despite living in communities severely impacted by HIV.
Gaining insight into participants’ use – and nonuse – of HIV prevention products
VOICE C and VOICE D are qualitative behavioral studies that were designed to help address important questions about women’s use and nonuse of products in VOICE.
VOICE C, also known as the Community and Adherence Sub-study, aimed to identify the factors and beliefs within women’s communities, social groups and households that may have influenced their ability and willingness to follow the daily regimens. It was conducted in parallel with VOICE at a single research site – one of 15 for VOICE – and involved VOICE participants, their male partners, community advisors and stakeholders. According to the summary of findings from focus group discussions and interviews with the VOICE participants, most women claimed being able to use their assigned products but implicated others for not following the study’s regimens. The reasons they gave for women not using the products included the stigma associated with using ARVs meant for HIV-infected people; ambivalence about being in a blinded clinical trial and not knowing whether they were assigned to use an active product or placebo, or that the active products were even effective; and pressure from or strains on relationships with partners, family and friends. Additional results, including from interviews and focus groups with male partners and community advisors, are expected later in 2014.
VOICE D, which is still underway, was designed to be conducted after women completed their participation in VOICE, and it includes women from all three countries where VOICE was conducted. The study is designed to allow for more open discussion, and interviews with participants in VOICE D are being conducted by research staff that was not involved in VOICE. Stage two of the study, still underway, involves women assigned to use an active product during VOICE for whom stored blood samples have been tested for presence of drug. Results are expected by the end of 2014.
Ringing in the next generation of vaginal microbicides: ASPIRE and other studies of vaginal rings
ASPIRE – A Study to Prevent Infection with a Ring for Extended Use, also known as MTN-020, is a Phase III clinical trial 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 and will enroll up to 3,476 women at 15 sites in Africa, is being conducted in parallel with a second trial, The Ring Study, led by the International Partnership for Microbicides (IPM), which developed the ring.
Vaginal rings are flexible products that fit comfortably inside the vagina and provide sustained delivery of a drug over a period of time. They are already used in many countries to deliver hormonal contraception. ASPIRE and The Ring Study are the first effectiveness trials of a vaginal ring for HIV prevention, as well as of an HIV prevention product that contains an ARV other than tenofovir or a tenofovir combination. As sister studies, the two trials are designed to provide the strength of evidence to support potential licensure of the dapivirine vaginal ring for preventing HIV in women.
Approval of the dapivirine ring will also be contingent on data from a suite of studies, including a Phase I safety study, MTN-023/IPM 30, of the dapivirine vaginal ring in adolescent girls, and MTN-024/IPM 31, a Phase I safety study of the ring in post-menopausal women – the first microbicide trial involving this population of women. In another first, the MTN-013/IPM 026 Phase I trial of the dapivirine-maraviroc vaginal ring was the first clinical trial of a vaginal microbicide with two ARV drugs, and with the inclusion of maraviroc, the first involving an ARV belonging to a class of anti-HIV drugs called entry inhibitors.
On the forefront of rectal microbicide development
Although historically the field has focused mostly on products for preventing HIV through vaginal sex, the MTN has advanced a scientific agenda that recognizes the need for products for both men and women who engage in anal sex. According to some estimates, the risk of becoming infected with HIV through unprotected anal sex is as much as 20 times greater than with unprotected vaginal sex. Like a vaginal microbicide, a rectal microbicide would represent an HIV prevention strategy that doesn’t have to be controlled by one’s sexual partner. As a gel or lubricant, a rectal microbicide may also enhance sexual pleasure, helping to motivate consistent use.
Researchers are now conducting the first Phase II trial of a rectal microbicide. In MTN-017, researchers are evaluating the rectal safety, drug absorption and acceptability of a reduced glycerin formulation of tenofovir gel, as well as oral Truvada, among MSM and transgender women. The study, which began in September 2013, plans to enroll 186 participants at sites in Peru, South Africa, Thailand and the U.S., including Puerto Rico. The unique design of MTN-017 allows for routine blood tests to confirm the presence of study product and for these results to be shared with participants as part of their ongoing adherence counseling sessions on product use during the course of the study. Results of MTN-017, expected early 2016, will determine whether further testing can be conducted on the effectiveness of the reduced glycerin gel in preventing the transmission of HIV from anal sex. The reduced glycerin formulation of tenofovir gel differs from the formulation originally developed for vaginal use. It was developed in response to an earlier study called RMP-02/MTN-006, which found that rectal use of the vaginal gel caused gastrointestinal side effects in some study participants. The reformulated gel was found to be safe and acceptable in a follow-up Phase I study, MTN-007, prior to MTN-017.
MTN researchers and collaborators continue to conduct pioneering research in this area and anticipate that other products will enter clinical testing in the next year or two. Possible formulations for future study include suppositories, rectal tablets and douches.
Baby steps go far in first studies of pregnant and breastfeeding women
The MTN has long recognized that women need products 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. The MTN was the first and remains the only research organization to have conducted trials evaluating the use of HIV prevention products among pregnant and breastfeeding women. These trials are part of a comprehensive research program that was purposefully designed to take incremental steps in determining whether HIV prevention products are safe and effective in protecting women against HIV infection during all stages of pregnancy and motherhood.
The first study, MTN-002, involved giving a single dose of tenofovir gel to healthy, HIV-uninfected women hours before they gave birth by scheduled Cesarean section. Results, reported in 2010, found only small amounts of drug were absorbed into the mother’s bloodstream, amniotic fluid and umbilical cord (fetal) blood; and no serious side effects in either the mothers or their newborns. As a follow-up to MTN-002, MTN-008 was designed to determine whether tenofovir gel is safe for women to use daily for one week during late-stage pregnancy and while breastfeeding. It was the first clinical trial of tenofovir gel conducted among breastfeeding women. Results of MTN-008 are expected before the end of 2014.
Meanwhile, MTN-016, also known as EMBRACE (Evaluation of Maternal and Baby outcome Registry After Chemoprophylactic Exposure) is the first observational study tracking the effects that vaginal microbicides or ARV tablets used as HIV prevention may have on a woman’s pregnancy outcome or her baby’s general growth and development. The study involves the creation of a database of health information collected from women who as participants in either VOICE or ASPIRE unintentionally got pregnant during the trial, or who participated in studies like MTN-002 and MTN-008, as well as information about the health of their babies.
Innovative laboratory models: Where the road to success begins
Although MTN’s clinical trials include numerous measures to protect the safety and wellbeing of research participants, attention to safety actually begins well before a clinical trial of a product is even considered. Sophisticated laboratory studies help to streamline product selection and move only the safest and most promising microbicides to testing in people. For example, 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 similar tests are often conducted as part of Phase I trials looking to assess the clinical safety of a product but also how the active drug is absorbed and distributed within blood and the cells in the vaginal and rectum – where protection against HIV infection is most important. Findings can sometimes suggest that the need for further development of a product.
In MTN-023/IPM 026, for example, the combination dapivirine-maraviroc ring was found to be safe in women who wore it for 28 days, but only dapivirine was detected in cervical tissue and blood. Moreover, laboratory tests of cervical tissue biopsies from women showed that dapivirine was able to block HIV infection, though levels of maraviroc were not sufficient to have a similar effect. IPM, which developed the ring, now plans to look for ways to increase the amount of maraviroc that gets released.
The rebirth of contraception: Expanding the method mix of options for trial participants
In trials such as VOICE and ASPIRE, as with any HIV prevention trial of an unproven biomedical intervention, only women who are willing to use an effective contraceptive throughout the study may be enrolled. Women are counseled on a range of contraceptive methods available in the countries where they live, and they make their own choices of what to use, together with clinic staff and other providers. But in many African countries, the options are limited. Injectable hormonal contraceptives are widely used and very popular. Some observational studies have raised concerns that use of the injectable contraception called DMPA may put women in Africa at increased risk of HIV; other studies have found there is not a risk with DMPA.
With a goal of diversifying the range of effective contraceptive methods available to study participants, and in part due to the uncertainty about DMPA, the MTN formed the Contraception Action Team in 2012. Through this effort, site staff are gaining the necessary training to provide a variety of methods, including the copper intrauterine device (IUD) and implants, directly at the clinic. In just two years, there has been a major transformation. While the majority of women (71 percent) in the VOICE study chose to use injectable contraception, in ASPIRE, fewer than half are using an injectable contraceptive. Most notable has been the uptake of the IUD. During VOICE, only eight participants (less than 1 percent) of the 5,029 women used an IUD, while more than 22 percent of ASPIRE participants have chosen to use an IUD for contraception. Other long-acting contraceptives such as hormonal implants were used by only 5 percent of VOICE participants; in ASPIRE, the use of these methods has tripled.
# # #
To learn more about the Microbicide Trials Network go to www.mtnstopshiv.org.