Microbicides are products (such as gels, films, intravaginal rings (IVR), enemas, inserts, or suppositories) that can be formulated for use in reproductive and gastrointestinal tracts (GI) to prevent sexual transmission of HIV and other sexually transmitted infections (STIs). An optimal microbicide would be desirable for use by a wide variety of individuals at risk for HIV or STIs regardless of sex, gender or age, and would be, safe, inexpensive, long-acting and easy to use and store. Microbicides should be available in both contraceptive and non-contraceptive formulations so that women can remain protected whether or not they are trying to conceive a child.
In 2010, the CAPRISA 004 trial in South Africa found that tenofovir 1 percent vaginal gel when used before and after sexual intercourse reduced HIV acquisition by an estimated 39 percent and Herpes Simplex Virus (HSV) by 51 percent. However in 2013, the Microbicide Trials Network (MTN) Vaginal and Oral Interventions to Control the Epidemic trial also known as VOICE or MTN 003 reported that none of the products tested (daily dosing of tenofovir 1 percent vaginal gel, oral tenofovir, and oral Truvada) were effective in preventing HIV and few participants used their assigned study products on a daily basis as instructed. Younger, unmarried women were least likely to use the study products, and were also most likely to acquire HIV. Similar to VOICE, the FACTS 001, a follow-on study of CAPRISA 004, found low adherence to the regimen and no efficacy of the tenofovir 1% gel. In both studies, post-hoc analyses showed evidence of HIV protection among women with laboratory detection of higher adherence to tenofovir gel use.
Two VOICE sub-studies have since highlighted the social factors, behavioral issues, and reasons for low product use among the participants, and emphasized the need for microbicide development efforts to address product desirability. Behavioral and social science research is integrated into all levels of microbicide development to help determine the factors that impact acceptability and use, with the goal of developing a microbicide that is not only safe and effective but also appealing, easy to use and one that can be integrated into the lifestyles of people at-risk of HIV infection.
Recently, the NIAID-funded ASPIRE study (MTN-020) found the dapivirine ring to safely reduce the risk of HIV infection in African women ages 18-45 (27 percent in the study population overall and 61 percent in women ages 25 and older). The dapivirine ring did not provide statistically significant protection in women younger than 25 years overall, however, post-hoc analyses showed protection down to age 22. In follow-up, NIAID is funding an open-label extension study of the dapivirine ring in which all participants will be invited to use the ring for HIV prevention. The new study, known as the HIV Open-Label Prevention Extension (HOPE) or MTN-025, will gather additional data on the safety and acceptability of the dapivirine ring and participants’ adherence to it. In addition, NIAID is funding a separate study to address why the dapivirine ring did not protect the youngest women enrolled in ASPIRE. This study (MTN-034) will seek to determine whether the ring was ineffective for the youngest women due to behavioral issues (for example, adherence challenges or frequency/type of sexual activity) or if there is something biologically different about these women that counteracts the ring’s protective properties.
NIAID’s microbicide program continues to emphasize the need for additional discovery, preclinical, nonclinical, and clinical research to create a sustainable pipeline of prevention products and to better understand differing clinical outcomes.
Microbicide development is designed to identify the safest and most active microbicide product and optimal drug delivery system (DDS). Initial microbicide discovery and preclinical testing follows the Food and Drug Administration (FDA) guidance on development of antiviral drugs and also includes additional microbicide-specific tests. (See NIAID Topical Microbicide Screening Algorithm.) Before clinical testing is initiated, all safety issues are identified according to the FDA Guidance for Industry: Vaginal Microbicides: Development for the Prevention of HIV Infection.
A DDS for microbicides can take many forms, including an intravaginal ring (IVR), gel, quick dissolve film, tablet (insert), suppository, enema/douche, or foam. Delivery systems are: tested to determine if they release appropriate amounts of drug in a given timeframe; evaluated under different storage conditions (e.g., temperature, humidity); and assessed for their activity in and penetration of specific tissue. A parallel process occurs to assess the manufacturing of a microbicide product and to develop assays that can measure its drug level in secretions, tissues, and blood. Such measurements have become important for monitoring and assessing adherence in clinical trials.
While the emphasis of preclinical development has focused on microbicides that inhibit HIV transmission, ideally they would also be active against other STDs, especially those that have been associated with increased risk of HIV infection or a poor prognosis, including
Following successful completion of preclinical testing per regulatory guidelines, promising microbicide candidates may advance to clinical evaluation, which NIAID pursues through its Microbicide Trials Network (MTN). The MTN, a network of international investigators, community stakeholders, and industry partners, was established in 2006 with funding from NIAID as well as the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. It conducts
Once a Phase 3 trial (or multiple trials) is well underway, additional Phase 2 studies may be implemented to evaluate safety in distinct populations for which HIV susceptibility may be greater. This includes pregnant and lactating women as well as adolescents who may have unique factors related to biological development that influence HIV risk. Once product efficacy/effectiveness is demonstrated, there is an ethical obligation to provide the proven product to former Phase 3 trial participants who are HIV-uninfected and would not otherwise have access to the product until after licensure. Follow-on studies address this and can also obtain additional safety and adherence data in the context of an open-label trial, where participants know they are receiving the effective product and where clinical visits and other safety assessments reflect a more “real world” experience. These studies can also provide guidance for clinical management in healthy, HIV-uninfected people.
Ongoing and planned clinical microbicide research efforts are designed to identify, develop, and/or evaluate
Inclusion of contraception in a vaginal microbicide could have a significant impact on uptake and use due to the desire for effective contraception and the lower stigma associated with family planning than HIV prevention. Microbicide candidates have been proposed that have both anti-HIV and contraceptive activity; however, their development has not continued due to potential safety issues (enhancement of HIV infection) or lack of efficacy in Phase 3 clinical trials. As an alternative, the development of Multipurpose Prevention Technologies (MPTs) are now being considered as a way to incorporate contraception into an anti-HIV microbicide. An MPT may be composed of an anti-HIV compound with a licensed hormonal contraceptive either co-formulated with the anti-HIV compound, such as an IVR with antiviral and hormone(s), or co-delivered with the anti-HIV agent (contraceptive barrier device that is loaded with a microbicide). Although MPTs have the potential to be a highly effective way to couple HIV prevention and contraception, they are still in the early stages of development and clinical testing. See the Initiative for Multipurpose Prevention Technologies for additional information.
While microbicide researchers and developers have always recognized the importance of integrating social and behavioral sciences in all phases of microbicide clinical development, initial efforts were focused on determining microbicide "acceptability" as a way to assure adherence. Over time, the field has evolved, especially with lessons learned from the VOICE and other trials, where self-reported product use did not equal actual use.
VOICE C, the Community and Adherence Sub-study, was conducted in parallel with the VOICE trial to identify factors and beliefs within the participants’ communities, social groups, and households that might have influenced their willingness to participate in the study and follow the daily regimen. The results suggest that the women did not adhere to the regimen due to concerns about side effects, stigma associated with use of a microbicide that is also used for HIV treatment, lack of knowledge about whether or not they were really taking an active drug or a placebo, and pressure from partners, family, and friends.
The vast majority of women interviewed in VOICE C and the first stage of VOICE D (conducted after the VOICE trial ended to assess factors that might have diluted effectiveness of the study drugs) did not acknowledge their own lack of product use and instead commented primarily on the actions/attitudes of other trial participants. Only after showing women their own drug-detection information in the second phase of VOICE D did they acknowledge their own non-use and the reasons behind it. The primary reasons noted were fear of side effects or harm and the desire to access the health benefits provided by the trial without an interest in the products being provided. VOICE D participants clearly stated that ongoing monitoring of drug levels is important to really assess adherence.
These two sub-studies illustrate the importance of fully integrating robust social and behavioral science into microbicide trials. The qualitative and quantitative data obtained from behavioral questionnaires, in-depth interviews, and focus group discussions continue to provide a more comprehensive understanding of the perceived benefits and barriers to product use, which can inform adherence counseling during study conduct. New areas of expertise, such as behavioral economics, are also contributing to the development of microbicide products to ensure that they are not simply acceptable but that women also desire to use them.
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Last Updated April 14, 2016