HIV Prevention Knowledge Base
Biomedical Interventions: Microbicides
Microbicide Trials Network Statement on Decision to Discontinue Use of Tenofovir Gel in VOICE, a Major HIV Prevention Study in Women
The Microbicide Trials Network dropped tenofovir gel from its Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial following a routine Data Safety and Monitoring Board review that concluded that tenofovir gel was not effective in preventing HIV in the women enrolled in the trial. VOICE, an HIV prevention trial, has been evaluating two antiretroviral approaches for preventing the sexual transmission of HIV in women—daily use of one of two different antiretroviral tablets (tenofovir or tenofovir emtricitabine) or of a vaginal gel. The trial has enrolled 5,029 women at 15 sites in Uganda, South Africa, and Zimbabwe, and had earlier discontinued the oral tenofovir. The study found no safety concerns with any of the study products. It is not clear why tenofovir gel did not reduce the risk of HIV acquisition among women in this trial when an earlier trial (CAPRISA 004, which followed a different dosing schedule) showed a reduction in risk. Complete analysis of the trial data will take place after the trial is completed and all of the data are analyzed. The trial team expects results to be available in late 2012 or early 2013.
Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women
This is the first clinical trial indicating the effectiveness of a vaginal microbicide in reducing HIV infection in women. Nearly 900 sexually active women aged 18 to 40 in Durban and Vulindlela, South Africa, were randomized to receive tenofovir or placebo within 12 hours before having sex and as soon as possible within 12 hours after having sex. Monthly support meetings with participants highlighted the importance of consistent and correct microbicide use, identified ways to overcome obstacles to use, and set goals for perfect adherence for each month. Despite this, 40 percent of the study participants used the gel for less than 50 percent of sex acts. After 12 and 24 months of follow-up, HIV incidence in the tenofovir arm was 50 percent and 40 percent lower than the placebo arm, respectively. HIV incidence among women with the best adherence was 54 percent lower than placebo, indicating that effectiveness was linked to adherence. Furthermore, the study found tenofovir safe. Despite the small sample size, this study provided “proof of concept” for tenofovir microbicide prophylaxis. More studies are needed to corroborate these findings.
Intravaginal Insertion in Kwazulu-Natal: Sexual Practices and Preferences in the Context of Microbicide Gel Use
Cited preferences for “dry” sex among certain populations in sub-Saharan Africa raise concerns about the acceptability of vaginal gel microbicides. To identify whether such use would be problematic, 118 in-depth interviews and 15 focus group discussions with women participating in a microbicide gel trial in Kwazulu-Natal and their partners collected detailed information on intravaginal insertions. Unexpectedly, 49 of 63 interviewed women and 4 of 8 men said the microbicide enhanced their sexual pleasure; the remainder reported no effect of the microbicide on their sexual experience. Participants stated that the gel increased sexual pleasure by making sex “hot,” “tight,” “smooth,” and “dry.” Women also reported enjoying the lubricating effect of the gel. According to this research, the notion of “dry” sex is not one of complete dryness, just lack of excessive wetness in the vagina. Furthermore, as intravaginal “potions” were commonly used to improve sexual pleasure among this population, a microbicide may be more easily understood in a local context using local terms. The authors conclude that microbicides may be more acceptable for HIV prevention than expected, as previous associations between intravaginal insertions and dry sex were “overstated.”
International Microbicides Conference 2010: Program & Abstracts
This document contains the abstracts of all oral presentations and poster sessions given at the 2010 International Microbicides Conference. Organized by conference days, readers can browse through the content, search the document for authors or keywords, or scroll to the author index at the back of the document. The theme of this conference was “Building Bridges to HIV Prevention,” which is reflected in the abstracts.
An Acceptability and Safety Study of the Duet® Cervical Barrier and Gel Delivery System in Zimbabwe
This study assessed the acceptability of the Duet® cervical barrier together with a gel in 103 primarily married women in peri-urban Zimbabwe. Women were randomized to use the Duet continuously for 14 days, then only use it before having sex; another arm was randomized to the same regimen in reverse sequence. Approximately 90 percent of the women reported adhering to their assigned regimen 80 percent of the time. Overall, acceptability was high. Half of the participants preferred using the barrier during sex, 39 percent preferred continuous use, and the remainder reported no preference. The most positive attribute women assigned Duet was “normal/natural sex.” No serious adverse events were found among the study participants. Of note, 5 percent of women in both arms reported unspecified “fear” related to use. This study was small and only followed women for one month. Longer-term use may affect acceptability; adverse events may also differ with long-term use.
Microbicides in the Prevention of HIV Infection: Current Status and Future Directions
An in-depth review of the history of microbicide development for HIV prevention, this article also presents new microbicides under development. These include antiretroviral drugs and drug combinations that can be administered in different ways, including daily delivery and sustained delivery mechanisms. In addition to specifically targeted HIV replication, new product options related to timing of use can potentially improve product effectiveness. Potential new microbicides, however, come with concerns about toxicity and resistance. Additional challenges to microbicide development, such as need to remain stable in a tropical environment, are also addressed in the article. The author details concerns and further challenges to introducing a microbicide widely in a population, including knowing its safety profile among pregnant women or women who want to become pregnant. Despite recent encouraging news about microbicides, the road to their widespread and effective use for HIV prevention remains long.
In Vitro and Ex Vivo Testing of Tenofovir Shows It Is Effective As an HIV-1 Microbicide
Describing their in vitro and ex vivo testing of tenofovir, the authors make the case that preclinical testing of microbicide products has advanced tremendously over the last decade. Previous microbicides shown to cause cell irritation were not tested so extensively prior to their use in phase II and phase III trials. This study used human ectocervical and colorectal tissue to understand the effects of tenofovir gel on such tissue. In vitro tests found viscosity similar to other commonly-used vaginal and rectal lubricants, constant tenofovir release rates in the gel, and penetration of the drug into mucosal tissue, albeit at varying rates. The gel had no negative effect on vaginal flora, even in the presence of four different bacteria, including gonorrhea. Furthermore, tenofovir reduced the presence of HIV in the tests. Thus the authors conclude that tenofovir is effective and may be a viable candidate for pre-exposure prophylaxis in humans.
HIV “Prevention” Gel PRO 2000 Proven Ineffective
This press release from the Microbicides Development Program (MDP) summarizes the outcome of the MDP 301 trial that tested the effectiveness of PRO 2000 vaginal microbicide gel against placebo for HIV prevention. Disappointingly, data from over 9,000 women in four countries in Africa over 12 months (24 months in Uganda) found no difference in HIV acquisition rates between microbicide and placebo users. HIV incidence was 4.5 per 100 women years in the PRO 2000 group and 4.3 per 100 in the placebo group. Readers can find links to PDF files after the press release with additional information, including questions and answers about the trial, the results, quick facts, a technical fact sheet, and “Women’s Voices,” a sheet with study participants’ perspectives of the trial.
Complete Protection from Repeated Vaginal Simian-Human Immunodeficiency Virus Exposures in Macaques by a Topical Gel Containing Tenofovir Alone or with Emtricitabine
Safety and efficacy studies are needed before microbicides can be tested in humans. This trial assessed how well tenofovir (TVF) vaginal gel or TVF with emtricitabine (FTC) protected 17 macaques from simian HIV (SIV) infection over a period of 20 weeks. The gel was administered twice weekly; simian-human immunodeficiency virus was administered 30 minutes after the gel. Five of six macaques in the placebo arm and both in the control arm (no intervention) became infected with SIV in an average of 2.5 weeks. None of the six macaques assigned active gel (TVF alone or TVF+FTC) became infected over 20 weeks (40 total SIV exposures). Furthermore, there was no evidence of damage to vaginal mucosa with use of either active microbicide. Despite study limitations, the authors conclude that this study suggests TFV gel can be used before intercourse to protect women from SIV without the need for daily use.
Predictors of Adherent Use of Diaphragms and Microbicide Gel in a Four-Arm, Randomized Pilot Study Among Female Sex Workers in Madagascar
Researchers undertook this pilot study to identify ways to maximize adherence to diaphragms and microbicide gel ahead of a future study on microbicide effectiveness. Nearly 200 female sex workers (FSWs) in four cities in Madagascar were randomized into four groups: the gel microbicide Acidform plus diaphragm; placebo gel plus diaphragm; placebo gel; and Acidform gel. These were collapsed into two arms for data analysis: diaphragm plus gel or gel alone. Weekly follow-up meetings over one month collected information on product use and sexual practices with clients and regular partners. A statistically significant difference was found in adherence among women randomized to diaphragms (43 percent at first follow-up and 67 percent at last follow-up) compared to gel-only users (28 percent at first follow-up and 45 percent at last follow-up). Compliance improved over time in both groups. The authors believe this was due to the product protocol: diaphragm insertion was a daily event independent of sex, while the gel was to be used prior to coitus. Study findings will help develop counseling messages for future microbicides studies, helping women understand that discreet use is possible, but also indicating that some women choose to disclose product use to their partners.
Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel
HIV transmission during anal sex is higher than with vaginal sex due to physiologic factors. As such, a microbicide that can be safely used with anal intercourse could benefit heterosexual and homosexual couples alike. This study in 16 macaques assessed the effectiveness of a rectal tenofovir microbicide gel in preventing simian HIV (SIV) when administered up to two hours before and 15 minutes after rectal exposure to SIV. All placebo-arm macaques and two of the three receiving tenofovir after HIV exposure became infected with SIV. Eight of nine macaques assigned tenofovir before HIV exposure were completely or partially protected from SIV. The higher the tenofovir concentration in the blood 15 minutes after its administration, the greater the protection against SIV. Activated T-cells were found in the blood of the macaques protected from SIV, indicating that such exposure may be able to “prime and/or boost immune responses elicited with experimental vaccines.” This study’s results suggest that tenofovir rectal microbicide gel may have promise in humans.
Vaginal Microbicides and the Prevention of HIV Transmission
This review of 118 studies—45 clinical and 73 preclinical—from a biomedical perspective assesses the state of microbicide development for HIV prevention. The authors first discuss the sexual HIV transmission pathways and how microbicides are being developed to address them. The different types of microbicides (e.g., viral entry inhibitors) are described, along with the current state of research for each type. The authors also discuss epidemiological and biological issues that make microbicide research challenging. Epidemiologic issues include HIV incidence, study populations, and discreet use of microbicides. Among biologic challenges are developing combination microbicides when each component must be first tested individually. The authors conclude that while the development of effective microbicides is difficult, the potential benefits are so great that they greatly outweigh any known risks—and possibly unforeseen risks as well.
SAVVY Vaginal Gel (C31G) for Prevention of HIV Infection: A Randomized Controlled Trial in Nigeria
Over 2,100 women in Lagos and Ibadan, Nigeria participated in a double-blind, randomized, placebo-controlled trial to assess the effectiveness of SAVVY vaginal microbicide gel in preventing HIV transmission. Participants filled out monthly questionnaires on sexual behavior, condom use, gel use, and any medical problems and were given 60 condoms and 60 vials of gel every month. Condom and gel use decreased over the 12-month study period over time, but was generally high. Adverse event rates were the same in both study arms, with no significant difference in chlamydia, bacterial vaginosis, candidiasis, or trichomoniasis rates between arms at the six-month follow-up visit. The study ended early due to lack of power to detect a statistically significant difference in HIV rates between study arms. While the ratio of HIV infections was higher in the SAVVY arm than placebo, the difference was not statistically significant. However, because of the study’s low power, the results cannot conclusively support that SAVVY does not increase risk of HIV infection. This study highlights research challenges in measuring microbicide effectiveness.
Rectal Microbicide Development
This article describes the progress made in recent years to develop microbicides—gels, suppositories, or other topical formulations that prevent HIV—for rectal use. The design and results of early vaginal microbicide trials informed the research direction for evaluating potential rectal microbicide candidates, as did early acceptability studies among men who have sex with men, who are highly vulnerable to HIV because of the common practice of unprotected receptive anal intercourse. Most rectal microbicides in the pipeline have reached only the preclinical study stage. Only two products—UC781, a non-nucleoside reverse transcriptase inhibitor, and tenofovir, a nucleotide inhibitor—have reached the clinical study stage, although L’644, a promising fusion inhibitor, is now also being evaluated. Qualitative and clinical studies of acceptability for different rectal microbicide formulations have found gels to be most acceptable. Rectal safety became the focus of research soon after researchers found that vaginal microbicide candidates were not optimal for rectal use, causing mucosal damage in the rectum; recent research findings show that reducing the glycerin in the formulation may be less harmful. The author describes the preclinical evaluation of four rectal microbicide candidates that have undergone Phase I trials: HIVNET-008 (N9 gel), RMP-01 (UC781 gel), RMP-02/MTN-006 (tenofovir gel), and MTN-007 (tenofovir gel with reduced glycerin). In his conclusion, the author suggests that Phase I studies on rectal microbicides will continue to produce important data on safety, acceptability, and pharmacokinetics that will contribute to early product development.
Topical Microbicides for Prevention of Sexually Transmitted Infections
The authors of this systematic review found that by the end of 2011, nine randomized controlled trials (RCTs) enrolling 31,941 sexually active women in 11 countries, with HIV incidence as the primary outcome, had demonstrated limited evidence that vaginal microbicides reduce acquisition of HIV and herpes simplex virus (HSV-2) infection in women. As a result, the authors do not recommend topical microbicides for HIV or STI prevention, but do suggest that development of new microbicides continue. Of the nine RCTs, the authors found that CAPRISA 004, a small proof-of-concept RCT enrolling 889 women, demonstrated that tenofovir—a nucleotide reverse transcriptase inhibitor—may reduce the risk of acquiring HIV and HSV-2. The authors are currently awaiting data from a second tenofovir trial enrolling 5,000 women, which was stopped early due to futility of results demonstrating a protective effect. According to the authors, other types of topical microbicides did not demonstrate a reduction in the risk of acquiring HIV or sexually transmitted infections (STIs), and none of the trials demonstrated that microbicides reduce the acquisition of other STIs, including gonorrhea, syphilis, genital warts, trichomoniasis, or human papillomavirus infection. The authors stress that if further studies demonstrate the effectiveness of tenofovir-based microbicides, efforts must be made to achieve rapid regulatory approval and create appropriate mechanisms for distribution.