Antimicrobials delivered in the products already used during sexual activity show great promise for protecting particularly vulnerable individuals against transmission of HIV.
The approval of Truvada as pre-exposure prophylaxis (PrEP) for people at high risk of HIV infection ushered in a new era in HIV prevention. For the first time, clinicians have something to recommend to high-risk patients beyond condoms, circumcision, and monogamy.
However, uptake of PREP has been slow. A December 2013 article in The New York Times noted that, “In some quarters, the idea that healthy gay men should take a medication to prevent infection . . . has met with hostility or indifference.” Barriers include cost, negative reactions from primary care physicians, and the stigma associated with taking the drug.
All of which point to an unmet need for other preventive options, said Sharon Hillier PhD of the University of Pittsburgh. “Yet in the HIV prevention world we’re still stuck on the notion of telling people to use condoms or not to have sex or to pick their partners more wisely,” she said, which, given that 50,000 people in this country alone are infected with HIV each year, is obviously not working.1
Enter microbicides. Microbicides are gels, capsules, tablets, films, and intravaginal rings that contain antiretroviral drugs. They are designed to be used long-term (as with the vaginal rings) or just before and after sex.2 Several are in early- and late-stage clinical trials, with the possibility that at least one could be on the market before decade’s end.
Microbicides for Women
Microbicide development for women is based on the success of IUDs, vaginal rings, and implantable contraceptives that minimize the risk of pregnancy due to non-adherence, said Dr. Hillier, who is leading several trials testing microbicides in women.
Infection rates in women are highest in young, unmarried females who are least likely to be monogamous, Dr. Hillier said. Women also have limited control over whether their partners use condoms, she said.
“The bottom line is that no matter how many condoms you pass out and how much people say they use them, it is very difficult for women to negotiate consistent condom use,” she said. In fact, she noted, studies find the Y chromosome (indicating unprotected sex) in the vaginal fluid of women who say their partner used a condom.
However, a vaginal ring that delivers tiny doses of antiretroviral drugs over a month could change that, she said. Because the drugs are delivered locally where infection occurs, they have fewer side effects than systemic treatment and should, theoretically, attack the virus before it can gain a foothold. Indeed, current guidelines recommend immediate antiretroviral therapy (ART) for people with acute infection, which may improve long-term outcomes for the infected individual as well as reducing the potential for viral transmission.3,4
An intravaginal ring implanted with dapivirine is already in testing in two multicenter global Phase III clinical trials, including centers associated with the Microbicide Trials Network (MTN), for which Dr. Hillier is a principal investigator. The organizers of the trials expect to enroll 2,500 high-risk women by March 2014, and to have results available in late 2015. (Enrollment information for the MTN trial is available here).
Earlier studies show that women find the ring easy to use, that their partners don’t feel it, and that it’s much simpler to use than an oral PrEP pill or microbicide gel, Dr. Hillier said.
“We’re also hearing from women that they’d like to have a contraceptive included with the ring,” she said, something other research consortiums are already investigating.
Given the dearth of preventive options for women, Dr. Hillier said, “We are thrilled with the idea of sustained local delivery for HIV.”
Microbicides in Men
The development of microbicides for men builds on existing behavior, namely, that men who have sex with men (MSM) already use lubricants during anal sex. Development is not as far along as microbicides for women, however, with the first Phase II trial just launched, said Ian McGowan MD PhD of the University of Pittsburgh. Dr. McGowan is also a principal investigator with the MTN.
Just as with women, microbicides for men are needed to fill an important unmet need. “For whatever reason, clearly a lot of men who have sex with men (MSM) and transgender women are unable or unwilling to use condoms,” he said.
Studies in non-human primates have already demonstrated significant effectiveness of rectal microbicides, Dr. McGowan said. His group is speeding clinical development by collecting rectal tissue explants before and after men use microbicides during Phase I studies, then trying to infect the tissue in the laboratory with the virus and assessing post-use infection and safety. Data collected to date in Phase I studies demonstrate significant efficacy for two antiretroviral microbicides (UC781 and tenofovir) using the explant assay.5
The formulation of the final microbicides will likely be either liquids or semi-solid compounds like gels or suppositories. Phase I trials find that combination ART (tenofovir [TDF] or emtricitabine [FTC] with UC781 and dapivirine) protects colorectal tissue more effectively against HIV-1 infection, even against drug-resistant HIV-1, than single agents.6 Several combinations of ART are being tested.
A Phase II study (MTN-017) comparing oral Truvada against a reduced glycerin tenofovir gel is now recruiting participants through the MTN network. It will enroll 186 MSM and transgender women in four countries, including the US. Participants will use the gel daily for eight weeks, then before and after sex for 8 weeks. Then they will take oral Truvada for eight weeks.
Microbicides are not designed for lifetime use, warn Drs. McGowan and Hillier, but for those periods when people are most at risk for infection, such as for young women of college age or gay young men when they are just coming out. “We know from work in other sexually transmitted diseases that there are windows ... when they are at much higher risk,” said Dr. Hillier.
The MTN recently received $70 million in funding from the National Institutes of Health to continue developing and testing products to prevent HIV.
1. Centers for Disease Control and Prevention. HIV in the United States: At a glance. Available at: http://www.cdc.gov/hiv/statistics/basics/ataglance.html. Accessed January 3, 2014.
2. Shattock RJ, Rosenberg Z. Microbicides: Topical prevention against HIV. Cold Spring Harb Perspect Med. (2012) 4:a007385.
3. HHS Panel on Antiretroviral Guideines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. February 12, 2013. Available at: http://aidsinfo.nih.gov/guidelines. Accessed January 3, 2014.
4. O’Brien M, Markowitz M. Should we treat acute HIV infection. Curr HIV/AIDS Reports. (2012) 9(2):101-110.
5. McGowan I. The development of rectal microbicides for HIV prevention. Expert Opin Drug Deliv. 2013;10(12):1-14.
6. Herrera C, Cranage M, McGowan I, et al. Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants. AIDS. (2011) 25(16):1971-9.