· Rectal microbicides are products – that could take the form of gels, enemas or fast-dissolving tablets – being developed and tested to reduce a person’s risk of HIV or other sexually transmitted infections from anal sex.
· The risk of becoming infected with HIV during unprotected anal sex is 10 to 20 times greater than unprotected vaginal sex. Because the rectal lining is only one-cell thick, the virus can more easily reach immune cells to infect.
· If proven effective, rectal microbicides could protect against HIV in people who are unable or reluctant to use condoms every time they have sex, or who do not want to take a daily pill (pre-exposure prophylaxis, or PrEP) to reduce their risk of HIV. Just as there are multiple choices in contraception to prevent pregnancy, a rectal microbicide could give people who practice anal sex an additional option for HIV prevention.
· Rectal microbicides are not yet available outside of clinical trials. Researchers first need to be sure they are safe and then conduct additional studies to find out whether they are effective against HIV.
· In the first Phase II trial of a rectal microbicide, completed in 2016, researchers found that a reduced glycerin formulation of tenofovir gel was safe and effective, particularly when used around the time of sex compared to daily use, among men who have sex with men (MSM) and transgender women. Researchers continue to explore new potential products and delivery methods for rectal microbicides.
Microbicides are products designed to prevent or reduce the sexual transmission of HIV or other sexually transmitted infections when applied inside the vagina or rectum. Most vaginal microbicides are currently being tested as rings, while rectal microbicides are primarily being tested as gels. Microbicides currently being tested contain antiretroviral (ARV) drugs, many of which are commonly used to treat people with HIV. In 2012, the U.S. Food and Drug Administration (FDA) approved an ARV drug called Truvada® as oral PrEP – a prevention approach in which HIV-negative people take an ARV tablet on a daily basis to reduce their risk of acquiring HIV.
Although most microbicide research has focused on products to prevent HIV during vaginal sex, anal sex is common among MSM, and practiced by women around the world. According to some estimates, the risk of becoming infected with HIV through anal sex is 20 times greater than vaginal sex because the rectal lining, the mucosa, is thinner and much more fragile than the lining of the vagina.
An important first step in the development of rectal microbicides has been evaluating the rectal safety of microbicides originally formulated as vaginal gels. The most studied ARV-based vaginal microbicide is tenofovir gel, which although found safe and moderately effective in reducing HIV risk in women who used it before and after vaginal sex in a study called CAPRISA 004, was found not effective in follow-up studies, VOICE and FACTS 001, due to low adherence to study products.
MTN researchers also have been conducting studies of tenofovir gel as a rectal microbicide. Unlike the earlier studies, this research is focused on a different population of high-risk individuals who acquire HIV through anal sex rather than vaginal sex. Because tenofovir gel may work differently against HIV in rectal tissue, researchers want to learn whether it is safe and acceptable to use rectally with an applicator. An early study found that the vaginal formulation of tenofovir gel caused gastrointestinal side effects when used in the rectum, so researchers tested a reformulated version of the gel with less glycerin in a follow-up study called MTN-007. That study found the reformulated gel to be safe and acceptable.
MTN has since completed a Phase II study of the reduced glycerin formulation of tenofovir gel among MSM and transgender women – the first ever of a rectal microbicide. The study, MTN-017, took place in Peru, South Africa, Thailand and the United States, including Puerto Rico. Results, announced in early 2016, found that the gel was safe, with participants preferring to use it around the time of sex compared to daily use. Another study being planned, MTN-026/IPM 038, will evaluate whether dapivirine, an ARV that prevents HIV from replicating, is safe when used as a gel in the rectum. The Phase I study is expected to begin in early 2017, and is co-sponsored by the International Partnership for Microbicides (IPM).
Two Phase I studies, CHARM-01 and CHARM-02, comparing the safety, acceptability and distribution of three formulations of tenofovir gel – the vaginal formulation, the reduced glycerin formulation and a rectal-specific formulation – have been completed. Another recently completed study, CHARM-03, comparing the safety, acceptability and distribution of maraviroc gel (used in the rectum and vagina) to oral maraviroc, is expecting results by early 2017. These studies are being led by the Combination HIV Antiretroviral Rectal Microbicide (CHARM) Program based at the University of Pittsburgh. An additional study, Project Gel, reported results in 2016, and found tenofovir gel safe and acceptable as a rectal microbicide in young MSM and transgender women.
Other research-based programs underway include DREAM (Delivery of Rectal Enema as Microbicide), which is exploring the delivery of a rectal microbicide as a single dose enema, and PREVENT (Griffithsin-based Rectal Microbicides for Prevention of Viral Entry), which is addressing the need for a non-ARV based rectal microbicide.
Why Do We Need Rectal Microbicides?
Worldwide, nearly 37 million people are currently living with HIV. Although significant strides have been made in the treatment of HIV, now, more than 30 years after the HIV virus was first identified, the prevention of new infections continues to be great a challenge. An estimated 2 million new HIV infections occur annually – approximately 5,600 every day. HIV continues to disproportionately affect racial minorities, MSM, and transgender women. In the United States, MSM account for 60 percent of all new HIV infections and represent more than half of the people currently living with HIV. Globally, MSM are 19 times more likely to be infected with HIV than the general population. Condomless anal sex is the primary driver of the HIV epidemic among this population.
According to estimates, 5 to 10 percent of the world’s population engages in anal sex. Condoms are an extremely effective method to prevent HIV during anal sex, but many people don’t use them correctly and consistently for a number of reasons – dynamics in sexual relationships, stigma about the practice of anal sex, or because they aren’t readily available in some countries. Similarly, PrEP – an HIV prevention strategy in which people take a pill called Truvada daily to prevent infection – has been shown to be highly effective, but not everyone can or will want to take a pill every day. If proven safe and effective, rectal microbicides could provide an important additional prevention option.
What Will it Take to Discover a Safe and Effective Rectal Microbicide?
Drug development can take as many as 20 years before a single agent is approved for use. Thousands of potential compounds may be considered, but only the most promising products are subjected to rigorous laboratory and animal studies, and fewer still make it to trials with people.
Clinical trials are carried out in several phases under the oversight of regulatory authorities and according to strict ethical and scientific guidelines. Phase I trials evaluate safety in a small number of people who are exposed to study products for short periods, say, one to two weeks. If results suggest the product is safe, investigation progresses to a Phase II trial, in which researchers continue to track safety over longer periods of time. Phase IIb and III trials are performed to determine the effectiveness a product and conducted with large numbers of participants, often at multiple clinical centers. These trials usually compare a product with an inactive product (a placebo) or another active product. Data from Phase IIb and III trials are often used by regulatory agencies to determine whether a particular product should be approved for widespread use.
Rectal microbicides research is in earlier phases of clinical development due in part to scientific challenges related to the biology of the rectum, and cultural reluctance to address anal sex. Several Phase I trials and one Phase II trial evaluating the rectal safety of microbicides have been completed to date.
Completed and Current Clinical Trials of Potential Rectal Microbicides
· RMP-01 – A Phase I study of the rectal use of a gel containing UC781 that was found to be safe and well- tolerated in 36 men and women. Conducted by the University of California, Los Angeles (UCLA) in collaboration with the Division of AIDS-sponsored Integrated Preclinical/Clinical Program (IPCP) for HIV Topical Microbicides at National Institute of Allergy and Infectious Diseases.
· RMP-02/MTN-006 – A Phase I study of tenofovir gel applied rectally compared to oral tenofovir. Compared to a placebo gel, the gel significantly inhibited HIV in rectal tissue taken from 18 men and women in the U.S. who used it daily for one week. To address side effects in a few participants, researchers subsequently reformulated the gel. Conducted by the MTN and UCLA/IPCP.
· MTN-007 – A Phase I follow-up study to RMP-02/MTN-006 testing the rectal use of a reformulated version of tenofovir gel that was found safe and acceptable in 65 men and women in the U.S. Conducted by the MTN.
· MTN-017 – A Phase II rectal safety and adherence study of reformulated version of tenofovir gel used daily and before and after sex, and oral Truvada. The study, which enrolled 195 MSM and transgender women, found the gel was safe and most acceptable to participants when used before and after sex compared to daily use. The study was conducted by the MTN at sites in Peru, South Africa, Thailand and the U.S., including Puerto Rico.
· MTN-026/IPM 038 – A Phase I safety and acceptability study of dapivirine formulated as a rectal gel, slated to begin early 2017. Conducted by MTN and IPM.
· MTN-033/IPM 044 – A Phase I study of the safety and distribution of dapivirine gel when administered rectally with the use of an applicator compared to a phallic device, expected to begin in early 2017. Conducted by MTN and IPM.
· CHARM-01 & CHARM-02 – Phase I studies that compared the safety, acceptability and distribution of three formulations of tenofovir gel – a vaginal formulation, a reduced glycerin formulation and a rectal-specific formulation, and found all three safe and acceptable. Conducted by the CHARM Program.
· CHARM-03– Phase I study comparing the safety, acceptability and distribution of maraviroc gel (used in the rectum and vagina) to oral maraviroc, with results expected in early 2017. Conducted by the CHARM Program.
· Project Gel – Multi-stage trial focused on rectal microbicide acceptability, safety and adherence in young MSM and transgender women at sites in the U.S., including Puerto Rico, that found tenofovir gel safe and acceptable. Conducted by the University of Pittsburgh.
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The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, 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 – from the earliest phases of clinical study to large-scale trials that support potential licensure of these products for widespread use. More information about the MTN is available at http://www.mtnstopshiv.org.