A gel developed to protect against HIV during vaginal sex has also been found to produce a strong antiviral effect when used in the rectum, according to the results of an early-phase study by UCLA researchers and colleagues.
The findings — presented Feb. 28 at the 18th Conference on Retroviruses and Opportunistic Infections in Boston — are based on rectal tissue biopsies taken from HIV-negative men and women who used the product daily for one week. These tissues were exposed to HIV in a laboratory.
This is the first evidence that tenofovir gel could help reduce the risk of HIV from anal sex, even though the vaginal gel formulation may not be optimal for rectal use, the researchers said.
Most men and women in the study reported they would be likely to use the gel if it became available in the future as a method for preventing HIV. Although the study found use of the gel generally safe, side effects were problematic to a few study participants. In hopes of making tenofovir gel more acceptable for rectal use, researchers have since modified the gel and are now testing it in another study.
"We are very encouraged about these findings that indicate applying tenofovir gel topically to the rectum could be a promising approach to HIV prevention," said Dr. Peter Anton, director of the Center for Prevention Research at UCLA and a member of the UCLA AIDS Institute.
Anton, who is also a professor of medicine in the division of digestive diseases at the David Geffen School of Medicine at UCLA, co-led the study with Dr. Ian McGowan, co-principal investigator of the Microbicide Trials Network and a professor of medicine at the University of Pittsburgh.
"These are early results but help set the stage for current and future trials of rectal microbicides and the development of a rectal-specific formulation of tenofovir gel," said McGowan, who is leading a second study of the new gel formulation.
Microbicides — products applied on the inside of the rectum or vagina — are being designed and tested to help prevent or reduce the sexual transmission of HIV or other sexually transmitted infections. The majority of microbicide research thus far has focused on products to prevent HIV during vaginal sex. Yet the risk of becoming infected with HIV from unprotected anal sex may be at least 20 times greater than unprotected vaginal sex, in part because the vagina has multiple cell layers while the rectal lining is only one-cell thick, making it easier for the virus to reach cells to infect.
This study is the first clinical trial of tenofovir gel for rectal use. Last year, tenofovir gel was shown in a separate trial to reduce the risk of HIV infection in women who used it before and after vaginal sex.
Conducted at UCLA and the University of Pittsburgh, the current trial tested two products — tenofovir gel and oral tenofovir — in 18 sexually abstinent, HIV-negative men and women. Oral tenofovir, an antiretroviral tablet commonly used to treat people with HIV in combination with other antiretroviral therapies, is being explored as a means to prevent infection in people who are HIV-negative through an approach called pre-exposure prophylaxis, or PrEP.
The trial first compared the anti-HIV activity of a single dose of oral tenofovir to a single dose of rectally applied tenofovir gel. This was followed by six days of at-home dosing of the tenofovir gel or a placebo gel, with the seventh — and final — dose given at the clinic.
A novel approach was used to determine whether any actual protection was provided by the drug given in the different regimens — as a single-dose oral tablet, as a single-dose gel and as a seven-day gel (or placebo). Small biopsies were taken from the rectal lining of the participants using a standard clinical procedure known as a sigmoidoscopy. The tissue samples were then sent directly to the laboratory, where they were exposed to HIV to determine how well the study products protected the tissue from infection.
The researchers found that HIV was significantly inhibited in tissue samples from participants who used the tenofovir gel daily for one week, compared with tissue from participants who used the placebo gel. While a slight antiviral effect was noted in tissue from participants who received just a single dose of the tenofovir gel, the finding was not statistically significant. The single dose of oral tenofovir did not provide any protection against HIV in rectal tissue samples.
"These kinds of efforts early in the development phase of rectal microbicides can give us insight into a particular product's potential efficacy, which enables us to better design and hasten the pace of future clinical trials," Anton said.
According to self-reports, only 25 percent of men and women who had used the tenofovir gel said they liked it. However, when asked whether they would consider using the product in the future, 75 percent of these participants reported a high likelihood of future use. Two of the 12 participants who received the gel reported severe gastrointestinal side effects, including diarrhea and lower abdominal cramps.
"These results tell us that tenofovir gel was relatively safe to use in the rectum for most participants, but we need to address side effects to make it more acceptable to use," said Anton, who reported the findings at the Boston conference. "Even though three-quarters of the participants reported they didn't like the gel, we are very encouraged that the majority would consider using such a product in the future."
Another study is using a formulation of tenofovir gel with less glycerin, a common additive found in many gel-like products, in the hope that this will make it better tolerated when used in the rectum. Laboratory tests of the reformulated gel suggest it is just as effective as the original formulation but less irritating to the epithelium — the layer of cells that serves as a protective barrier inside the rectum. That study began in October 2010 and is enrolling 60 men and women at three sites: the University of Pittsburgh, the University of Alabama at Birmingham and Fenway Health in Boston.
In addition to Drs. Anton and McGowan, other authors of the current study are Ross Cranston of the University of Pittsburgh; Alex Carballo-Dieguez of Columbia University; Angela Kashuba of the University of North Carolina; Elena Khanukhova, Julie Elliott and William Cumberland of UCLA; Laura Janocko, of the Microbicide Trials Network (MTN) and Magee-Womens Research Institute; and Christine Mauck of CONRAD.
The study was a collaboration between the Microbicide Development Program at UCLA and the MTN. UCLA's Microbicide Development Program is funded by the Division of AIDS Integrated Preclinical/Clinical Program for HIV Topical Microbicides at the National Institute of Allergy and Infectious Diseases. The study products were developed by Gilead Sciences Inc., of Foster City, Calif., which assigned the rights for tenofovir gel to the International Partnership for Microbicides of Silver Spring, Md., and CONRAD, of Arlington, Va., in December 2006. Gilead Sciences and CONRAD provided the study products free of charge.
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 who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.
The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.