Tenofovir gel makes strides in development
Microbicide research is moving forward with two new developments: the Food and Drug Administration (FDA) has granted Fast Track approval designation for 1% tenofovir gel, which will facilitate the development and expedite the review of the drug. Also, in a second development, the microbicide will be examined in a separate early phase trial to determine its safety and acceptability in rectal use.
The FDA met with key stakeholders in October 2010 to determine the next steps required for U.S. licensure of 1% tenofovir gel, which recently was found to be effective at reducing the rate of HIV and herpes infection in women when used before and after sex.1 In the recent CAPRISA 004 clinical trial, the microbicide was found to be 39% effective in reducing a woman's risk of becoming infected with HIV during sex. Women who reported using the gel more than 80% of the time they engaged in sexual relations had a 54% reduction in HIV infection, whereas those who used the gel less than half the time had a 28% reduction.1 The study also showed that the gel was effective in preventing transmission of genital herpes simplex virus (HSV-2). The women using the tenofovir gel had 51% fewer cases of HSV-2 infection than the control group.1 Results of that clinical trial represent the first "proof of concept" for a vaginal microbicide.
Fast Track status is granted to drugs in development that have the ability to impact a serious, life-threatening condition and also address an unmet medical need, explains Jill Schwartz, MD, medical director for CONRAD, a division of the Eastern Virginia Medical School in Norfolk, VA. CONRAD was one of the partners in the CAPRISA 004 study. CONRAD and the International Partnership for Microbicides based in Silver Springs, MD, hold a co-exclusive, royalty-free license from Gilead Sciences in Foster City, CA, to develop the microbicide for HIV prevention.
The next step in development is to obtain results of the VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial, which is an ongoing study managed by the Microbicides Trial Network (MTN) based at the University of Pittsburgh and Magee-Womens Research Institute in Pittsburgh to evaluate daily use of tenofovir gel. Study results might be available by early 2013. If the trial is successful, advocates can move forward in filing a New Drug Application for the gel. The FDA also has asked for data on use of the gel in adolescents as well as post-menopausal women, as well as in vivo drug interaction studies with commonly used vaginal products, says Schwartz.
"I think the FDA has provided us a clear path for testing and licensure of 1% tenofovir gel," says Schwartz. "That's where we are moving forward."
Study eyes rectal use
In other research news, tenofovir gel is the subject of a new trial looking at its safety and acceptability when used rectally. The results of the MTN-007 study, being led by the Microbicide Trials Network, will help determine if the gel should be evaluated further for its potential to prevent HIV among men and women who engage in receptive anal intercourse.
While condoms are protective against HIV and other sexually transmitted infections, most acts of anal sex go unprotected. Research indicates unprotected anal intercourse is a high-risk practice for HIV transmission in heterosexuals and men who have sex with men (MSM).2
While the CAPRISA 004 results are promising for vaginal use, it is important to look at how the gel functions in rectal use, says Ian McGowan, MD, PhD, co-principal investigator of the MTN and professor of medicine in the Division of Gastroenterology, Hepatology, and Nutrition at the University of Pittsburgh School of Medicine. "We can't just assume that a product developed for use as a vaginal microbicide will be equally safe or effective when used in the rectum for preventing HIV transmitted through receptive anal intercourse," said McGowan in a statement announcing the new trial. "So while VOICE or other trials may very well prove tenofovir gel is highly effective for preventing vaginal transmission, we need to understand much more about what happens to the cells and tissue when tenofovir gel is used rectally before considering a trial testing its effectiveness against HIV."
The new study will enroll 60 men and women at the trial sites at the University of Pittsburgh, University of Alabama at Birmingham, and Fenway Health in Boston. It is designed to see if rectal use of tenofovir gel is safe, as well as acceptable for use to men and women as a rectal microbicide. The trial will study enroll men who have sex with men, as well as heterosexual men and women, says Clare Collins, a MTN spokesperson. Estimated completion date for this early phase trial is June or July 2011, she states.
MTN researchers recently have completed a Phase I trial of tenofovir gel in rectal use. While results of the study, conducted in collaboration with the Microbicide Development Program at the University of California, Los Angeles are not expected until early 2011, researchers already have recommended modifications to the gel's formulation. The upcoming MTN-007 trial will evaluate the new formulation, which contains the same amount of active drug (1% tenofovir) but has a lower concentration of glycerin to make it more amenable for rectal use.
- Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010;329:1168-1174.
- Baggaley RF, White RG, Boily MC. HIV transmission risk through anal intercourse: systematic review, meta-analysis and implications for HIV prevention. Int J Epidemiol 2010;39:1048-1063.