What will it take for microbicides to go from research to reality? 

Science/policy research, public education, advocacy will speed process

The need for female-controlled protection against HIV and sexually transmitted diseases (STDs) has never been greater. While early in the epidemic, HIV infection and AIDS were diagnosed for relatively few women, the HIV/AIDS epidemic now represents a growing and persistent health threat to women in the United States as well as throughout the world.

Check out the most recent statistics from the Centers for Disease Control and Prevention (CDC): In 2001, HIV infection was the leading cause of death for African American women ages 25-34.1 It was among the four leading causes of death for African American women ages 20-24 and 35-44, as well as Hispanic women ages 35-44.1 In the same year, HIV infection was the sixth-leading cause of death among all women ages 25-34 and the fourth-leading cause of death among all women ages 35-44.1 On a global level, of the 14,000 people newly infected with HIV each day, nearly half are women.2

Getting a microbicide candidate from test tube to market shelf takes time — and money. A 2002 estimate pegged the cost of developing a single microbicide from preclinical research to market registration at about $57 million.3 No major pharmaceutical company has yet stepped forth to develop a product. Current clinical trials under way are supported almost exclusively by small biotechnology companies, academic centers, nonprofit and government organizations, and private foundations.3

Microbicide advocates are pushing on all fronts to speed progress of microbicide development. The Silver Spring, MD-based Alliance for Microbicide Development and the Washington, DC-based Global Campaign for Microbicides have just received grants totaling $5.7 million from the Seattle-based Bill & Melinda Gates Foundation to further their efforts in aiding science and policy research, public education, and advocacy for microbicides.

Progress is being made on the legislative level, as U.S. Senators Jon Corzine (D-NJ), Barack Obama (D-IL), and Olympia Snowe (R-ME) have introduced the Microbicide Development Act of 2005 in the Senate. The bill seeks to establish a microbicide research and development unit at the Bethesda, MD-based National Institutes of Health (NIH) and strengthen microbicide activity at the Washington, DC-based United States Agency for International Development and the CDC. It should be introduced in the second half of 2005 in the House of Representatives, says Heather Boonstra, senior public policy associate in the Washington, DC, office of the New York City-based Alan Guttmacher Institute.

Here’s how they work

How do microbicides work in warding off infection? Microbicides under development generally fall into four categories:

  • vaginal defense enhancers, products which boost the body’s natural defenses;
  • surfactants, which rupture the surface membranes of disease pathogens, thereby disabling them and preventing infection;
  • entry and fusion inhibitors, which bind to disease pathogens or to healthy cells before pathogens have a chance to attack them;
  • replication inhibitors, formulations that prevent viruses from replicating in invaded cells.3

While there are several microbicide candidates in the research pipeline, five are in Phase III clinical status. Of those five, BufferGel (ReProtect, Baltimore) is a vaginal defense enhancer; Savvy (C31G, Cellegy Pharmaceuticals, Brisbane, CA) is a surfactant; and Carraguard (Population Council, New York City), PRO 2000 (Indevus Pharmaceuticals, Lexington, MA), and Ushercell (cellulose sulfate, Polydex Pharmaceuticals Limited, Toronto) are all entry and fusion inhibitors. No replication inhibitor candidates have reached Phase III testing.3 Some of the microbicides under development will be able to provide HIV/STD protection and contraception.3

Five in advanced trials

Take a closer look at the five microbicides in advanced trials:

  • BufferGel (carbomer 974P).

BufferGel (carbomer 974P), developed at Baltimore-based Johns Hopkins University and ReProtect, is a gel that reinforces the protective vaginal acidity to kill sperm and inactivate several STD organisms, including HIV.4,5 It is involved in two advanced trials, one which is looking at its effectiveness as a contraceptive in conjunction with a diaphragm, and the other which is examining its potential in HIV protection. The contraceptive efficacy trial is completed, but it is not yet unblinded, says Richard Cone, PhD, ReProtect president. The HIV trial began enrollment in February at sites in Malawi, South Africa, Tanzania, Zambia, Zimbabwe, and the United States, he reports.

  • Carraguard (PC-515).

Carraguard, formerly known as PC-515, is a gel made from carrageenan, a substance derived from seaweed. In March 2004, the Population Council began a Phase III randomized, double-blind, placebo-controlled, efficacy study of the microbicidal product at three sites in South Africa, reports Diane Rubino, Population Council spokeswoman. The council is working with the Gugulethu-based University of Cape Town, the Soshanguve-based Medical University of Southern Africa, and the Isipingo-based Medical Research Council in these studies, says Rubino. Findings from safety and acceptability studies in South Africa and Thailand confirmed the topical safety of the compound.6

  • PRO 2000 (polynaphthalene sulphonate).

PRO 2000 (polynaphthalene sulphonate) is a compound that binds to HIV and other STD pathogens and prevents them from infecting human cells. Phase I testing indicated the product’s safety and acceptability,7 and it now is involved in a Phase II/IIb trial with BufferGel to test its effectiveness in protection against HIV infection in women. The microbicide also is scheduled to undergo Phase III testing in Uganda, South Africa, Tanzania, and Zambia in a study funded by the British government.8

  • Savvy (C31G).

C31G is an antimicrobial and spermicidal agent that contains two surface-active compounds: cetyl betaine and myristamine oxide. Used in a gel formulation, Savvy is being evaluated for its prevention of HIV transmission in two Phase III clinical trials in progress in Africa; it also is being evaluated in Phase III testing for use as a contraceptive.9

  • Ushercell (cellulose sulfate).

Ushercell, a gel formulation of 6% cellulose sulfate, is being tested on a number of fronts, reports Henry Gabelnick, PhD, director of the CONRAD program of the Eastern Virginia Medical School in Arlington. CONRAD is working in collaboration with Polydex Pharmaceuticals in developing the compound. CONRAD has just received a $12 million grant from the Bill & Melinda Gates Foundation and matching USAID funds to allow two multicountry Phase III clinical trials to test the product’s effectiveness in preventing HIV/ AIDS transmission.

One trial is a randomized, placebo-controlled Phase III study to determine the effectiveness of Ushercell to prevent HIV transmission when used vaginally in the same manner as a spermicide, says Gabelnick. Studies sites are located in Benin, Burkina Faso, Uganda, and South Africa.

A similar trial is being conducted in Nigeria by the Research Triangle Park, NC-based research organization Family Health International (FHI), with the drug supplies provided by CONRAD, says Gabelnick. FHI is providing statistical, monitoring, and social and behavioral science support for the multicountry trial, he states.

Moving forward on the microbicide front poses unique difficulties, observes Michael Rosenberg, MD, MPH, clinical professor of obstetrics and gynecology and adjunct professor of epidemiology at the University of North Carolina at Chapel Hill and president of Health Decisions, a private research firm specializing in reproductive health.

"The intensive search for a microbicide has been under way for more than a decade, with little to show for the modestly funded efforts to date," states Rosenberg, whose firm has been involved in microbicide testing. "This type of research is difficult because of the difficulty of enrolling and retaining large numbers of women using vaginal preparations for an extended time."

While one study of vaginal preparations recently was terminated because of inadequate enrollment, another study being conducted by Health Decisions under NIH contract has enrolled at a record rate, says Rosenberg. Lessons from this effort are being distilled in order to facilitate similar studies elsewhere, he adds.

References

1. Anderson RN, Smith BL. Deaths: Leading causes for 2001. National Vital Statistics Reports 2003; 52:32-33, 53-54.

2. Reuters. Women are key to reversing AIDS epidemic. Dec. 1, 2004. Accessed at: www.msnbc.msn.com/id/6630882/.

3. Upadhyay U. Microbicides: New Potential for Protection. INFO Reports, No. 3. Baltimore, Johns Hopkins Bloomberg School of Public Health, The INFO Project, January 2004.

4. Olmsted SS, Dubin NH, Cone RA, et al. The rate at which human sperm are immobilized and killed by mild activity. Fertil Steril 2000; 73:687-693.

5. Zeitlin L, Hoen T, Achilles S, et al. Tests of BufferGel for contraception and prevention of sexually transmitted diseases in animal models. Sex Transm Dis 2001; 28:417-423.

6. Population Council. The Population Council’s Lead Candidate Microbicide: Carraguard. Accessed at: www.popcouncil.org/biomed/carraguard.html.

7. Mayer KH, Karim SA, Kelly C, et al. Safety and tolerability of vaginal PRO 2000 gel in sexually active HIV-uninfected and abstinent HIV-infected women. AIDS 2003; 17:321-329.

8. BBC. UK funding for anti-HIV gel trial. April 5, 2005. Accessed at: http://news.bbc.co.uk/1/hi/health/4411877.stm.

9. Cellegy Pharmaceuticals. Concentrate on Savvy (C31G vaginal gel 1%). Accessed at: www.cellegy.com/products/savvy.html.