Research halted on cellulose sulfate microbicide — What's next in research?

Scientists push onward, candidates proceed in Phase III testing

While two advanced trials have been closed for one microbicide candidate for HIV prevention in women, researchers are pressing forward in examining other contenders that may prove safe and effective in the fight against the AIDS epidemic.

CONRAD, a reproductive health research organization in Arlington, VA, halted its Phase III clinical trial of a cellulose sulfate gel after preliminary results indicated it could lead to an increased risk of HIV infection in women who use the compound. A separate advanced study of the microbicide, conducted by Family Health International (FHI), a Research Triangle Park, NC-based research group, also was closed after scientists determined there was no evidence that the product was effective in preventing HIV. Announcement of both trials' closing was made in January 2007.

Known as Ushercell, the cellulose sulfate gel is a cotton-based compound developed by Polydex Pharmaceuticals Ltd. in Toronto. Prior to the advanced trials, the compound had been evaluated in 11 clinical safety and contraceptive trials involving more than 500 participants. Results from these studies indicated that the compound was safe; in laboratory studies, cellulose sulfate exhibited antimicrobial activity against several sexually transmitted infections, including HIV.

A 'profound disappointment'

While the closing of the trials is a "profound disappointment" for the microbicide field, science must continue to advance in the search for female- controlled HIV prevention, says Zeda Rosenberg, ScD, chief executive officer of the International Partnership for Microbicides, a nonprofit research group. In 2006, about 17.7 million women around the world were living with HIV, an increase of more than 1 million compared with 2004 figures.1) "Prevention is the only way out of this epidemic, and a safe and effective microbicide can be a vital tool," said Rosenberg in a statement on the trials' closing. "This is why we and others have been working so hard to expand the microbicide pipeline."

Developing new tools to prevent HIV — particularly for women — is an urgent priority, says Henry Gabelnick, PhD, CONRAD executive director. "We are committed to learning as much as possible from the trials of cellulose sulfate and will use that knowledge to continue searching for compounds and collecting evidence to find a successful microbicide," said Gabelnick in a statement following the trial's cessation. "Continued support for microbicide research is critical to our eventual success."

What led to closing?

Recruitment for the CONRAD Phase III study began in July 2005. The research was held at sites in South Africa, Benin, Uganda, and India. To perform the double-blinded randomized trial, half of the participating women were given cellulose sulfate, and half were given a placebo gel. All women in the study received intensive HIV prevention counseling at each monthly visit and were provided condoms free of charge. Participants received regular testing and treatment for sexually transmitted infections (STIs).

It is not clear why use of cellulose sulfate was associated with an increased risk of HIV infection in the CONRAD trial. An independent advisory group of experts will conduct a detailed review of the data to better understand the findings and help determine any implications for other microbicide studies.

The FHI study was conducted among about 1,700 women in Lagos and Port Harcourt, Nigeria. As with the CONRAD trial, participants received HIV prevention counseling, condoms and, when needed, treatment for STIs. While an independent review board did not find any evidence of greater risk of HIV infection in the interim results from the trial, it also found no evidence that the study gel was effective in preventing HIV.

In a press statement on the Ushercell trial closings, Polydex said it will continue to evaluate Ushercell's attributes, including its potential use as a contraceptive product.2 Research presented in 2006 indicates that Ushercell may be as effective as N-9 as a contraceptive.3

What will work?

The road to a safe, effective microbicide has not been a smooth one. Investigations of nonoxynol-9 (N-9) as a potential microbicide candidate ended after research indicated that multiple uses of a low N-9 gel formulation, known as COL-1492 or Advantage-S, could cause toxic effects, enhancing HIV-1 infection.4

In August 2006, FHI halted a Phase 3 trial in Nigeria of a vaginal gel, Savvy (C-31G), after an interim data review concluded the trial was unlikely to provide convincing evidence that the gel conferred HIV protection. A Savvy trial in Ghana also was closed on similar grounds by FHI in November 2005.

Three Phase III studies are ongoing on the following microbicide candidates:

• Carraguard.

Carraguard (PC-915) is a noncontraceptive product made from carrageenan, which is derived from seaweed. The study, sponsored by the Population Council, a New York City-based research group, is being conducted in three sites in South Africa. Enrollment ended in June 2006. Results are expected at the end of 2007.

• PRO 2000.

PRO 2000 (polynaphthalene sulphonate) is a synthetic polymer that binds to the HIV virus. Under development by Indevus Pharmaceuticals of Lexington, MA, the candidate is being tested in one study in five sites in South Africa, Tanzania and Uganda, as well as in a second study in seven sites in Malawi, South Africa, Zambia, and Zimbabwe. Results from the five-site trial are expected in 2009, while results from the seven-site study are scheduled for 2008.

• BufferGel.

BufferGel (carbomer 974p), is a gel that reinforces the protective vaginal acidity to kill sperm and inactivate several STI organisms, including HIV. Under development by ReProtect in Baltimore, it is being evaluated in the same trial in Malawi, South Africa, Zambia, and Zimbabwe as PRO 2000.

BufferGel is considered a vaginal defense enhancer, while Carraguard and PRO 2000 are known as HIV entry inhibitors.

Research moves forward

While scientists continue to review the data from the closed cellulose sulfate trials, researchers are moving forward on other microbicide candidates. According to the Alliance for Microbicide Development, a Silver Spring, MD-based advocacy group, studies of vaginal defense enhancers, HIV entry/fusion inhibitors, and replication inhibitors are now in various stages of research.

While the halting of the cellulose sulfate trials is a "disappointing and unexpected setback," the need to continue research to find a user-controlled means of preventing HIV infection in women is urgent, say officials with UNAIDS and the World Health Organization. "Despite the effectiveness and availability of condoms, the HIV epidemic continues to spread, and the search for a safe and effective microbicide is a vital part of the effort to stem the spread of the HIV epidemic," organization officials said in a joint statement.

References

  1. UNAIDS/WHO. Global facts and figures. Fact sheet. Accessed at: data.unaids.org.
  2. Polydex Pharmaceuticals Limited. Polydex Pharmaceuticals reports Phase III trial of Ushercell for HIV Prevention Halted. Press release. Jan. 31, 2007.
  3. Mauck CK, Frezieres RG, Walsh TL, et al. Noncom-parative contraceptive effectiveness trial of cellulose sulfate gel. Obstet Gynecol 2006;107:14S.
  4. Van Damme L, Ramjee G, Alary M, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: A randomised controlled trial. Lancet 2002; 360:971-977.