CROI 2009: Microbicide May Be First to Protect Against HIV Infection

Bob Roehr

February 09, 2009

February 9, 2009 (Montreal, Canada) — The first successful clinical trial of a microbicide, a topical gel that can protect against vaginal infection of HIV, is offering hope to a field that has been battered by numerous failures.

Although the result was not statistically significant, there was a 30% reduction in new HIV infections among women using 0.5% PRO 2000 gel (Indevus Pharmaceuticals Inc), compared with those using a control gel in this phase 2b study, principal investigator Salim Abdool Karim, MD, from the Center for the AIDS Program of Research in South Africa (CAPRISA), in Durban, reported on behalf of colleagues.

A second microbicide tested in the trial, BufferGel (ReProtect Inc.), showed no efficacy in reducing transmission.

Results were presented here at the 16th Conference on Retroviruses and Opportunistic Infections. In addition to his position at CAPRISA, Dr. Karim is pro vice-chancellor at the University of KwaZulu-Natal, in South Africa, professor of clinical epidemiology at Columbia University, in New York City, and adjunct professor of medicine at Cornell University, in Ithaca, New York.

At the meeting, session cochair Myron Cohen, MD, from the University of North Carolina, in Chapel Hill, called this “a very important study. We finally have a [positive] signal in the microbicide field, and that is a thrilling event.”

Study Design

PRO 2000 is a negatively charged polyanion that is thought to bind to the negatively charged V3 loop of the virus. HIV uses the V3 loop to bind to a cell, but when the compound preferentially binds, it prevents that first step of viral entry and infection.

HPTN 035 was a phase 2b study designed to test whether PRO 2000 and BufferGel separately might protect against infection through vaginal exposure to HIV.

The 4-group study randomly assigned 3099 women at sites in 7 countries in southern Africa and the United States to receive no gel, a placebo gel, BufferGel, or PRO 2000 (0.5-mg dose). They were followed for an average of 20.4 months, retaining 93.6% throughout the duration of the trial, with similar retention in all groups. Safety issues were minimal and similar across all of the groups.

A total of 194 HIV infections occurred during the study: 36 in the PRO 2000 group, 54 in the BufferGel group, 51 in the placebo group, and 53 in the no-gel group. Self-reported use of the gel was similar (81%) in all 3 groups.

Condom use rate was 81% among women who did not use a gel, but it was 72% among women who used a gel, increasing the concern that use of microbicides might lead to behavior inhibitions, such as decreased use of condoms, which increases a person's overall risk for infection.

There was no benefit to using the placebo gel, a substance similar to the lubricant KY jelly, over using no gel.

BufferGel provided no additional protection, compared with placebo, a result confirming what has been seen in other trials. Its mechanism of action is to enhance the vagina's natural acidity, which is neutralized by the introduction of semen, which is alkali.

Results Not Statistically Significant in ITT Analysis

Comparing PRO 2000 with the placebo gel, the study found a hazard ratio of 0.7 (95% CI, 0.5 – 1.1; P = .10). "That translates to a 30% level of protection" using the intention-to-treat (ITT) analysis of the original protocol, Dr. Karim explained. However, he added, this level of protection "is just outside [of being] statistically significant."

Women who became pregnant were asked to stop using the product for the duration of that pregnancy. A post hoc per-protocol analysis that excluded these women for the time they were not using PRO 2000 found a 36% reduction in HIV infection, which was significant (P = .04).

However, Dr. Karim chose to hew to the more conservative ITT analysis. Those results approached but did not achieve statistical significance; the trial was not adequately powered to demonstrate statistical significance, he said. "Additional evidence is needed to conclusively determine whether PRO 2000 is an effective microbicide."

Self-reported median use of the gel occurred during 85% of sexual acts. An analysis that stratified participants into high and low groups along this axis found a benefit for those who used the microbicide more frequently. He said women who combined low use of condoms with high use of gel had a 78% reduction in HIV infection, compared with 13% in women with low use of both condoms and gel.

Speaking from the audience during the question-and-answer session, a University of Toronto researcher thought that Dr. Karim was parsing the line of significance too finely. He asserted, within a public-health setting, "the conclusion is that this product works."

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, called the results "encouraging" in a statement released by his office. He cautioned: "More data are needed to conclusively determine whether PRO 2000 protects women from HIV infection." He added that such a product "would be a valuable tool that women could use to protect themselves against HIV."

Dr. Karim told Medscape HIV/AIDS that an ongoing trial of PRO 2000, sponsored by the UK Microbicides Development Programme (MDP), should have results by the end of 2009. It is a shorter-duration phase 3 trial involving more than 9000 women in South Africa, Tanzania, Uganda, and Zambia. It is effectively powered to answer the question of efficacy.

Increasing Options

Within a public-health context, particularly for married women who want to become pregnant and who may not be able to trust their husband to remain monogamous, "30% to me is a big difference," he said. It is less important in a context where women might be able to get men to use condoms. "It is important if it increases the options that are available."

Dr. Karim believes that regulatory consideration of PRO 2000 will vary by jurisdiction and prevalence of infection in that country. It will also "depend upon how compelling the MDP study result is" and how narrow the confidence interval is in that study.

He believes the safety of the product is established. Given that, and "based upon the public health benefit," the current trial and the ongoing MDP trial may be sufficient for approval in South Africa. Approval in the United States and Europe is likely to be more difficult, although the case for use by high-risk populations may be sufficient to warrant some kind of approval.

The HPTN 035 study was supported by National Institute of Allergy and Infectious Diseases. BufferGel and PRO 2000 were provided by the companies developing them. Dr. Salim and Dr. Cohen have disclosed no relevant financial relationships. Dr. Fauci's agency provided funding for the study.

CROI 2009: 16th Conference on Retroviruses and Opportunistic Infections: Abstract 48LB. Presented February 9, 2009.

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