References:
Van Damme L et al. Phase III trial of 6% cellulose sulfate (CS) gel for the prevention of HIV transmission. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract WESS301, 2007.
Halpern V et al. Effectiveness of cellulose sulfate gel for prevention of HIV: results of the phase III trial in Nigeria. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract WESS302, 2007.
The cellulose sulphate microbicide UsherCell did not protect women against sexual transmission of HIV, and may even have contributed to an increased risk, according to two studies presented on Wednesday at the 4th International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention in Sydney.
In an effort to further reduce the spread of HIV, researchers have sought to develop women-controlled prevention methods. One such technology is microbicides, gels or similar products applied in the vagina or rectum to prevent HIV infection.
UsherCell is a microbicide gel containing 6% cellulose sulphate. It has shown activity against HIV and other sexually transmitted infections, and also has been tested as a contraceptive.
The gel gave no indication of potential for harm in preclinical testing, and it appeared acceptable to women and caused minimal side effects when used vaginally. In ten earlier human safety studies and two contraceptive trials, cellulose sulphate showed no evidence of harm. Women using UsherCell had similar symptoms, laboratory results and incidence of vaginal infections as those using an inactive placebo gel.
However, a large-scale phase III study of UsherCell conducted by CONRAD in Benin, South Africa, Uganda and India was halted in January 2007 by the study’s Independent Data Monitoring Committee after an interim analysis showed that there were actually more HIV seroconversions among women using cellulose sulphate gel compared with women using placebo gel.
In the interest of safety, Family Health International (FHI) also discontinued a similar UsherCell trial in Nigeria, even though interim data from that study did not show an increased risk of HIV infection.
At the Conference on Retroviruses and Opportunistic Infections this past February, lead investigator Dr. Lut van Damme discussed the discontinuation of the CONRAD trial, but announced that data would only be released after further analysis. While analysis is still ongoing, she presented some of this data in Sydney.
The CONRAD investigators planned to recruit 2574 HIV-negative women with multiple partners who were considered to be at high risk of HIV infection. At the time the study was stopped, 2985 women had been screened and 1428 had been enrolled. About 88% completed the full one-year follow-up period, 10% were lost to follow-up and 2% discontinued early.
Across all five study sites, the average age of the participants was 30 years, about 90% had been pregnant, and they had had vaginal intercourse an average of eleven times during the past seven days. Self-reported condom use was about 60% at screening, rising to about 80% at the time of enrolment.
In this blinded trial, participants were randomly assigned to receive either 6% cellulose sulphate or placebo gel. They were instructed to apply the gel vaginally, using an applicator, no more than one hour before sexual intercourse.
At the time of the interim analysis, 35 women were newly infected with HIV: 24 in the UsherCell arm and eleven in the placebo arm. The relative risk in the UsherCell arm was 2.23, or about twice the risk.
In the final intention-to-treat analysis, which included all women who were randomised and for whom follow-up data were available, there were 25 new HIV infections in the UsherCell arm and 16 in the placebo arm, a difference that did not reach statistical significance.
Looking at other sexually transmitted infections, 53 women in the UsherCell arm and 49 in the placebo arm were diagnosed with gonorrhoea and 37 and 52 women, respectively, were diagnosed with chlamydia. The difference in infection rates was not statistically significant for either disease.
The investigators concluded that cellulose sulphate is not effective against HIV transmission. Further, Dr. Van Damme said, “there may be an indication of increased risk” for women using UsherCell.
As noted, the interim findings from the CONRAD trial also led to the premature termination of the FHI UsherCell trial. William Cates presented data from that study in Sydney.
This phase III trial was conducted in Lagos and Port Harcourt, Nigeria. The study planned to recruit 2160 HIV-negative, at-risk women. At the time the trial was stopped, 3618 had been screened, 1644 had enrolled, and 1153 had completed the full study before its termination.
Compared with the CONRAD study, the women in the FHI trial were younger (average age 23 years), 80% had been pregnant, and they had had vaginal sex an average of six times during the prior week. Rates of condom use were similar to those in the CONRAD study.
In this trial, too, participants were randomly assigned to apply 6% cellulose sulphate gel or a placebo gel before each act of vaginal intercourse.
At the time the study was halted in late January, there had been 21 total new HIV infections: nine in the UsherCell arm and twelve in the placebo group. In a final intention-to-treat analysis, there were ten new infections in the UsherCell group and thirteen in the placebo group. Neither of these differences was statistically significant.
The researchers concluded that they did not observe any effect - in either direction -- of cellulose sulphate gel on the risk of vaginal HIV transmission.
The reasons for the larger number of new HIV infections in the UsherCell arm of the CONRAD trial are not clear, nor are divergent outcomes in the CONRAD and FHI studies.
Dr. Van Damme suggested some possible hypotheses, including inflammatory reactions, localised immune dysfunction or disruption of the normal vaginal flora with frequent cellulose sulphate use. Researchers are currently conducting extensive testing to shed further light on the CONRAD results.