Two studies of cellulose sulfate microbicide halted; fails to protect women against HIV in one study

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An international phase III study of Ushercell, a cellulose sulfate microbicide, has been halted after the trial organiser found a higher rate of HIV infections in women randomised to receive the microbicide. A second study, in Nigeria, has been halted by sponsor Family Health International as a precautionary measure.

The reproductive health organisation CONRAD halted the study of the vaginal microbicide in South Africa, Benin, Uganda and India after seeing a higher rate of HIV infection in the microbicide group in a preliminary analysis. The study began in 2005 and was designed to recruit around 2500 women to test whether the cellulose sulfate microbicide could reduce HIV incidence in women by half compared to the placebo group.

Previous safety studies of Ushercell had produced no suggestion that the product posed any kind of risk to women. It was found to be just as safe as marketed spermicides and vaginal lubricants when tested across a wide range of studies, using endpoints such as vaginal irritation, changes in vaginal microflora, colposcopic changes, adherence and acceptability.

Glossary

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

Independent Data Monitoring Committee (IDMC)

An independent committee of clinical research experts that reviews data not available to the study team while a clinical trial is in progress to ensure that participants are not exposed to undue risks. A DSMB can recommend that the study be stopped if the intervention is not effective, is causing harm to participants or the study is not likely to serve its scientific purpose. Also known as an Independent Data Monitoring Committee (IDMC).

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

efficacy

How well something works (in a research study). See also ‘effectiveness’.

At this point, say the organisers of the study, it’s not clear why use of cellulose sulfate was associated with an increased risk of HIV infection in the CONRAD study. The Independent Data Monitoring Committee (IDMC), an independent advisory group of experts overseeing the trial, will conduct a detailed review of the data to better understand the findings, and help determine any implications for other microbicide studies.

Dr Lut Van Damme, principal investigator of the CONRAD trial, stated: "It was our hope that this product would have helped women in protecting themselves from HIV. While the findings are unexpected and disappointing, we will learn scientifically important information from this trial that will inform future HIV prevention research."

All participants received intensive HIV prevention counselling at each monthly visit and all women were given high-quality condoms free of charge. Participants received regular testing and treatment for sexually transmitted infections. Pregnant women were not included in the study. As part of the trial preparation, CONRAD set aside funding for women who become HIV-positive during the trial to ensure adequate health care, including HIV antiretroviral treatment when needed.

Family Health International has halted a second Phase III Ushercell trial in Nigeria. Although the FHI trial did not detect an increased HIV risk associated with cellulose sulfate, the decision was made as a precautionary measure, given the preliminary results in the CONRAD trial.

The Ushercell study is the second microbicide product trial to be halted by FHI. It halted a phase III study of Savvy in Nigeria last August because of a lower than expected rate of HIV infections in both arms of the study. The investigators concluded that a large trial of that product was unlikely to provide conclusive proof of efficacy because of the lowered rate of HIV acquisition.

Currently there are three other Phase III microbicide studies under way. The Carraguard study (sponsored by the Population Council and conducted in three sites in South Africa) is nearing completion and results are expected by the end of 2007.

Another product, PRO 2000, is being tested in one study in five sites in South Africa, Tanzania and Uganda (results expected in 2009) as well as in a second study in seven sites in Malawi, South Africa, Zambia and Zimbabwe (results expected in 2008). In this second study a further compound, BufferGel, (a vaginal defence enhancer) is being tested. All the other compounds mentioned are products that block HIV infection – known as HIV entry inhibitors – and have a similar presumed mechanism of action.