It took just 35 laboratory tests to bring more than seven years and millions of dollars of research to a shocking halt last week — and to dampen the hopes of protecting millions of women against HIV infection.
The Ushercell microbicide trial was stopped prematurely after the independent safety oversight committee discovered that more women using the anti-HIV gel in the overall trial had become infected with the virus than those using the placebo. Microbicides are gels or creams intended to be inserted into the vagina to protect women against HIV, and, potentially, other sexually transmitted diseases.
During the 18 months of the four-country trial, 35 of the 1 333 women taking part in clinical trials in South Africa, Uganda, Benin and India became HIV-positive. Of the 604 South African women who participated, about 20 became infected with HIV.
The research into the microbicide — known as a ‘chemical condom†— was being conducted for the United States-based non-profit health research organisation Conrad. Scientists are perplexed by the bad news from the Conrad trial because the microbicide had already undergone 11 safety trials involving more than 500 people in India, Africa and the US. Ushercell is a cotton-derived compound containing cellulose sulphate that does not act against the HI-virus itself, but is an entry inhibitor. Inserted less than an hour before sex, the microbicide spreads out, providing a physical barrier that prevents the virus from getting to cells in the vagina. It is also acts as a contraceptive.
So far, only basic data about the number of new infections in all the trial sites has been released. Because it is a double-blind trial, the South African researchers do not know who is receiving the placebo and who is receiving the trial drug, nor do they have access to the data given to the oversight committee that halted the trial. As a result, they cannot yet determine how many of the newly-infected HIV-positive participants are South African, or how many were in the control group and how many were in the groups using the gel. A thorough understanding of the trial result in South Africa will have to wait another couple of months until a detailed analysis is completed. This will break down the data by trial site and take into account other factors affecting trial results, such as the social behaviour of the participants.
The lead researcher for the South African arm of the trial is Dr Roshini Govinden of the Medical Research Council in Durban. Govinden says scientists do not understand the Conrad study finding because the large clinical trial conducted in Nigeria and the multiple safety tests dating back to 1999 had shown nothing of concern. ‘Hopefully, when we do the final analysis, we could learn something that will guide future trials. But if there is an increased risk, then we are ethically bound to stop.â€
The Nigerian trial found no adverse effects from use of the active gel. However, it was also stopped last week by its sponsors, Family Health International, because the compound failed to show a sufficient protective effect.
Scientists are also concerned about public misconceptions caused by the abrogation of the trials.
In an electronic newsletter this week the Treatment Action Campaign criticised a myth that ‘has been perpetuated by at least two senior South African politicians and we have encountered journalists who have mistakenly believed it. The myth is that participants in microbicide trials (as well as vaccine trials and the recently conducted circumcision trials) are encouraged to have unprotected sex or, in the myth’s most extreme version, exposed to HIV by researchers. This is false.â€
To get regulatory permission to do a clinical trial, researchers have to provide intensive ongoing HIV prevention counselling, including access to condoms and treatment for sexually transmitted diseases. Professor Helen Rees of the Reproductive Health and HIV Research Unit at Chris Hani Baragwanath Hospital says it has been found worldwide that women taking part in anti-HIV trials have lower infection rates than those from the same communities who do not participate, because of the prevention efforts built into the trials.
Health Minister Manto Tshabalala-Msimang has asked the newly formed National Health Research Ethics Council to investigate the microbicide trials under way in South Africa, including the Ushercell trial, to check whether all protocols have been followed correctly.
MRC president Professor Anthony Mbewu says his organisation agreed with the minister of health that an investigation be conducted. ‘I am certain the trials were conducted at the highest medical standards and with rigid adherence [to the protocols]. The problem is [with] rumours about trial irregularities — people may become reluctant to volunteer. Clinical trials are not a luxury or an intellectual curiosity, they are mandatory in South Africa.
‘My main concern is the anxiety and stress to women on this trial or other microbicide trials, and for South Africans who volunteer for clinical trials. Implying the MRC would be irresponsible in the way it conducts a clinical trial is very unfortunate. We have 500 000 new infections each year, of which about 200 000 are women aged less than 25. A microbicide could protect 100 000 women a year if it was only 50% effective. This is about saving the lives of young women.â€
Three other Phase III trials are under way, all involving South African sites. One, using the seaweed-derived Carraguard, is due to finish very shortly, and should present its results by the end of the year.
A researcher says the interim data analysis has left him ‘hopeful†about this microbicide’s safety and effectiveness.
The abrogation of this latest microbicide trial echoes a previous setback, when the COL-1492 microbicide trial among sex workers in KwaZulu-Natal was also found to produce more infections among women using the active product. In that case, the active ingredient was the spermicide, nonoxynol-9, which was found to cause inflammation that made it easier for HIV to enter vaginal cells. This factor had not been picked up in earlier studies because scientists had not realised how frequently the sex workers taking part in the study would use the microbicide — in this case up to 10 times a day.