The largest study ever conducted of a microbicide designed to prevent HIV infection has resulted in yet another case of high hopes being dashed about a promising product. Earlier in the year, a smaller study of the same vaginal gel gave a hint that it might offer modest protection, but the new results put the question to rest. "It doesn't work," says clinical epidemiologist Sheena McCormack, who ran the four-country study for the Clinical Trials Unit of the U.K.'s Medical Research Council.
McCormack says the data mark the end of the road not just for this vaginal gel but the whole class of microbicides that use nonspecific compounds to prevent HIV-infection. The placebo-controlled trial in nearly 9500 women tested a gel called PRO 2000, a so-called polyanion that prevented the AIDS virus from entering human cells in test-tube and monkey studies. The 4-year, $44 million study at six sites in sub-Saharan Africa found no difference between the equally sized treatment and placebo arms of the study: There were 130 HIV infections in the women who used PRO 2000 and 123 in those who used a dummy gel.
Researchers in the beleaguered HIV-prevention field often see glimmers of hope even in dispiriting results from clinical trials--witness the recently completed AIDS vaccine study in Thailand. But that is not the case with these findings. "When I first looked at the data with the statistician I said, 'You're not going to need any more analysis, are you?' " said McCormack, who is based in London. "It's really clear-cut."
In February, a similar study of PRO 2000 that only involved about one-third as many women found 30% fewer HIV infections in the treated group , but with a p-value of 0.10--a positive trend that did not reach statistical significance. That $90 million study, financed by the U.S. National Institutes of Health (NIH), startled many in the field who, based on other failures of nonspecific microbicides, had predicted the product would do nothing. But McCormack notes that the new results actually are consistent with the data from the earlier trial, which had a wide confidence interval and included the possibility that the product did not work.
McCormack says there's one upside of the failure: It informs future clinical trials. Because the findings clearly show that the positive test-tube and monkey studies of PRO 2000 were misleading, researchers now know to use more stringent requirements to deem a product worthy of human trials.
The microbicide field now has had several failed efficacy studies both with polyanions and another class of nonspecific compounds called surfactants. Trials are now under way with several products that target HIV specifically. Sharon Hillier and Ian McGowan of the U.S.-based Microbicide Trials Network, which ran the NIH-funded study of PRO 2000, said in a release issued today that the new results "raise little doubt that at this juncture, agents with specific action against HIV, such as antiretroviral drugs, offer the most hope."