When a field is besieged by failures, small steps forward seem like great triumphs. That’s the case with the latest effort to protect women at high risk of being infected with HIV. Two large trials of a vaginal ring that slowly secretes an antiretroviral drug into the vagina found that it reduced infections by about 30%. The placebo-controlled trials involved a total of 4500 women in four countries in sub-Saharan Africa. “It’s an enormous victory,” says Sharon Hillier, a reproductive infectious disease specialist at the University of Pittsburgh in Pennsylvania who helped coordinate ASPIRE, the larger of the two studies—and has led trials of similar interventions that failed.
Others who are not involved with the studies are more measured. “The good news is the trials provide a consistent finding: The ring provided modest protection,” says Mitchell Warren, who heads AVAC, a nonprofit in New York City that advocates for HIV prevention. “But it is oh so modest.”
Researchers long have attempted to develop an HIV preventative specifically for women. But the most promising candidates—compounds called vaginal microbicides that thwart the virus at the site of infection—have failed repeatedly in clinical trials. “This [set of studies] was the last hope for microbicides in many ways,” says Thomas Hope of Northwestern University’s Feinberg School of Medicine in Chicago, Illinois. Hope, who was not involved with the new studies, says, “I was expecting the results to be depressing.”
The ring, a silicon band that releases an experimental antiretroviral called dapivirine, was tested in South Africa, Malawi, Uganda, and Zimbabwe among 18- to 45-year-olds. The ASPIRE trial found 27% efficacy overall, while the second trial—called The Ring Study—found a 31% efficacy.
But the ring didn’t do nearly as much for women aged 18 to 21, conferring a mere 15% protection in The Ring Study and had none whatsoever in the ASPIRE trial. In women over 21, however, efficacy hit 56% in ASPIRE; The Ring Study showed 37% protection in the older group. No serious safety concerns surfaced in either study.
The findings were presented publicly for the first time today at a press briefing at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. ASPIRE results also appear in a paper published online today in The New England Journal of Medicine. Researchers from both trials will present their findings in more detail later this week in scientific sessions at CROI.
Each study—held in parallel to speed up regulatory approval—cost an estimated $72 million. The U.S. National Institute of Allergy and Infectious Diseases provided the main funding for ASPIRE, which was run by the Microbicide Trials Network that Hillier heads. The International Partnership for Microbicides (IPM), a nonprofit headquartered in Silver Spring, Maryland, led The Ring Study. IPM also developed the ring and licensed dapivirine from Janssen Sciences Ireland UC.
“I think it’s a bold step in the right direction, and it gives the field something to build on,” says Robin Shattock, who studies mucosal immunology and HIV transmission at Imperial College London and chairs IPM’s scientific advisory board. “Scientifically, there’s lots that can be done to improve on this and make it better.”
Preliminary evidence suggests the ring offered less protection in younger women because many did not wear it for the entire 28 days between each study visit. Levels of dapivirine—which go down each day that the rings are used—were higher in some used rings than others. Greater protection occurred when there was less dapivirine left. “It’s a bit of a ‘duh’ moment,” says epidemiologist Zeda Rosenberg, CEO of IPM. “Anything will only work if it’s used.”
Adherence issues have dogged other pre-exposure prophylaxis, or PrEP, strategies designed to prevent HIV infection, most of which require taking an anti-HIV pill each day. But researchers had hoped that a ring that can be inserted once a month and left alone would circumvent that problem. Based on monthly blood samples, Hillier says, they initially thought they were right. But they may have been misled by trial participants who reinserted rings before study visits to please the researchers. “We call this the ‘white coat’ effect,” Hillier says, explaining that if women inserted the ring the day before testing, they would have ample drug in their blood.
Biological factors could also help explain the lower efficacy in the younger women. “Differences in the genital tract may make them more susceptible to infection,” Shattock says. Another possibility is that they had more sex with HIV-infected partners. But in ASPIRE, the rate of new infections in women who received rings containing a placebo was 5.4% per year in the 21 and younger group—similar to the 6.1% incidence per year in the 22-to-26 age bracket.
In the future, researchers hope to test higher levels of the drug—or more potent antiretrovirals—in vaginal rings. IPM plans to make a ring that secretes the drug for 3 months. And researchers imagine that many women would find the product more appealing if it combined anti-HIV drugs with contraceptive hormones, which are already sold worldwide in vaginal rings.
Whatever the shortcomings of the 28-day dapivirine ring tested in these two studies, IPM plans to apply for regulatory approval in about 1 year. Rosenberg anticipates that each ring initially will sell for about $5.