Microbicide researchers are focusing on adherence strategies as setbacks mount
IAS conference held uninspiring news
As microbicide research for HIV prevention emerges from its infancy, researchers are learning many hard lessons. "These can be phrased as either design challenges or lessons learned in terms of how to make the future trials better," says Ward Cates, MD, MPH, president of research for Family Health International of Research Triangle Park, NC. Cates spoke about clinical trial design challenges in HIV prevention research at the 4th International AIDS Society (IAS) conference on HIV Pathogenesis, Treatment, and Prevention, held July 22-25, 2007, in Sydney, Australia.
Cates was among the investigators who presented research at IAS about one of the year's largest microbicide disappointments: cellulose sulfate gel.
Earlier this year, investigators prematurely stopped microbicide trials in Nigeria, studying cellulose sulfate gel, after an interim analysis showed an unexpected trend of women using the study product being put at greater HIV risk.1
The reasons for this result are still unclear, but researchers of other HIV microbicide trials say that one of their chief problems involves adherence.
Measuring adherence is such a complex process, says Veronica Miller, PhD, director of the Forum for Collaborative HIV Research in Washington, DC, and a research professor in the department of prevention and community health in the School of Public Health and Health Services at The George Washington University.
In the case of oral microbicides or pre-exposure prophylactics, investigators could use the MEMScap device to measure adherence. This involves having participants open a pill bottle that has a microchip installed, which measures the time and date they open the bottle to take a pill, Miller says.
"You can also, from time to time, check their plasma drug levels and see if there's any drug in the person's blood," Miller says.
But it's a logistical challenge to measure adherence for microbicide methods that are dependent on being used before a sex act, Miller notes.
For this reason, some microbicide researchers are looking into some new ways to measure and improve adherence.
For instance, one new method in microbicide research would be similar to directly-observed therapy.
It would work by having women visited or having them come into a clinic when it's time to insert their product. They'd be left alone for the actual insertion to maintain their privacy.
"That's something we've been talking about, adapting a directly-observed therapy approach, says Zeda F. Rosenberg, ScD, chief executive officer of the International Partnership for Microbicides (IPM) of Silver Spring, MD.
"It may not have to be in a clinic," Rosenberg says. "There are many novel ways of contacting women daily, including home visits, drop-in centers, so long as they are afforded privacy so there is not someone actually watching the gel insertion."
IPM is looking at models to pilot in studies to see how women in the communities heavily impacted by the epidemic feel about this approach, she adds.
Adherence might have been one of the reasons why one study involving using a diaphragm and standard lubricant gel showed no impact on preventing HIV infection, notes Nancy Padian, PhD, a professor in obstetrics, gynecology, and reproductive health sciences, and an executive director of the Women's Global Health Imperative, at the University of California — San Francisco. Padian presented findings on the diaphragm study and other research at the recent IAS conference.
"We're just digesting our results and trying to understand why we had no [positive] results," Padian says.
"We think many things are going on, and one is it could be adherence," Padian says. "If people are not going to use the diaphragms, then they're not going to be effective."
Investigators need to understand how they can do a better job of improving adherence, Padian says.
Another issue involves whether adherence to microbicides will work in the real world once a microbicide product has been proven effective.
If study participants are not adequately motivated to adhere to their study intervention, then will women be motivated once the drug is on the market?
While this is an interesting question, many microbicide researchers believe motivation will be greater in the real world.
"Once you know something works, your motivation for using it changes," Rosenberg says. "What we really need to do, and the highest priority is [obtaining] a proof of concept that a microbicide can prevent HIV, and then there's a huge amount of work that can go into figuring out the ideal formulation."
"Say a daily microbicide gel is shown to work," Rosenberg says. "Then we can work on the monthly rings, and there a number of different ways we can improve compliance — that's the history of contraception."
There are multiple ways to improve the overall adherence and adapt a product to women's lives, but first investigators have to show that the product works, she adds.
If women in studies don't adhere well to the intervention, then the study will lose the power it needs to prove the concept, she notes.
Microbicide researchers say they're committed to finding an HIV prevention product that is female-controlled, even though the latest research has not been promising.
Many studies involving microbicides were presented at the 4th International AIDS Society (IAS) conference on HIV Pathogenesis, Treatment, and Prevention, held July 22-25, 2007, in Sydney, Australia, but their combined news was uninspiring, HIV researchers say.
"In terms of prevention, it wasn't a particularly uplifting conference," Rosenberg notes.
"The needs for women-initiated intervention clearly does not go away," Rosenberg says. "I think we all knew it would be difficult to develop prevention technologies, and these trials confirm that difficulty, but I don't think anybody is giving up by any means."
Other women researchers echo these sentiments: "I'm still absolutely committed to female-controlled methods," Padian says.
The diaphragm study did not involve a microbicide, but investigators still expected some HIV prevention benefits for women who used the barrier contraceptive method, but the results showed no additional protection against HIV, Padian says.
All study participants received education and support in using existing prevention methods, in-cluding condoms and sexually-transmitted disease (STD) treatment, Padian notes.
"We were looking at whether the diaphragm and lubricant gel provided additional benefits, but it didn't," she says.
In light of these trying times for microbicide and female-controlled prevention research, it's important that all prevention approaches continue to be studied and pursued, Miller says.
The global prevention agenda focuses on clinical trials for microbicides, vaccines, and other approaches, as well as on the behavioral component, which remains a very important part of HIV prevention, Miller says.
The same behaviors promoted to prevent HIV are what also are needed to make the microbicides work, Miller notes.
"If we have an HIV vaccine, then you'd get a shot, and that's it," Miller says.
But if a microbicide is shown to be effective in preventing HIV, then people will need to be taught to take it each day or to use it each time they have sex, and this behavioral change will be more difficult to implement, Miller explains.
On the positive side, there's been very good news with regard to the circumcision trials, and the international health community plans to implement circumcision programs as safely and quickly as possible, the experts say
"In terms of a technology that can reduce new infections, it is without equal at this time," Rosenberg says. "It's a great intervention."
Circumcision is a very important prevention strategy, but the HIV community still needs methods women can use, Padian says.
For instance, maybe oral prophylaxis studies will show good results before investigators find a vaginal method, and then the vaginal method will be less important, Padian suggests.
"We want something out there that will work as fast as we can get it," she says.
The microbicides field faces incredible challenges, Miller notes.
"It's such a wonderful idea if we could show that it works with something completely female-controlled, female-used," Miller says. "The challenge is that we don't have a microbicide that works currently in preventing disease, so we're starting from scratch."
Meantime, there is always the female condom, which has proven its prevention efficacy, Padian says.
"In my plenary [at the IAS conference] I said, 'I think we have to keep the female condom on the radar screen,'" Padian says. "There are new female condoms out that are cool and easy to use, and even if only a few women use them, then it's still something, and there may be no one magic bullet."
- Halpern V; et al. Effectiveness of cellulose sulfate gel for prevention of HIV: results of the phase III trial in Nigeria. Presented at the 4th International AIDS Society (IAS) conference on HIV Pathogenesis, Treatment, and Prevention, held July 22-25, 2007, in Sydney, Australia.