Expert offers look at issues in microbicide research

Here is what needs to be overcome

Along with adherence, there are a number of challenges HIV researchers face when they work in the field of microbicides.

Ward Cates, MD, MPH, president of research for Family Health International (FHI) of Research Triangle Park, NC, offers these examples of some of the bigger obstacles that need to be overcome:

1. Adherence to study product:" What we've learned is that there are better ways that we can assess whether or not a product, such as microbicides, are being used," Cates says.

Microbicides typically are difficult for patients to adhere to because some require use with coitus and others must be used on a daily basis, he notes.

The problem for HIV investigators is measuring adherence of a product that needs to be inserted.

"We have some new approaches to improving accuracy, including testing applicators to see if they've been inserted," Cates says.

Also, computer-assisted reports by patients tend to be more accurate indicators than the reports patients give to counselors, he says.

Trial participants often will tell counselors that they're using more product than they are, Cates adds.

The reason for this has to do with social desirability bias.

"What we have found in areas involving sensitive questions, and especially in settings where you have a particular counselor communicating with participants that they need to use condoms all the time and the [microbicide] gel all the time, is that when we ask them if they've used condoms or gel, they try to please the person asking them the question," Cates explains.

When the participant is asked the same question on a computer, they tend to give a more accurate answer, according to studies, Cates adds.

"We have a variety of different approaches to measuring adherence," Cates says. "We're doing some studies where we're testing drug levels, and there are designs that are being talked about now that will involve direct observation."

Direct observation would involve having women come to a clinic each day to pick up their applicator, and then they are sent to the restroom to insert it, he explains.

2. Avoid unintended pregnancies: In HIV prevention research in resource-poor countries, it is a challenge to avoid unintended pregnancies among study participants.

"We have found unexpectedly high levels of pregnancy in National Institutes of Health studies," Cates says. "We have held workshops about this, and we've built into future designs the screening tools for identifying [and recruiting] people who don't want to get pregnant."

The second strategy is to provide participants with effective contraception at the study visit, Cates adds.

"In the past, we accepted their word that they did not want to get pregnant, and we referred them to a family planning center," Cates says.

3. Anticipate low levels of HIV incidence: Microbicide researchers often have discovered lower levels of HIV incidence in trials than they had estimated prior to initiating the studies, Cates says.

One of the problems was they had used crude measurements of HIV prevalence and estimates of HIV incidence, he says.

"In various studies, we'd go in with pre-trial estimates of incidence of 3 or 4 percent, and we'd sometimes find much lower rates," Cates says.

The good news was that participation in the trial tended to provide participants with effective standards of prevention care, including condoms, and this partly contributed to lower rates of infection, Cates says.

But it created scientific and statistical problems.

"So we're trying to improve our estimates," Cates says. "We may need more participants or to run the trial longer for us to validly prove [the product's efficacy]."

For example, in some West African microbicide trials, the studies were stopped because there wasn't high enough HIV incidence, Cates says.

"The trials had to be stopped because we didn't get an answer," he says.

Once a trial has begun and this problem arises, it cannot be easily fixed.

"You have a design and [you] assume that the HIV incidence was 4 per 100 persons, and you calculate the sample size and budget based on recruiting that number of people, and you are getting that number of end points through the trial," Cates says. "Then you realize that the number of end points you're getting is much lower than what you'd need, and so you have to make a judgment call as to whether to spend more money to recruit more participants or to follow participants longer, and whether or not the early distribution of events you have had would justify your spending more money."

With the trial of 331G in Ghana, FHI looked at this problem and decided there was no clear trend toward a protective affect in the 331G arm, so they stopped the trial because of feasibility, Cates says.

"We did not have enough events or positive distribution to justify spending additional money on a gamble that this would be an effective product," Cates says.

It's a very valuable lesson learned that scientists in a variety of organizations and studies have made this decision to stop a trial because the HIV incidence was so low and they could not achieve their end points, Cates says.

The solution to this dilemma is to use better measures, including measures of acute infection through pooled specimens, Cates says.

"These will make better estimates of what will be the true incidence in a trial, and allow comparisons," he says.

4. Provide follow-up on participants who seroconvert: There needs to be an ethical standard of care for people who volunteer for trials, and they should be provided further access to health care, Cates says.

Also, the follow-up might provide interesting study answers and questions.

"Some of these interventions may have an effect on actual viral progression itself," Cates says.

For example, the current vaccines under study, and at least one antiretroviral drug being tested in monkeys, has shown less effect on preventing infection and more of an effect on lowering the initial viral load during the acute phase, Cates explains.

This meant the people who did seroconvert had a lower viral set point and a better HIV prognosis, he adds.

"So it would be important to recruit all of the seroconverters, whether in the active arm or the placebo arm, and follow them further in time to see if the preventive effect would be less on those acquiring infection and more on disease progression," Cates says. "That would be a valuable less learned."

In other words, through follow-up, investigators might witness secondary prevention effects, he says.

This is not a new concept, Cates notes.

In the early polio vaccine studies, researchers found that the vaccine didn't impact polio infection, but it mitigated some of the consequences of polio among those who did become infected, Cates adds.

5. Make trials more cost efficient: Prevention studies are very expensive because researchers have to follow thousands of people to come up with the necessary end points, Cates says.

"If HIV incidence determines validity, and there's a cost per participant, then you have to build a budget around the estimated number of participants you have to recruit and follow," Cates says. "The cost per end point is only something you can judge accurately at the end of the trial, depending on what the true incidence was."

Research sites tended to underestimate the costs of HIV prevention trials previously, and then they'd run out of money before they had the opportunity to address the research question, Cates says.

"That goes closely with the lesson learned about incidence rates, as well," he adds.

6. Learn to communicate well: Lastly, there's a need for investigators to do communications planning because of all of these challenges in conducting HIV prevention trials, Cates says.

"We've seen examples of where reactions to particular trials have stopped those trials, or that the results have been misinterpreted or overinterpreted," Cates says. "So just like we have a statistical and monitoring and analysis plan, many investigators now have a communications plan so that we can act accordingly."

For example, some studies have a communications expert who serves as a consultant to the trial, and the expert trains participants on how to talk with the media, Cates says.

"We have a Q&A prepared about what the trial is doing, and there's a much more sophisticated approach to communication," Cates says. "Just like we have standard operating procedures for running a trial, now we have standard operating communications for having the elements of that trial properly communicated."