By Skip Connett

Special to BioWorld Today

GENEVA — "Bridging the Gap," the timely yet ambitious theme of the 12th World AIDS Conference, may not have spanned as many miles as hoped, but it did help identify the treatment gaps not only between industrialized and developing countries, but between theory and practice, as well.

Nothing is simple in the world of AIDS, and as the focus has shifted from the virus as a deadly disease to HIV as a lifelong infection, complexity and ambiguity are the prevailing winds at this stage of the epidemic. Like the weather here all last week — partly sunny, partly cloudy — bright spots of good news were trailed by shadows of pessimism.

For example, highly active antiretroviral therapy (HAART) saves lives — AIDS cases in the U.S. were down 23 percent for 1996 — and at least two studies presented at the conference indicated HAART is cost effective, even when initiated early in infection.

But a question that gained stature here was: How many patients are going to put up with the growing list of side effects when they have no symptoms of disease? Without long-term proof, more healthy patients may become leery of hitting the virus hard and early, particularly if the drugs hit them back with toxicity. It's a concern that many clinicians left here without having nice, neat answers to take back to their patients.

Therapeutic Vaccines May Aid Drug Combinations

Also, more studies are showing that antiretroviral drugs can rebuild the immune system, but there is conflicting evidence on the extent of restoration. And what happens when treatment is stopped? The handful of nonprogressors who have discontinued therapy and have not seen a bounce in viral load seem to be the rare exception, blessed with genetic traits that may provide researchers with new targets for therapy and vaccines.

Indeed, a study of long-term nonprogressors from the University of California at San Francisco found 11 percent of infected men sustained CD4 counts above 500 at 10 years but only 2 percent remained nonprogressors after 18 years.

One potential immune restoration strategy was presented by David Ho, director of the Aaron Diamond AIDS Research Center, in New York, who discussed the concept of administering therapeutic vaccines to patients once HAART has suppressed the virus. The added boost could enable the immune system to stave off viral replication indefinitely, so that treatment could be discontinued.

Beyond theory, however, there was little exciting news on preventive vaccine research presented in Geneva. The first large vaccine trial is getting under way in the U.S. and Thailand, but vaccine experts remain divided over the potential success of the genetically engineered product from VaxGen Inc., of South San Francisco.

Additionally, doubt was cast over an attenuated simian immunodeficiency virus (SIV) vaccine that was seen as the best model for a human trial. Researchers from the Dana Farber Cancer Institute, in Boston, reported newborn monkeys who were vaccinated either became ill or died from SIV. With so many barriers, the consensus is vaccine development remains 10 years away — the same time frame given more than a decade ago.

As with vaccines, researchers reported various microbicide products are in Phase I and Phase II testing, yet an effective product remains years away from the market. Follow-up data presented on a large trial in Cameroon measuring sexually transmitted disease (STD) and HIV protection from a nonoxinol-9 film indicated the spermicide appears not to increase the risk of HIV transmission but offers little or no protection.

More evidence was presented showing the presence of other STDs can enhance HIV transmission. Epithelial cells lining the prostate and cervix normally provide protection against HIV, but are altered by infection with other STDs, the Centers for Disease Control and Prevention, in Atlanta, reported.

However, a large study of Ugandan women demonstrated massive STD treatment did not impact HIV transmission rates — a sharp contradiction to a similar 1995 study showing that STD prevention cut HIV rates by 40 percent.

Call For Longer Follow-Up Studies

With wide discrepancies between how patients respond in clinical trials vs. the clinic, bridging the gap between theory and practice is needed more than ever, researchers said. The first step would be developing long-term drug trials and receiving a commitment from pharmaceutical companies to present a more complete picture of trial results, said Melanie Thompson, director of the Atlanta AIDS Research Consortium.

Thompson set the stage for more dialogue about study design and statistical analysis on the first day of the conference. Her theme was picked up by other speakers also concerned that too many researchers present the more favorable "as treated" analysis rather than the more rigorous "intent-to-treat" analysis, which considers patients who drop out as treatment failures.

"There are a lot of differences in statistical analysis that may actually bias our perceptions of efficacy, and we are not always aware of how data is analyzed and presented," she told BioWorld Today.

Thompson expressed concern over industry studies designed so patients who stop taking the drug are removed from the trial and not followed up.

"Patients drop out for different reasons and if you are not following those patients, then you can't really do an intent-to-treat analysis because you don't actually have [their] viral load and CD4 results out to 48 weeks," she said.

"I'm not opposed to making drugs more widely available by licensing them based on relatively short-term data. But I do believe the FDA should require long-term follow-up of all the drugs they license. They should certainly require long-term follow-up of patients in clinical trials, and I think they should make pharmaceutical companies follow all patients on study as best they can throughout the entire course of the study."

Gilead Long-Term Study A Positive Model

As an example of how short-term trials may mask the true impact of a drug, Thompson mentioned how a kidney side effect — a renal tubular disorder — wasn't observed during the first six months of a trial testing adefovir, the antiretroviral drug developed by Gilead Sciences Inc., of Foster City, Calif.

"The side effect appears to be mild, reversible, and may not be a huge problem, but it didn't show up in the first 24 weeks of trial," she explained. "The fact that Gilead designed the trial so that they continued to follow patients for longer allowed them to learn about this toxicity."

Real-life practices tend not to match industry trial results for other reasons as well. Thompson presented results of a study looking at the clinical outcomes of nearly 5,000 patients in trials compared with those in an observational cohort.

Researchers found those enrolled in trials did significantly better than those in the clinical cohorts, even when the results were stratified by the same site and care. Patients in clinical trials lived 66 percent longer and had fewer opportunistic diseases than those not in clinical trials. The results were independent of CD4 count, AIDS diagnosis and antiretroviral therapy, she said.

"It appears to me that clinical trials actually elevate the standard of care for our patients," she explained. "We use an extensive screening process that identifies obstacles to care. Many studies are able to provide access to transportation, child care, social services as well as an education process that helps patients understand drugs and clinical side effects." *