Conference underscores differences between AIDS theory and practice
Conference underscores differences between AIDS theory and practice
Researchers call for drug companies to present complete study results
"Bridging the Gap," the timely yet ambitious theme of the 12th World AIDS Conference in Geneva, Switzerland, may not have spanned as great a distance as hoped, but it did help identify the treatment gaps not only between industrialized and developing countries, but between theory and practice, as well.
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 during the week-long conference - partly sunny, partly cloudy - bright spots of good news were trailed by shadows of pessimism.
Some cases in point:
· Highly active antiretroviral therapy (HAART) saves lives, as demonstrated by the fact that AIDS cases in the United States were down 23% for 1996, and at least two studies presented at the conference indicate that HAART is cost-effective, even when initiated early in the infection. (See related story on p. 99.) However, one question gained stature at the conference: How many patients are going to put up with the growing list of drug side effects when they have no symptoms of disease?
Researchers from Brown University, for example, found that about 40% of 151 patients who had tried one or more of the four available protease inhibitors eventually discontinued the drug. Gastrointestinal and systemic side effects, followed by treatment failure, were the most common reasons given for stopping.
Without long-term proof of efficacy, experts say healthier patients may become leery of hitting the virus hard and early, particularly if the drugs hit them back with toxicity. Many clinicians left Geneva without having nice, neat answers on this issue to take back to their patients.
· More than half of HIV patients studied in San Francisco who achieved undetectable viral loads with combination therapy experienced a resurgence in virus within a year, researchers from the University of California at San Francisco reported. Analyzing 233 patients, 55% of whom had an AIDS diagnosis and 51% of whom had fewer than 200 T-cells at the start of the study, researchers found that 55% experienced a return to detectable levels during 10 months of follow-up.
"It's good news that the vast majority of patients are doing well clinically, though over one-half had a resurgence in their viral load," says John Nienow, MD, assistant clinical professor of medicine at UCSF. "What is surprising is that, so far, many of the viral load breakthroughs have not been very high, and we have seen very little progression of HIV disease."
The findings suggest that patients may be able to sustain good health without maintaining undetectable levels of virus, he says. Although the reasons for the "breakthroughs" could not be analyzed in the study, Nienow points out that the findings raise questions about existing guidelines for when to change therapy.
"Breakthrough viral load is often recommended as a reason to change treatment, when more clinical predictors may not need to be taken into account," he says. "We may need to raise the viral load level at which we make decisions to change treatment."
· 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 San Francisco found that 11% of infected men they followed sustained CD4 counts above 500 at 10 years, but only 2% remained nonprogressors after 18 years.
One potential immune restoration strategy was presented by David Ho, MD, director of the Aaron Diamond AIDS Research Center in New York City, 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. (See story on p. 102 for more immune-restoration studies.)
Beyond theory, however, there was little exciting news on vaccine research presented in Geneva. The first large vaccine trial is getting under way in the United States and Thailand, but vaccine experts remain divided over the potential success of the genetically engineered product from Vaxgen of San Francisco.
Vaccine still at least 10 years away
Also, doubt was cast over an attenuated simian virus vaccine that was seen as the best model for a human trial. Researchers from the Dana Farber Cancer Institute report that newborn monkeys who were vaccinated had either become ill or had died from SIV. With so many barriers, the consensus is that vaccine development remains 10 years away - the same time frame given more than a decade ago.
As with vaccines, researchers reported that various microbicide products are in Phase I and Phase II testing, and yet an effective product remains years away from the market. Follow-up data presented on a large trial in Cameroon measuring STD and HIV protection from a nonoxynol-9 film indicates that the spermicide appears not to increase the risk of HIV transmission, but it offers little or no protection.
· More evidence was presented showing that the presence of other sexually transmitted diseases (STDs) can enhance HIV transmission. Normally functioning epithelial cells lining the prostate and cervix provide protection against HIV but are altered by infection from other STDs, the Centers for Disease Control and Prevention reported. And yet a large study of Ugandan women showed that massive STD treatment did not affect HIV transmission rates - a sharp contradiction to a similar 1995 study showing that STD prevention cut HIV rates by 40%.
With wide discrepancies between how patients respond in clinical trials vs. the clinic, bridging the gap between theory and practice is more important than ever, researchers say. 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, says Melanie Thompson, MD, director of the Atlanta AIDS Research Consortium.
Thompson set the stage for 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 tells AIDS Alert.
Thompson expressed concern over industry studies designed so that 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 says. "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 in the study as best they can throughout the entire course of the study."
As an example of how short-term trials may mask the true impact of a drug, she mentions how a kidney side effect - a renal tubular disorder - wasn't observed during the first six months of a trial testing adefavir, the antiretroviral drug developed by Gilead Sciences in Foster City, CA.
"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 explains. "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 examining the clinical outcomes of nearly 5,000 patients in trials compared with those in an observational cohort. Researchers found that 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% 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 explains. "We use an extensive screening process that identifies obstacles to care. Many studies are able to provide access to transportation, child care, and social services, as well as an education process that helps patients understand drugs and clinical side effects."
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