Better agreement on clinically relevant resistance will be key
Researchers may be able to sidestep HIV drug-resistance by creating drug resistance profiles of patients before they begin treatment, says a scientist at Jefferson Medical College. By knowing which drugs a patient is resistant to, doctors may someday custom design therapies against HIV, the AIDS virus, and, it's hoped, improve treatment.
Yet, such profiles and individual therapies are still some time away from reality, says Roger J. Pomerantz, M.D., professor of medicine, biochemistry and molecular pharmacology, director of the Center for Human Virology and chief of the division of infectious diseases at Thomas Jefferson University in Philadelphia. Much more research is needed to understand drug resistance, and scientists must agree on when a patient's viral resistance means something clinically.
In an editorial September 22 in JAMA, the Journal of the American Medical Association, Dr. Pomerantz comments on two studies published in the issue that focus on two groups of patients living in different geographic areas. Many of the patients in both studies were resistant to a commonly prescribed and frequently effective cocktail of drugs known as highly active antiretroviral therapy (HAART).
The researchers in both studies defined drug resistance differently, leading to different opinions about the degree of such resistance found in the study populations.
Dr. Pomerantz draws several conclusions from the studies' observations. "Two things need to be done," he says. "We need to understand how large the problem of drug resistance is, and part of that means watching different geographic areas to gauge how much multidrug resistance is developing. Then we have to find a way to agree on what the degree of clinically relevant resistance is for each drug.
"Clinically relevant drug resistance will differ for each drug, just as it is different for penicillin and vancomycin for bacteria," he says. "We have to find out if a three-fold increase in viral resistance means something about the effectiveness of one drug compared to what it means for another," he says.
In the JAMA editorial, he recommends medical officials be more alert to multidrug resistance. "If you give a patient a cocktail of drugs the first time and they don't respond, and you can't find it's from noncompliance, you have to think they have primary resistance."
Eventually, all patients may need to be profiled for both their virus's genetic makeup and their disease status, "just like we do for pneumococcus and tuberculosis before treatment," he says.
"That has to be one of the next steps," he says. "What does it mean when you have X resistance to AZT, and at the same time, what does it mean regarding a different drug, such as a certain protease inhibitor? It would be nice to tell patients you are this much resistant to drug X and that much resistant to drug Y and not to these others."
Dr. Pomerantz sees the day when each anti-HIV drug would actually have a profile of standard viral resistance. "Eventually, you could say to a patient, 'This is your virus, this is what drugs it's resistant to, and this is what we'll use against it.'"
He suggests that "tailor-made, designer therapies" may eventually be more common.
Dr. Pomerantz compares the current AIDS drug resistance situation to the early days of bacteriology at the turn of the century. Doctors watched how new drugs affected different patients, and devised new definitions of clinically relevant conditions. "HIV evolves differently in different areas in the country," he says. "Defining resistance for each drug is exactly what we did in the early part of the century for bacterial infections such as tuberculosis, when people were developing resistance."
But detailing the precise viral genetic make-up of each HIV-infected individual would cause treatment costs to rise significantly, he says. This would be a particular problem with Third World nations struggling against the onslaught of AIDS. Millions are infected, and many lack primary medical care. No one knows the scope of drug resistance there, he says, because in many cases, patients do not receive adequate medical attention, let alone consistent therapy.