AIDSWEEKLY Plus; Monday, October 26, 1998
Daniel J. DeNoon, Senior Editor
Highly active antiretroviral therapy (HAART) regimens can provide durable suppression of HIV replication. But when these regimens begin to fail, clinicians are left with the thorny problem of what to do next - and when to do it.
"We should tailor therapy to the patient," said Jonathan Schapiro of Tel Hashomer Hospital, Tel Aviv, Israel. "In treatment-naive patients we should go for durable suppression. In treatment- experienced patients we should go for durable low viral load. In highly experienced patients we should go for reduced viral load."
Schapiro spoke in a state-of-the-art seminar on antiretroviral therapy at the American Society for Microbiology's 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 24-27, 1998, in San Diego, California.
The clinical researcher suggested that the decision of when to switch HAART regimens should be based on a patient's chances of durable HIV suppression and on whether an early or late switch would better serve the patient.
He suggested that while the chances that HAART will provide durable HIV suppression in treatment-naive patients is high, the probability drops to less than 50 percent in patients who have failed a first-line HAART regimen. In highly experienced patients there is only a low probability of achieving durable suppression.
An early change of HAART is advisable when good therapeutic options remain available, when the current regimen is challenging to the patient, or when the patient's immunologic status is deteriorating.
A later change in treatment regimen is advisable when there are few therapeutic options left, when the current regimen is well tolerated, and when a patient's immunologic status is stable or improving regardless of increased viral load.
It is this latter case that is most troubling to clinicians.
"In our practice we keep seeing patients whose viral load goes up but whose CD4 counts rise or remain stable," Schapiro said.
Arguing in favor of a switch in such patients is the odds that increased viral replication will increase the percentage of circulating virus with resistance phenotypes, and the observation that decreased viral load is usually associated with improved clinical outcome.
Arguing against a switch in such patients is the fact that these patients are currently stable or improving, that their short-term prognosis is favorable, that too early a switch may squander limited therapeutic options.
"We only have so many options," Schapiro warned. "If we shoot too early we may find ourselves with no options."
Another factor to take into account is the cause of drug failure. This may be due to two sets of circumstances.
The first is that the drug may not be getting to the bug. This could be due to patient adherence problems related to dosing and toxicity, or to pharmacokinetic problems related to drug absorption, metabolism, or interactions with other medications.
The second is that the drug may be getting to the bug but not working.
"Only after we are convinced that the patient is taking the drug and that there are no drug interactions can we consider drug failure," Schapiro warned.
The current availability of genotypic and phenotypic assays for HIV drug resistance poses as many questions as it answers, Schapiro suggested.
Genotypic assays either provide a complete sequence of the HIV protease gene and large portions of the reverse-transcriptase gene or identify mutation only at key codons. Phenotypic assays provide a direct assay of HIV sensitivity to each drug. A genotypic assay costs about $500, a phenotypic assay costs about $800.
The key question, of course, is what relevant information on clinical resistance these laboratory tests provide.
Schapiro identified four situations in which resistance assays can be helpful:
* To rule out infections with resistant virus before starting therapy.
* To assist in determining a patient's cause of drug failure.
* To determine the next appropriate drug regimen in patients failing their current regimens.
* To assist in the decision to discontinue antiretroviral therapy in advanced patients with multidrug resistant virus. "There are some advanced patients we are giving a lot of drugs to, and it's costing the patients a lot," Schapiro warned.
Despite their current availability, Schapiro said that resistance assays still have several hurdles to clear in order to justify their expense:
* The assays must prove they can predict which drugs will no longer help a patient.
* The assays must prove they can predict which drugs will still benefit a patient the most.
* The assays must prove they will improve clinical outcomes over currently available (and less costly) tools.
"Resistance assays must make patients live longer and better than they are now to prove they are a really useful clinical tool," Schapiro said.
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