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Drug Resistance Factors Into HIV Treatment Failures


BETHESDA, MD. — Drug resistance poses a problem in treating HIV patients, in part because of the virus's high mutation rate, Roy M. Gulick, M.D., said at an annual conference on antimicrobial resistance sponsored by the National Foundation for Infectious Diseases.

Factors affecting HIV drug resistance include the virus itself, the antiretroviral drugs used, and the characteristics of the individual patient. Drug resistance is one of the main reasons why HIV treatments fail, said Dr. Gulick, director of the Cornell HIV Clinical Trials Unit at Weill Medical College of Cornell University, New York.

The goal of antiretroviral therapy (ART) is to suppress the viral load to as low a level as possible for as long as possible, he noted. Due to the high rate of mutation in the HIV virus, viral diversity is extensive. Failure to suppress viral load levels in the presence of antiretroviral drugs leads to the development of a resistant strain, Dr. Gulick explained.

Patient-related factors that can contribute to the development of resistance include the stage of disease, use of other medications, medication adherence, and side effects.

“We used to follow resistance clinically. If someone was taking their drugs, and their viral load went down, but then rose again, if we were sure that they were taking the medication, we assumed that they had developed resistance,” he said. Today, genotypic tests provide viral sequencing of a patient's viral strain, and phenotypic tests can grow the patient's virus in vitro and assess resistance in the presence of the available antiretroviral drugs.

Are resistance tests clinically valuable? Dr. Gulick cited three studies, including one published in the Lancet, in which several hundred patients who had failed drug therapies were randomized to either genotypic or phenotypic drug resistance testing or standard care (Lancet 1999;353:2195–9).

Overall, the patients who fared better in terms of viral load reduction on their new regimens were those who had the resistance tests. “Simply put, resistance tests help clinicians choose active drugs for the next regimen,” Dr. Gulick said. Guidelines from the Department of Health and Human Services recommend resistance tests in the clinical setting in cases of virologic failure, suboptimal virologic suppression, and acute HIV infection.

These tests could be considered in cases of HIV infection before starting ART, but they are generally not recommended for patients more than 4 weeks after ART drug use ends, or when viral load levels are less than 1,000 copies per million.

However, studies of the effectiveness of resistance testing are limited by several factors, including problems with the clinical cutoffs—when the drugs lose activity over time—and questions as to whether the studies had enrolled patients who had failed multiple treatments.

Other studies show conflicting results on the use of resistance tests, especially for highly resistant patients. “The best resistance tests can't help a patient if they have no drug options to go to,” Dr. Gulick said.

Asked whether he recommends genotypic or phenotypic testing for patients who are just starting antiretroviral therapy or who already have resistance, Dr. Gulick commented that although sufficient clinical evidence is lacking, most experts recommend a genotype test for patients who are treatment naive or have failed their first regimen, when it is relatively easy to figure out what the mutations mean. But in patients who have been through multiple regimens, phenotype is easier to interpret.

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