Stanford researchers present new findings on drug resistance at World AIDS Conference

STANFORD, Calif. - Two Stanford researchers addressed the challenge of drug resistance in AIDS care and how doctors treat their patients with medication. In the first study, researchers investigated how well doctors can predict which patients are likely to develop resistance to AIDS drugs. In the second, researchers studied how different subtypes of the HIV virus develop drug resistance. The presentations were made at the ongoing World AIDS Conference in Barcelona this week.

Drug resistance is a major concern in AIDS treatment. Up to 80 percent of patients have developed some level of resistance, and a third of newly infected patients are infected with drug-resistant strains of the HIV virus, explained Andrew Zolopa, MD, assistant professor of medicine in the Department of Infectious Diseases at Stanford University Medical Center. Unfortunately, all drugs used to fight HIV eventually encounter a resistant strain of the virus. 'Drug resistance is an epidemic,' Zolopa said. 'The virus is very unforgiving in that it easily develops resistance to drugs.'

Guess study tests accuracy of interpretations

In the first study, known as the Guess Study, Stanford researchers looked at how well experts predict resistance and how consistent they were among each other. The findings surprised Zolopa, the study's primary investigator and director of the AIDS-focused Positive Care Clinic at Stanford.

'Contrary to the prevailing wisdom that there's really no consensus, experts were good at predicting resistance, and they were highly consistent with one another,' he said.

The 16 drugs used to treat HIV are remarkably successful, Zolopa explained, but they are used in complicated combinations. Two tests help practitioners determine which drugs will work best for each patient. The drawback is that the test results are difficult to interpret. Most practitioners rely on expert interpretations included with test results to determine treatment combinations for their patients.

'We know the technology of the tests is very good,' said Zolopa, 'but we don't know how reliable the expert opinion is. That's what this study looked at.'

Zolopa took an international panel of 12 experts and gave each of them 50 complex genotypes from real patients. He asked experts to predict the degree of resistance to each of the 16 drugs, and to determine if the drugs will be active or not, and whether they would be recommended for use.

'If expert opinion can be translated to help guide doctors in making better treatment choices for their patients, then we should see less resistance emerging in patients on therapy,' said Zolopa.

Understanding how drug resistance works across borders

Over the past few years, researchers have discovered that drugs developed to treat subtype B strains of the HIV virus found in the United States and Europe also effectively treat the very different HIV subtypes found in other parts of the world. In this second study, Stanford researchers looked at whether drug-resistance testing, which has become routine in the West, can be used in countries where the two most prevalent strains of HIV are subtypes C and A.

'Our interim results suggest that non-B strains usually develop drug resistance by the same genetic mechanisms as subtype B strains,' said Robert Shafer, MD, assistant professor of medicine in Stanford's Department of Infectious Diseases. This finding implies that practitioners worldwide can use resistance testing, he said. However, Shafer pointed out that no one laboratory has sufficient data to answer this question with certainty.

Because of the scarcity of data on patients with non-B subtypes, Shafer, together with post-doctoral fellow Rami Kantor, MD, and David Katzenstein, MD, associate professor of medicine, collaborated with scientists in South Africa, Zimbabwe, Israel, Thailand and two European centers with large immigrant populations to solicit data on non-B strains arising during unsuccessful HIV treatment. The group analyzed sequences from 677 subtype A-infected persons and 288 subtype C- infected persons, and compared them to sequences from over 2,500 subtype B-infected individuals.

'We observed that each of the major mutations found in subtype B are also seen in subtypes A and C,' said Shafer, implying a similarity in how the viruses develop drug resistance. Shafer pointed out, however, that researchers can't exclude the possibility of other drug-resistant mutations being missed, or that the mutations are occurring at different rates than the drug-resistance mutations in subtype B strains.

Despite the already large number of sequences collected, the Stanford group plans to expand its collaboration. 'Considerably larger data sets are required to have the statistical power to confirm the trends we have observed so far,' said Shafer. 'Not doing this would be unfair to the millions of infected persons with non-B HIV for whom treatment is no longer considered an impossibility.'

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