John Mellors of the University of Pittsburgh opened Tuesday's session on antiretroviral resistance by reviewing the Lake Maggiori meeting on that topic, held last week. Two of the most important findings reported at that conference, he reported, were that multi-drug resistant viruses are being transmitted at clinically important frequencies and that retrospective studies in experienced patients show that baseline viral phenotype and genotype predict response to antiretrovirals -- both singly and in combinations. What is most important for resistance studies, Mellors said, is that rapid, high throughput commercial assays for viral genotype and phenotype will be available soon.

Sabine Yerly of the laboratory of virology in Geneva illustrated the first of Mellors' points by presenting data on the frequency of resistance mutations in virus isolates from 67 persons with primary HIV infection. Reverse transcriptase (RT) and protease genes were sequenced from virus isolated within three months of acute seroconversion and before initiation of therapy. Five (7.5%) isolates had RT mutations known to be associated with resistance to AZT, while one isolate carried mutations conferring resistance to ddC, 3TC and nevirapine. After 12 months without therapy, in about half of those who started with an AZT-resistance mutation the genotype had reverted to being susceptible to that drug, Yerly reported. These results suggest that, in the absence of the drug, the resistance mutations may be eventually "out-competed" by the wildtype virus.

Six individuals' isolates had major protease inhibitor-resistance mutations, in combination with one to four minor mutations. Resistance mutations were found to all four approved PIs. All isolates were still sensitive to amprenavir, a newer protease inhibitor now in clinical trials.

Kurt Hertogs of Belgium generated complete PI resistance profiles for 2,900 isolates. Among isolates with more than ten-fold resistance to any one PI, 60% to 80% were equally resistant to the other three. Cross-resistance to all four PIs was seen in 64 isolates.

Comparing resistance profiles with patients' PI experience showed that 75% of patients with resistant viruses had been treated with two or more PIs. Moreover, "Resistance to all four PIs can occur following initial treatment with any PI," Hertogs said. "There is a clear need for design of a second-generation PI," he concluded.

this story can also be found in The Bridge, the onsite print newspaper

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