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Drug Resistance the Topic of National HIV Teleconference

By Lloyd Parker

February 1999

On November 11, 1998, a satellite video teleconference on "Managing Resistance in the Era of HAART" was held at the Stanford School of Medicine in California. Atlanta was one of several cities chosen to participate in the remote link up with a panel of five distinguished specialists. A number of local and regional infectious disease specialists, health care professionals and interested individuals convened at the Westin Peachtree Hotel in Atlanta to hear current insights about resistance issues as they relate to treatment of HIV disease. A question and answer session with the panel, facilitated by Dennis Melton, MD, of the Centers for Treatment of Infectious Disease, was held afterward.

Sarah Palmer, Ph.D., of the Stanford University School of Medicine, began the conference with a comparison on the various types of genotypic and phenotypic analysis testing being performed at the Stanford Center for AIDS Research. Her conclusions were that: a) genotypic analysis is quick and inexpensive, but has limited clinical utility; b) the usefulness of mutational analysis is limited as patients accumulate more primary and secondary mutations; and c) phenotypic analysis is more relevant for problems of drug resistance, but is expensive and takes too long for clinical use.

Eric Daar, MD, the Director of the Division of Infectious Diseases at Cedars-Sinai Medical Center in Los Angeles, lectured on HIV patterns of resistance seen in patients using reverse transcriptase inhibitors (RTIs). His lecture reaffirmed what came out of the Geneva conference: that newly infected patients in the population are showing signs of initial drug resistance. With respect to abacavir, one of the newest RTIs, Dr. Daar concluded that based on phenotypic analysis, it appears resistance to three or more RTIs predicts a lack of virologic response to abacavir. Furthermore, the nucleotide RTIs PMEA and PMPA exhibit increased sensitivity to viruses with the M184V mutation, which is seen in patients experienced with ddI, ddC, 3TC, and abacavir. Little information was provided on the NNRTIs efavirenz, nevirapine, and delavirdine.

Mark Holodniy, MD, Director of the AIDS Research Center at the VA Palo Alto Health Care System, covered patterns of resistance seen in patients taking protease inhibitors (PIs). Dr. Holodniy presented data showing that salvage therapy with two PIs after treatment failure with a HAART regimen containing nelfinavir was more effective than if indinavir or ritonavir was used as a first line PI. He also stated that viral response was better if patients failing indinavir or nelfinavir therapy switched to ritonavir and saquinavir while viral load was less than 15,000 copies/ml. Amprenavir and other investigational PIs were mentioned for their possible unique primary mutations, but no data was available yet to confirm their efficacy as second line PIs in a clinical setting. PI sparing regimens were also discussed as possible alternatives in initial treatments.

William O'Brien, MS, MD, of the AIDS Research Program at the University of Texas Medical Branch in Galveston, Texas, lectured on patterns of resistance in combination therapy. Dr. O'Brien presented data showing that implementation of simultaneous triple therapy, as opposed to sequential additions of drugs, was more effective in containing viral mutations. He went on to discuss the use of Hydroxyurea (HU) in a treatment regimen. According to Dr. O'Brien, HU apparently restores susceptibility to some NRTI drug resistant viral strains (particularly ddI). Also, HU enhances activity of the nucleotide RTIs PMEA and PMPA. Dr. O'Brien stated that there are mutational differences in viral strains cultured in a person's CSF, plasma and semen. He warned of recycling drugs due to rebound of drug resistant viruses and concluded that tissue compartment penetration needs to be considered.

Andrew Zolopa, MD, Director of Stanford Health Services Positive Care Clinic, ended the lecture series with insights into the clinical utility of genotypic and phenotypic testing. His conclusions were that in newly infected patients, testing may be beneficial in ruling out multi-drug resistant infections. Also, testing may be beneficial for patients considering salvage therapy if failing current HAART regimens. Dr. Zolopa said that definitive data on the predictive value of genotypic and phenotypic testing is inconclusive, but it appears to be a potentially useful prognosticating tool once standardization of testing methods is implemented.

Afterwards, questions from the various satellite cities were put to the Stanford panel. Queries ranged from efficacy of vaccines, interleukins, mega-HAART, etc.

When asked for his assessment of the teleconference and his opinion regarding resistance and testing, our facilitator, Dr. Melton, provided us with this response: "The information presented shows that, over the past year, a great deal has been learned about how to use genotypic and phenotypic testing in the clinic. This information, if accurate, can be very helpful in selecting antiviral drug regimens. However, I still have some concerns. The current tests may miss a small population of resistant virus. The tests are only as good as the laboratory performing them -- incomplete or incorrect data could be as harmful as no data. What appears to be the preferred test, phenotypic testing, has an unacceptable turnaround time to be clinically relevant. Possibly we can network with local experts (such as Dr. Victoria Johnson at UAB) to help us evaluate the testing being done here in Atlanta. This may give us practical information/guidance as to which testing to use."

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