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New Antiretrovirals Host Immunology, Pathogenesis and Dynamics Mechanisms of HIV-Drug Resistance Drug Resistance, Exposure and Treatment Response Genotype/Phenotype Relationship, Modelling and Algorithms (Abstracts 50, 51, 52)
Speakers: Charles Boucher, Brendan Larder, John Mellors, Doug Richman
This session was a summary presentation by four leading resistance researchers, who reviewed "highlights" from the annual meeting, which focuses exclusively on news about resistance of HIV to medications. This conference is among the most exclusive, in that only researchers who have data accepted for presentation are invited to attend, allowing a small meeting where such data can be carefully reviewed.
While there was no single presentation that would dramatically alter clinical practice, there were several highlights that are clinically relevant. These included:
- The spread of resistant HIV in recently infected untreated persons continues. In a survey done over the past several years of about 400 people in nine North American cities, the overall rate of detecting any resistance has increased from 4% in prior years to 14% in the most recent year. Resistance was noted in all three classes of antivirals in use, with about 8% of people showing resistance to each of the three classes of antivirals. Some harbored strains with multiple drug class resistance, including a troubling 6% with resistance to at least two of the classes of antivirals (nucleosides, non-nucleosides, and protease inhibitors). It was also shown that this resistance appears to be clinically meaningful, in that there was a blunted response to treatment when drugs from these classes were used in those who had resistance to them compared to what is seen in those without resistance.
- Resistance assays are becoming more widespread in their use in the clinical setting. Several studies have shown the role they can play in improving responses when changing regimens. There was a presentation showing the limitations of these tests. A study was done evaluating the impact of a phenotype assay for those who had viral rebound on their first or second PI-containing regimen. This study did not show a benefit of an improved response in the arm that had guidance from resistance testing. The presentation suggested that one reason for this was the problem of defining appropriate cut-offs for some drugs, which limits interpretation of these test results for some of the antivirals, especially stavudine (d4T, Zerit) or didanosine (ddI, Videx). The results did suggest that if more updated cutoffs are used, the test could likely still contribute to improved outcomes, especially in those with more extensive pretreatment histories, a group even more in need of such testing. Added clarity about these tests was also provided from another presentation, showing the use of these tests when switching to the combination of ritonavir and indinavir. Here, researchers suggested that a phenotypic cut-off of 25-fold may be helpful when considering this PI combination, as those showing indinavir resistance over 25-fold are less likely to have activity from this combination.
- Quality control of resistance testing and its interpretation was the focus of several presentations. A predefined mixture of HIV isolates, some resistant to medications, was sent to several testing labs. The results showed that while there is agreement and reliability to several labs, there were some labs that had less accurate reports. There was no disclosure of which labs were either preferred or less accurate, but it will be an ongoing effort to ensure that all labs are regularly assessed for best performance. Similarly, interpretation of genotypic results can be done with a variety of "algorithms," or interpretation flowcharts, that help define the importance of the various mutations that are observed when this test is ordered. However, these algorithms sometimes differ in their interpretation to some degree.
Several presentations presented comparative results of these interpretations, suggesting that for some medications in particular (amprenavir, d4T, ddI, abacavir), there are important differences in judging resistance. The role of phenotype testing for such medications is potentially of heightened importance. As this in part reflects a lack of clarity in the field about the genotypic correlates of resistance to these medications, efforts are ongoing to define the role that specific mutations play in altering the activity of any specific drug. Fortunately, there is progress with these tests as well, and one phenotype assay from ViroLogic can now also test for resistance with the newest class of medications, the entry inhibitors, including T-20, the drug furthest along in this class.
- This meeting also reviewed some of the newest medications entering study. There was mention of the in vitro (test tube) activity of DPC 681/684, two new protease inhibitors being developed by Triangle, as well as two non-nucleosides in development by TiboTec. Tenofovir is the first nucleotide antiviral that is nearing U.S. FDA review and anticipated approval later this year. Researchers developing tenofovir had new data that suggested a cut-off of four-fold resistance might be useful for phenotypic tests when judging the potential activity of this agent.
- Finally, there was additional data about what happens when people remain on protease-inhibitor-containing regimens despite ongoing replication. It has been noted for years that there can -- at least for some individuals -- be a "stalemate" in terms of HIV replication for some people, and the CD4 count as a result can be relatively stable as well. This observation has led to widespread clinical discussion about how long this stalemate may last, and the "price" we may be paying for this.
Dr. Deeks updated these results, demonstrating that over time, there was a gradual but progressive increase in the degree of resistance of HIV to the protease inhibitors, and a resulting increase in the viral load as a result. Some mutations were associated with very small increases in viral load, while other mutations, called primary mutations, were associated with larger increases. The implication here is that at least for some, this stalemate will be temporary, and may have an impact on the activity of future regimens when using agents in this same class, given the broadening resistance of HIV as it grows in the presence of drugs.
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