The Body Covers: The 40th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
Meet the Experts Session
September 17, 2000
At this session Dr. William Cameron (Canada) detailed the very specific set of circumstances necessary for any antiviral regimen to work. He stressed the pivotal importance of patient adherence as the most important feature in designing a regimen, since without this, there will be a sharply decreased chance for success. In addition to adherence, he detailed key features of a successful regimen:
He showed an analysis of over ten thousand patients treated in England, and made two observations. One is that there do not appear to be any clear clinically significant differences overall in the success rates of strategies of treatment that begin the protease inhibitor (PI)-based regimens versus NNRTI-based regimens. Both show a similar initial success rate, and subsequent regimens appear to have similar success as well. Of note, however, is that the reported experience did show a loss of suppression over time, approaching 50% who were no longer successful (i.e., viral load rebounding) after about three years. Thus, he reflected that a key challenge is improving our performance in the variables needed to create success, since regimens are failing perhaps half the time in a short period of time. Since eradication will not occur in three years, and perhaps not ever, we must do far better in defining and implementing strategies that can last for decades, and not just for a few years.
Along these same lines, I presented data on cross resistance and lessons from the VIRA 3001 study. This study, first presented in February 2000 (CROI conference), showed the benefit of phenotypic resistance testing in those who had a viral rebound on their first PI-containing regimen. In addition to the overall results, a few new analyses help to amplify the basic message, and support the credibility of resistance testing: Those who were on lamivudine (3TC) in the initial "failing" regimen almost always have virus that has a mutation at position 184. There have been concerns about the performance of abacavir in the presence of this mutation, since the first mutation to arise in those treated with just abacavir is also at position 184. What was seen, however, is that the viral load response to abacavir was equivalent in those who had and did not have 3TC resistance at baseline. Of note was that regimens containing abacavir were more successful here than regimens that did not contain abacavir, although abacavir was used in a combination of other active agents. Almost all of the enrolled patients had not taken an NNRTI prior to this study. Clinicians were allowed to use this newer class at their own discretion, and, overall, about half did so. Of note was a difference in that those who had the phenotype were less likely to use the NNRTI class. This was done perhaps in the hope that there were medications that showed preserved activity in previously used classes, allowing the preservation of this class for a future regimen, if needed. There was a sharp difference in the impact of resistance testing in these two circumstances. Those who used the NNRTI had much less additional benefit from resistance testing, as the overall regimen was more potent. However, in those where the NNRTI was not used, there was a much more profound impact from resistance testing. This demonstrates the clear impact of resistance testing in helping clinicians define which of the unused medications in currently-used classes of antivirals were still active. Phenotype testing has shown a difference in the degree of cross resistance of different PIs -- specifically that indinavir resistance results in cross resistance to nelfinavir and ritonavir, while nelfinavir resistance appears to have minimal impact of the sensitivity to the other PIs. An analysis of outcomes of those who were on and resistant to these two PIs confirms the clinical relevance of these observations. Those on indinavir had a clear benefit from resistance testing, while those who came in on nelfinavir had very little added benefit from resistance testing. This could be expected since, after nelfinavir, all of the other PIs were active, and a test would not be as necessary to pick the next combination.
In summary, the clear challenge is to define the steps that allow us to create a regimen that does not succumb to resistance. We have defined the variables that determine success and can implement them in a way that prevents resistance to this regimen. Until we are 100% successful with this first regimen, resistance will be a concern. To this end, resistance testing can, in some circumstances, help play an important role in defining which medications have the best chance of success.
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