HIV drug-resistance testing on archived samples to help current clinical decisions

Recent studies have shown that the use of genotypic-resistance testing to assist therapeutic decision making has a significant benefit on virological response in pre-treated individuals switching to an alternative regimen [1]. In their editorial review, Rodriguez-Rosado et al. [2] list several clinical situations for which HIV drug-resistance testing may be useful, but state that in pre- treated patients without evidence of failure, drug-resistance profiling is currently not justified. In the past 10 months we have performed resistance testing using automated sequencing (TruGene HIV-1 genotyping assay; Visible Genetics Inc., Toronto, Canada) on archived samples for five patients, who at the time of the request had undetectable viral loads. These samples were taken and stored during previous periods of drug failure. On each occasion, although there was no evidence of failure on the current regimen, the development of severe drug side-effects (peripheral neuropathy in three cases) or the non-tolerance of one or more of the antiviral agents (ritonavir in two cases) led to a search for an alternative regimen. As these patients had taken at least three preceding antiviral combinations (median 4, range 3–7), therapeutic choices were limited. Table 1 summarizes previous antiretroviral regimens, genotypic-resistance test results, and clinical outcome for patients A–E. For patient A with peripheral neuropathy, the lack of zidovudine (ZDV) resistance allowed the re-cycling of this drug and the cessation of stavudine (d4T). The resistance assay for patient B suggested, in the absence of nucleoside resistance, that it may be safe to discontinue protease inhibitors (PI) as these drugs were unlikely to contribute significantly to virological suppression. Patient C had previously been intolerant of PI, but had not had virological rebound while taking this class of drug. The resistance assay in this case precluded the re-use of ZDV and therefore, on developing severe peripheral neuropathy, d4T was changed to amprenavir. In patient D, again after developing peripheral neuropathy, d4T was substituted by ZDV and lamivudine (3TC). Despite the previous use of ZDV, this combination was introduced to exploit the favourable effect that 3TC may have on the suppression of ZDV resistance, with the possibility of ZDV resensitization [3]. In addition, it was thought that 3TC might increase the fidelity of the HIV reverse transcriptase [4] and limit further transcription errors. Finally in patient E, ritonavir and indinavir were changed to amprenavir in the absence of specific mutations to the newer PI. In all these individuals retrospective genotypic-resistance testing, at times −34, −5, −24, −7 and −6 months, respectively, allowed a more informed choice for the next antiviral combination. Each patient has since reported an improvement of the original clinical problem, while maintaining virological suppression.Table 1: Previous antiretroviral regimens, genotypic-resistance test results, and clinical outcome for patients A–E. We therefore propose that retrospective resistance testing may play an important role in pre-treated patients without evidence of failure. Clinicians should be encouraged to store specimens at regular intervals, especially at the time of treatment failure, even if resistance testing at that specific time-point would not alter management. Given that long-term toxicity in this patient group is likely to increase over time, resistance testing on archived specimens may be useful at future time-points to ensure continued viral suppression and clinical benefit. Gillian L. Deana Martin Fishera Clive Lovedayb

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