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Virological failure and subsequent resistance profiles in individuals exposed to atazanavir
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[Research Letters]
AIDS:Volume 21(13)20 August 2007p 1826-1828
Stebbing, Justin; Nathan, Bif; Jones, Rachael; McKenna, Alex; Powles, Tom; Bower, Mark; Holmes, Paul; Gazzard, Brian; Nelson, Mark
Imperial College School of Science, Technology and Medicine, Department of HIV Medicine, The Chelsea and Westminster Hospital, London, UK.
Abstract
Few data exist regarding the resistance profile in individuals receiving atazanavir. We found that ritonavir-boosted atazanavir is not associated with the development of primary genotypic resistance in individuals failing this combination, without previous protease inhibitor failure. It is rarely associated with the acquisition of primary mutations in individuals with previous protease inhibitor exposure. This is particularly important because of the increasing use of atazanavir monotherapy, and implies that treatment failure is caused by lack of potency.
We have recently published our experience of 231 individuals commenced on ritonavir-boosted atazanavir sulphate (formerly BMS-232632) [1] with a median follow-up time of more than one year. In intent-to-treat and on-treatment analyses, this once daily protease inhibitor (PI) maintained and led to virological suppression and increases in the CD4 cell count in both PI-naive and experienced patients. Switching to atazanavir when the viral load was less than 50 copies/ml led to continued viral suppression, cholesterol levels decreased and the major adverse event was mild hyperbilirubinemia, which rarely led to treatment cessation. Resistance profiles were not reported, and overall its efficacy and safety profile was similar to that observed in previous randomized studies investigating its use [2-4].
The resistance profiles of nucleoside analogues, nucletodies, non-nucleoside reverse transcriptase inhibitors and unboosted PI are well documented. In individuals naive to PI who fail a ritonavir-boosted PI-based regimen, the development of PI resistance is rare, although it has been well documented for ritonavir-boosted saquinavir/lopinavir/fosamprenavir [5]. The genotypic resistance profile in individuals who fail ritonavir-boosted atazanavir is poorly documented although there are 14 key primary and secondary substitutions documented to contribute to atazanavir resistance [6].
From our published atazanavir database, which did not discuss specific resistance profiles, we identified 38 individuals who had evidence of virological failure on ritonavir-boosted atazanavir [1] (Table 1). Of these, 22 had previous evidence of virological failure to a PI, and 16 were previously naive to PI, or had switched to ritonavir-boosted atazanavir with an undetectable viral load.
In the group with no previous PI failure, five individuals developed secondary mutations associated with atazanavir, and none of these patients developed a new primary mutation. In those with previous PI failure, only one patient developed a primary mutation and four others developed secondary mutations.
In conclusion, ritonavir-boosted atazanavir is not associated with the development of genotypic resistance in individuals failing this combination, without previous PI failure. Furthermore, it is rarely associated with the acquisition of genotypic resistance in individuals with previous PI exposure.
Medication side effects and patient-reported symptoms are the foremost variables predictive of non-adherence to HAART [7]. Future HIV standards of care will emphasize the use of once daily therapies, especially as HAART penetrates the underdeveloped world [8]. There are now convincing data regarding maintenance therapy with ritonavir-boosted atazanavir alone following virological suppression [9]. This showed that in individuals who switched PI to atazanavir-ritonavir at entry and discontinued nucleoside reverse transcriptase inhibitors after 6 weeks, virological success (absence of failure) through 24 weeks of simplified therapy occurred in 31 out of 34 participants. Resistance testing at failure did not identify PI resistance mutations. A further study switched patients to atazanavir if they had maintained a viral load of less than 20 copies/ml for a minimum of 12 months on conventional HAART, with a subsequent atazanavir dose adjustment if plasma concentrations were low. This study was terminated when virological failure occurred in five out of 15 recruited patients. In those individuals, plasma atazanavir concentrations were not associated with outcome, and once again no PI resistance was found in samples from patients failing therapy [10]. Although these genotypic resistance data are of interest to clinicians prescribing atazanavir, the cause of viral rebound is likely to be the lack of potency of ritonavir-atazanavir, compared with conventional HAART.
Table 1. Resistance to atazanavir.
References
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