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Atazanavir Trough-Mutation Relation (GIQ Cutoff) Predicts Response
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8th International Workshop on Pharmacology of HIV Therapy
April 16-18, 2007, Budapest
Mark Mascolini
An atazanavir genotypic inhibitory quotient (GIQ) cutoff separated virologic responders from nonresponders in a retrospective analysis of PI-resistant people at three Dutch centers [1]. The study also identified an atazanavir minimum concentration (Cmin) cutoff for grade 3 or 4 hyperbilirubinemia.
David Burger (Radboud University Nijmegen Medical Center) analyzed data on 108 people whose atazanavir levels were measured by his therapeutic drug monitoring service. Seventy people used 300/100 mg of atazanavir/ritonavir once daily, while 38 used unboosted atazanavir at a 400-mg once-a-day dose. While 48 people switched to atazanavir with a viral load under 50 copies, 32 began atazanavir in their first regimen, and 26 had documented PI mutations (including 6 with a viral load under 50 copies).
The group's median CD4 count stood at 300 (interquartile range [IQR] 170 to 400), and median follow-up lasted 19 months (IQR 16 to 29 months). Median atazanavir Cmin measured 0.74 (IQR 0.49 to 1.04) mg/L with the ritonavir-boosted dose and 0.23 (IQR 0.09 to 0.41) mg/L with the unboosted dose.
Among people without PI mutations, all 48 who switched with a load below 50 copies maintained an undetectable load. Among 32 people starting atazanavir in their first regimen, 28 (88%) reached and maintained a viral load under 50 copies. In this group without PI mutations, Burger could find no link between atazanavir Cmin and virologic response.
Of the 26 people with PI mutations when they started atazanavir, 20 (77%) reached and maintained a viral load under 50 copies. With this group Burger calculated a GIQ response cutoff of 0.23 mg/L/mutation. Among 8 people with a GIQ under that mark, 4 (50%) had a sub-50 response, compared with 2 of 18 people (11%) with a GIQ above that level.
Forty-five people in the entire study group (42%) had grade 3 or 4 bilirubin elevations, a common atazanavir side effect. A Cmin above 0.76 mg/L predicted grade 3 or 4 hyperbilirubinemia: 25 of 42 people (60%) above 0.76 mg/L had grade 3 or 4 hyperbilirubinemia, compared with 20 of 66 (30%) at or below 0.76 mg/L.
Burger cautioned that the GIQ cutoff must be validated in a prospective study. He plans to analyze a bigger group of atazanavir-treated people with PI mutations to see if he can confirm this finding. For unboosted atazanavir, he noted, the median Cmin in these patients already equals the target GIQ with one PI mutation. In other words, this analysis indicates that unboosted atazanavir is a risky option in people with a single PI mutation.
Reflecting on the bilirubin findings, Burger suggested physicians might consider lowering the atazanavir dose for people with hyperbilirubinemia, a "supratherapeutic" atazanavir Cmin (above 0.76 mg/L), no or minimal PI mutations, and a risk of poor adherence because of bilirubin-related jaundice.
Reference
1. Cleijsen R, Van de Ende M, Kroon F, et al. Therapeutic drug monitoring of the HIV protease inhibitor Atazanavir in clinical practice: 8th International Workshop on Pharmacology of HIV Therapy. April 16-18, 2007. Budapest. Abstract 36.
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