JAC Advance Access originally published online on April 4, 2008
Journal of Antimicrobial Chemotherapy 2008 61(6):1362-1368; doi:10.1093/jac/dkn127
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Original research |
Clinically validated mutation scores for HIV-1 resistance to fosamprenavir/ritonavir
1 Laboratoire de Virologie, CHU de Bordeaux and EA 2968, Université Victor Segalen, Bordeaux, France 2 INSERM, U 720, Paris F-75013, France 3 Université Pierre et Marie Curie-Paris 6, UMR S 720, Paris F-75013, France 4 Laboratoire de Virologie, Hôpital Bichat-Claude Bernard, Paris, France 5 Laboratoire de Virologie, CHU de Lille, France 6 Laboratoire de Virologie, CHU de Nice, France 7 Laboratoire de Virologie, CHU de Rennes, France 8 Laboratoire de Virologie, Hôpital Pitié Salpêtrière, Paris, France 9 Laboratoire de Virologie, CHU de Saint-Antoine, APHP, Université, Paris VI, France 10 Laboratoire de Virologie, CHU de Marseille, France 11 Laboratoire de Virologie, Hôpital Européen Georges Pompidou, Paris, France 12 Laboratoire de Pharmacologie, Hôpital Bichat-Claude Bernard, Paris, France 13 Glaxo Smith Kline, Marly-le-Roi, France
Received 29 November 2007; returned 20 January 2008; revised 26 February 2008; accepted 4 March 2008
* Corresponding author. Tel: +33-5-56-79-55-10; Fax: +33-5-56-79-56-73; E-mail: bernard.masquelier{at}chu-bordeaux.fr
Background: We developed clinically relevant genotypic scores for resistance to fosamprenavir/ritonavir in HIV-1 protease inhibitor (PI)-experienced patients.
Methods: PI-experienced patients with virological failure receiving fosamprenavir/ritonavir as the sole PI for at least 3 months and with detectable fosamprenavir plasma levels were included. The impact of baseline protease mutations on virological response (VR, i.e. decrease in plasma HIV-1 RNA between baseline and month 3) was analysed using the Mann–Whitney test. Mutations with prevalence >10% and P value <0.10 were retained. The Jonckheere–Terpstra test was used to select the combination of mutations most strongly associated with VR. The association between score and VR was assessed by multivariate backward regression.
Results: In the 73 patients included, the median baseline HIV-1 RNA was 4.6 log10 copies/mL (range: 2.7–6.9) and the mean decrease at month 3 was –1.07 ± 1.40 log10 copies/mL. Ninety per cent of the patients were infected by HIV-1 subtype B variants. Two fosamprenavir/ritonavir mutation scores were constructed: score A (L10F/I/V + L33F + M36I + I54L/M/V/A/T/S + I62V + V82A/F/C/G + I84V + L90M) was based only on mutations associated with a worse VR, whereas score B (L10FIV + L33F + M36I + I54L/M/V/A/T/S + A71V – V77I – N88S + L90M) also took into account favourable mutations. Both scores were independent predictors of VR, however, co-administration of tenofovir was associated with a worse VR and the presence of the N88S protease mutation and co-administration of enfuvirtide with a better VR.
Conclusions: These clinically validated mutation scores should be of interest for the clinical management of PI-experienced patients. The fosamprenavir/ritonavir score A was introduced in the 2006 ANRS algorithm along with isolated mutations I50V and V32I + I47V.
Keywords: HIV-1 drug resistance , genotype , protease inhibitor
Participants are listed in the Acknowledgements section.
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