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Antimicrobial Agents and Chemotherapy, September 2008, p. 3237-3243, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00133-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tipranavir-Ritonavir Genotypic Resistance Score in Protease Inhibitor-Experienced Patients

Anne-Genevieve Marcelin,^1* Bernard Masquelier,² Diane Descamps,³ Jacques Izopet,⁴ Charlotte Charpentier,⁵ Chakib Alloui,⁶ Magali Bouvier-Alias,⁷ Anne Signori-Schmuck,⁸ Brigitte Montes,⁹ Marie-Laure Chaix,¹⁰ Corinne Amiel,¹¹ Georges Dos Santos,¹² Annick Ruffault,¹³ Francis Barin,¹⁴ Gilles Peytavin,¹⁵ Marc Lavignon,¹⁶ Philippe Flandre,¹⁷ and Vincent Calvez¹

Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, F 75013 Paris, and UPMC Univ Paris 06, EA2387, F 75005 Paris, France,¹ Laboratoire de Virologie, CHU de Bordeaux, and EA 2968, Université Victor Segalen, Bordeaux, France,² Laboratoire de Virologie, AP-HP, Groupe Hospitalier Bichat-Claude Bernard, F 75018 Paris, and Université Denis Diderot-Paris 7, INSERM U552, Paris, France,³ Laboratoire de Virologie, CHU de Toulouse, Toulouse, France,⁴ Laboratoire de Virologie, HEGP, AP-HP, Paris, France,⁵ Laboratoire de Virologie, CHU Avicenne, AP-HP, Avicenne, France,⁶ Laboratoire de Virologie, CHU Henri Mondor, AP-HP, Créteil, France,⁷ Laboratoire de Virologie, CHU de Grenoble, Grenoble, France,⁸ Laboratoire de Virologie, CHU de Montpellier, Montpellier, France,⁹ Laboratoire de Virologie, Hôpital Necker, AP-HP, Paris, France,¹⁰ Laboratoire de Virologie, Hôpital Tenon, AP-HP, Paris, France,¹¹ Laboratoire de Virologie, CHU de Fort de France, Fort de France, France,¹² Laboratoire de Virologie, CHU de Rennes, Rennes, France,¹³ Laboratoire de Virologie, CHU de Tours, Tours, France,¹⁴ Pharmacie, AP-HP, Groupe Hospitalier Bichat-Claude Bernard, F 75018 Paris, France,¹⁵ Boehringer Ingelheim, Reims, France,¹⁶ INSERM U720, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, F 75013 Paris, and UPMC Univ Paris 06, F 75005 Paris, France,¹⁷

Received 30 January 2008/ Returned for modification 10 March 2008/ Accepted 3 July 2008

To identify mutations associated with the virological response (VR) to a tipranavir-ritonavir (TPV/r)-based regimen, 143 patients previously treated with protease inhibitor (PI) were studied. VR was defined by a decrease of at least 1 log₁₀ in, or undetectable, human immunodeficiency virus (HIV) RNA at month 3. The effect of each mutation in the protease, considering all variants at a residue as a single variable, on the VR to TPV/r was investigated. Mutations at six residues were associated with a lower VR (E35D/G/K/N, M36I/L/V, Q58E, Q61D/E/G/H/N/R, H69I/K/N/Q/R/Y, and L89I/M/R/T/V), and one mutation was associated with a higher VR (F53L/W/Y). The genotypic score M36I/L/V – F53L/W/Y + Q58E + H69I/K/N/Q/R/Y + L89I/M/R/T/V was selected as providing a strong association with VR. For the seven patients with a genotypic score of –1 (viruses with only mutation at codon 53), the percentage of responders was 100% and the percentages were 79%, 56%, 33%, 21%, and 0% for those with scores of 0, 1, 2, 3, and 4, respectively. The percentage of patients showing a response to TPV/r was lower for patients infected with non-clade B viruses (n = 16, all non-B subtypes considered together) than for those infected with clade B viruses (n = 127) (25% and 59%, respectively; P = 0.015). Most mutations associated with VR to TPV/r had not previously been associated with PI resistance. This is consistent with phenotypic analysis showing that TPV has a unique resistance profile. Mutations at five positions (35, 36, 61, 69, and 89) were observed significantly more frequently in patients infected with a non-B subtype than in those infected with the B subtype, probably explaining the lower VR observed in these patients.

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* Corresponding author. Mailing address: Department of Virology, Pitié-Salpêtrière Hospital, 83 Boulevard de l'Hôpital, 75013 Paris, France. Phone: 33142177401. Fax: 33142177411. E-mail: anne-genevieve.marcelin{at}psl.aphp.fr

Published ahead of print on 14 July 2008.

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Antimicrobial Agents and Chemotherapy, September 2008, p. 3237-3243, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00133-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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