14th International HIV Drug Resistance Workshop 7-11 June 2005, Québec City, Canada

NON-RESPONSE TO TIPRANAVIR IS ASSOCIATED WITH PRE-TREATMENT RESISTANCE CHARACTERIZED BY TIPRANAVIR PHENOTYPE OR GENOTYPIC TIPRANAVIR SCORE

Antivir Ther. 10, Suppl 1:S29 (abstract no. 27)

H Valdez¹, DB Hall¹, VM Kohlbrenner¹, CA Boucher², J Schapiro³, J Baxter⁴, J Scherer¹, S McCallister¹, DL Mayers^1
1Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, USA ²University of Utrecht, Utrecht, The Netherlands ³Stanford University, Stanford, CA, USA ⁴Cooper Hospital, Camden, NJ, USA

BACKGROUND: In Phase 3 RESIST trials, tipranavir (TPV) with ritonavir boosting was introduced along with an optimized background regimen that could include enfuvirtide and any of the licensed antiretroviral nucleoside and non-nucleoside reverse transcriptase inhibitors. A small proportion of patients on TPV (13.8%) had no response to their study regimen with no more than a 0.5 log drop from baseline in HIV-1 RNA during the first 8 weeks of treatment. The relationship between non-response and baseline resistance to TPV was explored.

METHODS: Genotypic sequencing was performed by Virtual Phenotype™ or TRUGENE® assays. Phenotypic assays were performed using the VIRCO Antivirogram® and were available for 361 TPV/r treated patients. To be eligible for the clinical trial patients had to have used at least two protease inhibitor based HAART regimens and had to have at least one protease mutation from among 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, 90M with not more than two mutations at codons 33, 82, 84, and 90. Mutations were summarized in terms of the TPV score, consisting of the number of codons with mutations from among 10V, 13V, 20M/R, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V. The TPV score was derived using univariate and multivariate regression analysis of Phase 2 TPV clinical trial genotype to phenotype and genotype to virological response data.

RESULTS: Phenotypic susceptibility to TPV was associated with virological response, with 92% (233/252) response in those with baseline IC₅₀ fold change <3 compared to 68% (74/109) in those with baseline IC₅₀ fold change of three or greater. Similarly the TPV score was strongly associated with response. Patients with baseline TPV scores of two or less had 94% response (225/239); with scores of three to five had 84% response (374/446); and with scores of six or more had 72% response (43/60).

CONCLUSION: IC₅₀ fold change of <3 or a low TPV score predicted a response to TPV. Reduced susceptibility or high TPV score were associated with a greater non-response rate, however the majority of patients still responded to TPV.

PRESENTING AUTHOR: H Valdez

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2005-06-07
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