{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T22:52:40Z","timestamp":1790031160758,"version":"4.0.1"},"reference-count":24,"publisher":"American Society for Microbiology","issue":"21","license":[{"start":{"date-parts":[[2006,11,1]],"date-time":"2006-11-01T00:00:00Z","timestamp":1162339200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2006,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Tipranavir is a novel, nonpeptidic protease inhibitor of human immunodeficiency virus type 1 (HIV-1) with activity against clinical HIV-1 isolates from treatment-experienced patients. HIV-1 genotypic and phenotypic data from phase II and III clinical trials of tipranavir with protease inhibitor-experienced patients were analyzed to determine the association of protease mutations with reduced susceptibility and virologic response to tipranavir. Specific protease mutations were identified based on stepwise multiple-regression analyses of phase II study data sets. Validation included analyses of phase III study data sets to determine if the same mutations would be selected and to assess how these mutations contribute to multiple-regression models of tipranavir-related phenotype and of virologic response. A tipranavir mutation score was developed from these analyses, which consisted of a unique string of 16 protease positions and 21 mutations (10V, 13V, 20M\/R\/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A\/M\/V, 58E, 69K, 74P, 82L\/T, 83D, and 84V). HIV-1 isolates displaying an increasing number of these tipranavir resistance-associated mutations had a reduced phenotypic susceptibility and virologic response to tipranavir. Regression models for predicting virologic response in phase III trials revealed that each point in the tipranavir score was associated with a 0.16-log\n            <jats:sub>10<\/jats:sub>\n            copies\/ml-lower virologic response to tipranavir at week 24 of treatment. A lower number of points in the tipranavir score and a greater number of active drugs in the background regimen were predictive of virologic success. These analyses demonstrate that the tipranavir mutation score is a potentially valuable tool for predicting the virologic response to tipranavir in protease inhibitor-experienced patients.\n          <\/jats:p>","DOI":"10.1128\/jvi.00712-06","type":"journal-article","created":{"date-parts":[[2006,10,15]],"date-time":"2006-10-15T06:42:36Z","timestamp":1160894556000},"page":"10794-10801","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":101,"title":["Genotypic Changes in Human Immunodeficiency Virus Type 1 Protease Associated with Reduced Susceptibility and Virologic Response to the Protease Inhibitor Tipranavir"],"prefix":"10.1128","volume":"80","author":[{"given":"John D.","family":"Baxter","sequence":"first","affiliation":[{"name":"Cooper University Hospital\/UMDNJ-Robert Wood Johnson Medical School, Camden, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Schapiro","sequence":"additional","affiliation":[{"name":"Stanford University, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A. B.","family":"Boucher","sequence":"additional","affiliation":[{"name":"Eijkman-Winkler Center, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika M.","family":"Kohlbrenner","sequence":"additional","affiliation":[{"name":"Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Hall","sequence":"additional","affiliation":[{"name":"Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Scherer","sequence":"additional","affiliation":[{"name":"Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas L.","family":"Mayers","sequence":"additional","affiliation":[{"name":"Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200001070-00019"},{"key":"e_1_3_2_3_2","first-page":"1","year":"2006","unstructured":"Bartlett, J. G., H. C. Lane, and the Panel on Antiretroviral Guidelines for Adults and Adolescents, Office of AIDS Research Advisory Council. 4 May 2006. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents, p. 1-112. National Institutes of Health, Bethesda, Md. [Online.] http:\/\/aidsinfo.nih.gov\/contentfiles\/adultandadolescentGL.pdf .","journal-title":"Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents"},{"key":"e_1_3_2_4_2","unstructured":"Cahn P. and the RESIST-2 study team. 2004. 24-week data from RESIST-2: phase 3 study of the efficacy and safety of background therapy plus tipranavir\/ritonavir (TPV\/r) or optimized ritonavir-boosted standard-of-care (SOC) comparator PI (CPI) in a large randomized multicenter trial in treatment-experienced HIV+ patients. Presented at the 7th International Congress on Drug Therapy in HIV Infection Glasgow Scotland 14 to 18 November."},{"key":"e_1_3_2_5_2","unstructured":"Cahn P.I. and C. Hicks for the RESIST-2 and RESIST-1 study teams. 2005. RESIST-1 (R-1) and RESIST-2 (R-2) 48 week meta-analyses demonstrate superiority of protease inhibitor (PI) tipranavir+ritonavir (TPV\/r) over an optimized comparator PI (CPI\/r) regimen in antiretroviral (ARV) experienced patients. Presented at the 10th European AIDS Conference Dublin Ireland 17 to 20 November."},{"key":"e_1_3_2_6_2","first-page":"S12","volume":"7","year":"2002","unstructured":"Doyon, L., S. Tremblay, M. Cartier, and M. G. Cordingley. 2002. In vitro susceptibility of HIV-1 to tipranavir. Antivir. Ther.7:S12.","journal-title":"Antivir. Ther."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2005.07.003"},{"key":"e_1_3_2_8_2","unstructured":"Reference deleted."},{"key":"e_1_3_2_9_2","unstructured":"Hicks C. for the RESIST-1 study team. 2004. RESIST-1: randomized evaluation of strategic intervention in multi-drug resistant patients with tipranavir; phase 3 comparison of TPV\/r and standard-of-care boosted-comparator PI (CPI\/r) at 24 weeks. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy Washington D.C.."},{"key":"e_1_3_2_10_2","first-page":"215","volume":"11","year":"2003","unstructured":"Johnson, V. A., F. Brun-Vezinet,, B. Clotet, B. Conway, R. T. D'Aquila, L. M. Demeter, D. R. Kuritzkes, D. Pillay, J. M. Schapiro, A. Telenti, and D. D. Richman. 2003. Drug resistance mutations in HIV-1. Topics HIV Med.11:215-221.","journal-title":"Topics HIV Med."},{"key":"e_1_3_2_11_2","first-page":"51","volume":"13","year":"2005","unstructured":"Johnson, V. A., F. Brun-Vezinet, B. Clotet, B. Conway, D. R. Kuritzkes, D. Pillay, J. Schapiro, A. Telenti, and D. Richman. 2005. Update of the drug resistance mutations in HIV-1: 2005. Topics HIV Med.13:51-57.","journal-title":"Topics HIV Med."},{"key":"e_1_3_2_12_2","unstructured":"Kohlbrenner V. J. Gathe G. Pierone K. Arasteh P. Rubio R. LaLonde P. Piliero S. McCallister S. Garfinkel R. Chaves S. Spinosa C. Dohnanyi A. Quinson and D. Mayers. 2003. Tipranavir\/ritonavir (TPV\/r) demonstrates potent efficacy in multiple protease-inhibitor (PI)-experienced patients at 24 weeks: BI 1182.52. Presented at the 9th European AIDS Conference Warsaw Poland 26 to 29 October."},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200009080-00009"},{"key":"e_1_3_2_14_2","first-page":"79","volume":"4","year":"2004","unstructured":"Mayers, D., K. Curry, V. Kohlbrenner, and S. McCallister. 2004. Non-peptidic protease inhibitors (NPPIs): tipranavir. Adv. Antiviral Drug Res.4:79-98.","journal-title":"Adv. Antiviral Drug Res."},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(02)02054-0"},{"key":"e_1_3_2_16_2","unstructured":"Muzammil S. L. W. Kang A. A. Armstrong A. Jakalian P. R. Bonneau V. Schmelmer L. M. Amzel and E. Freire. 2005. Binding energetics analysis shows a unique response of tipranavir to HIV-1 protease mutations associated with drug resistance. Presented at the 3rd International AIDS Society meeting Rio de Janeiro Brazil 24 to 27 July."},{"key":"e_1_3_2_17_2","unstructured":"Muzammil S. L. W. Kang A. A. Armstrong A. Jakalian P. R. Bonneau V. Schmelmer L. M. Amzel and E. Freire. 2005. Unique response of tipranavir to multi-drug resistant HIV-1 proteases suggests new ways of combating drug resistance. Presented at the 14th International HIV Drug Resistance Workshop Quebec City Canada 7 to 11 June."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1110\/ps.03468904"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.5.1058"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-1293.2002.00116.x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.5.1328-1332.2000"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.7.6197-6202.1999"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.1.348"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm960541s"},{"key":"e_1_3_2_25_2","first-page":"S29","volume":"10","year":"2005","unstructured":"Valdez, H., D. B. Hall, V. M. Kohlbrenner, C. A. Boucher, J. Schapiro, J. Baxter, J. Scherer, S. McCallister, and D. L. Mayers. 2005. Non-response to tipranavir is associated with pretreatment resistance characterized by tipranavir phenotype or genotypic tipranavir score. Antivir. Ther.10:S29.","journal-title":"Antivir. Ther."}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00712-06","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00712-06","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T10:32:41Z","timestamp":1646476361000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.00712-06"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,11]]},"references-count":24,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2006,11]]}},"alternative-id":["10.1128\/JVI.00712-06"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00712-06","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,11]]},"assertion":[{"value":"2006-04-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-08-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-11-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}