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Stefano Rusconi - One of the best experts on this subject based on the ideXlab platform.
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inhibitors multidrug resistance to other protease isolates derived from patients with human immunodeficiency virus type 1 susceptibility to pnu 140690 Tipranavir of
2014Co-Authors: M Moroni, Massimo Galli, S Kurtagic, Michela Violin, Claudia Balotta, Stefano RusconiAbstract:In our study we examined the anti-human immunodeficiency virus type 1 (anti-HIV-1) activity of a novelHIV-1 protease inhibitor, PNU-140690 (Tipranavir), against patient-derived isolates resistant to multiple otherprotease inhibitors (PIs). The aim of our experiments was to investigate the genotypes and the in vitrophenotypes of drug resistance of PNU-140690. We carried out drug susceptibility tests with peripheral bloodmononuclear cells and a fixed amount of infectious virus (1,000 50% tissue culture infective doses) to determinethe 50% inhibitory concentration (IC
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Tipranavir in the protease inhibitors arena
Drugs in R & D, 2011Co-Authors: Barbara Vergani, Stefano RusconiAbstract:Highly active antiretroviral therapy (HAART) has become the standard for treating HIV infection.[1] HIV protease inhibitors (PIs) have been used as a major component of the HAART regimens over the past 10 years, along with nucleoside and non-nucleoside reverse transcriptase inhibitors. The introduction of these regimens resulted in an appreciable decline in morbidity and mortality due to HIV infection.[2,3] Tipranavir (TPV) is a nonpeptidic PI, approved by the US FDA and the European Medicines Agency for the treatment of HIV infection. The structure of this molecule is a sulfonamide-substituted dihydropyrone. Similar to other PIs, TPV binds directly to HIV aspartyl protease, disrupting the catalytic site of the enzyme and preventing protease-dependent cleavage of HIV gag and gag-pol polyproteins into smaller functional proteins.[4–6] For this reason, the chance to develop resistance is not so easy. TPV is active against PI multidrug resistant viruses and it has been very difficult to corner HIV to mutate through subsequent in vitro passages.[7–9] TPV plus low-dose ritonavir (TPV/r) is used in combination with other antiretroviral (ARV) drugs. The advantages of this approach include raising trough drug concentrations, minimizing inter-patient variability, prolonging drug elimination half-life, and reducing pill burden.[10,11] Results in the efficacy of the selected dose of TPV/r (500/200 mg twice daily) were quite encouraging in extensively treated HIV-infected patients. TPV is generally well tolerated; the most frequent adverse events were in the gastrointestinal system and laboratory abnormalities, such as alteration of the lipid profile and liver function.[12] Darunavir (DRV) is another new-generation nonpeptidic HIV protease inhibitor approved by the FDA, used with low doses of ritonavir (600/100 mg twice daily) for pharmacologic enhancement (boosting). It has demonstrated potent activity against multidrug-resistant HIV in heavily treatment-experienced patients with HIV infection. Like TPV, DRV needs multiple mutations in the HIV protease for the virus to build a significant resistance to these drugs. For this reason, TPV and DRV exhibit a high genetic barrier to the emergence of novel resistant strains.[13,14] Boosted DRV is generally well tolerated, with a lower incidence of diarrhea and modification of the lipid profile.[15] The aim of the POTENT trial[16] was the head-to-head comparison of the safety and efficacy of TPV versus DRV plus a low dose of ritonavir, each with an optimized background regimen (OBR) in triple-class-experienced HIV-infected patients, being resistant to more than one PI. This study was designed in 2007 (20 September) to enroll and treat 800 HIV-1-positive patients, randomly assigned (1 : 1) to one of the two arms: TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily), with a treatment period of 50 weeks. Both drugs were administered in combination with another selected ARV, based on patient therapeutic history (and virtual phenotype screening results). The major shortcoming of the POTENT trial was the very low enrollment numbers: only 39 patients (5% of the planned number) were randomized and received drugs prior to early termination of the study (1 July 2008). The data from the trial, due to poor patient enrollment and premature termination, are insufficient to assess primary and secondary previously established endpoints. For this reason, statistical tests were not applied to this collected observational data. The demonstrations of effect of TPV/r have been more evident in treatment-experienced patients with HIV infection receiving an OBR including two fully active drugs. The use of enfuvirtide for the first time has been correlated with a higher rate of virologic success when combined with TPV/r.[12] TPV/r is generally well tolerated, nevertheless clinical hepatitis and hepatic decompensation have been associated with its use. Although initially reported, a recent case review from the FDA did not identify new safety concerns regarding intracranial hemorrhage. Hepatic evaluation is highly recommended in co-infected patients who are at risk for hepatic decompensation.[17,18] There is evidence that mutations conferring resistance to TPV are not related to resistance to DRV. This may be important for the potential sequencing of these two PI in multiple ARV-experienced patients. A substantial susceptibility to TPV and DRV of viral isolates derived from patients with a massive ARV drug experience has been reported.[19] In multiple ARV-experienced patients with resistance to one or more PI, TPV and DRV remain the most likely active PIs for constructing an effective drug regimen. Nowadays, mostly achievable goals of ARV are to further reduce HIV-related morbidity and mortality, improve quality of life, and restore and preserve immunologic function in HIV-infected individuals through a sustained suppression of HIV replication.[20,21] It is not so easy to design a trial such as POTENT where even after significant efforts to enroll patients, the number of individuals included in the study and time in the follow-up were insufficient to draw definitive conclusions. Furthermore, the POTENT trial included a comparison between two PIs; however what we really need are combination regimens including drugs with new mechanisms of action, new cellular targets and novel chemical structures (e.g. co-receptor or integrase inhibitors), together with an improved tolerability profile.[22]
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Clinical validation and applicability of different Tipranavir/ritonavir genotypic scores in HIV-1 protease inhibitor-experienced patients.
Current HIV Research, 2009Co-Authors: Annalisa Saracino, Stefano Rusconi, Stefano Bonora, Franco Maggiolo, Laura Monno, Alessandra Tartaglia, Carmine Tinelli, Elena Seminari, Valeria Micheli, Sergio Lo CaputoAbstract:Tipranavir, a non-peptidic protease inhibitor which shows in vitro efficacy against some HIV-1-resistant strains, can be used in salvage therapies for multi-experienced HIV patients due to its peculiar resistance profile including 21 mutations at 16 protease positions according to International AIDS Society (IAS). Other genotypic scores, however, which attribute a different weight to single amino-acid substitutions, have been recently proposed. To validate the clinical utility of four different genotypic scores for selecting Tipranavir responders, the baseline resistance pattern of 176 HIV heavily experienced patients was correlated with virological success (HIV-RNA < 50 copies/ml) after 24 weeks of a new treatment based on Tipranavir/ritonavir. Virological suppression after 24 weeks was reached by 42.5% of patients. With univariate analysis, genotypic scores were all associated with outcome but showed a low accuracy with ROC analysis, with the weighted score (WS) by Scherer et al. demonstrating the best performance with an AUC of 68%. Only 52% of patients classified as susceptible (WS3) responded to the new therapy. The following variables were significantly associated (p < 0.05) to failure with multivariate analysis: WS, log peak of HIV-RNA, IAS mutations: L33F, I54AMV, Q58E, and non-IAS mutation: N37DES. On the contrary, the use of T20 in T20-naive patients and the V82AFSI and F53LY non-IAS mutations were associated with virological success. The study suggests that even if the “weighted” scores are able to interpret correctly the antiretroviral resistance profile of multi-experienced patients, it is difficult to individuate a cut-off which can be easily applied to this population for discriminating responders.
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clinical validation and applicability of different Tipranavir ritonavir genotypic scores in hiv 1 protease inhibitor experienced patients
Current HIV Research, 2009Co-Authors: Annalisa Saracino, Stefano Rusconi, Stefano Bonora, Franco Maggiolo, Laura Monno, Alessandra Tartaglia, Carmine Tinelli, Elena Seminari, Valeria Micheli, Sergio Lo CaputoAbstract:Tipranavir, a non-peptidic protease inhibitor which shows in vitro efficacy against some HIV-1-resistant strains, can be used in salvage therapies for multi-experienced HIV patients due to its peculiar resistance profile including 21 mutations at 16 protease positions according to International AIDS Society (IAS). Other genotypic scores, however, which attribute a different weight to single amino-acid substitutions, have been recently proposed. To validate the clinical utility of four different genotypic scores for selecting Tipranavir responders, the baseline resistance pattern of 176 HIV heavily experienced patients was correlated with virological success (HIV-RNA < 50 copies/ml) after 24 weeks of a new treatment based on Tipranavir/ritonavir. Virological suppression after 24 weeks was reached by 42.5% of patients. With univariate analysis, genotypic scores were all associated with outcome but showed a low accuracy with ROC analysis, with the weighted score (WS) by Scherer et al. demonstrating the best performance with an AUC of 68%. Only 52% of patients classified as susceptible (WS3) responded to the new therapy. The following variables were significantly associated (p < 0.05) to failure with multivariate analysis: WS, log peak of HIV-RNA, IAS mutations: L33F, I54AMV, Q58E, and non-IAS mutation: N37DES. On the contrary, the use of T20 in T20-naive patients and the V82AFSI and F53LY non-IAS mutations were associated with virological success. The study suggests that even if the “weighted” scores are able to interpret correctly the antiretroviral resistance profile of multi-experienced patients, it is difficult to individuate a cut-off which can be easily applied to this population for discriminating responders.
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Tipranavir a novel protease inhibitor for hiv therapy
Expert Review of Clinical Pharmacology, 2009Co-Authors: Stefano RusconiAbstract:Tipranavir (TPV) is a nonpeptidic protease inhibitor with potent in vitro activity against most HIV-1 strains resistant to other protease inhibitors. In vitro data have shown that resistance to TPV develops slowly. When coadministered with ritonavir (RTV) as a booster, TPV has shown potent antiviral activity in multiple antiretroviral-experienced patients. In the RESIST-1 and RESIST-2 studies, the efficacy and safety of TPV/RTV (500/200 mg twice daily) in highly treatment-experienced HIV-1-positive patients was assessed. Analysis at 48 weeks showed that TPV/RTV-containing regimens significantly improved immune and virological responses compared with a RTV-boosted comparator protease inhibitor plus optimized background regimen. TPV is generally well tolerated; nevertheless, clinical hepatitis and liver decompensation have been associated to its use, together with an indication of an increased risk of intracranial hemorrhage. Extensive listing of drug–drug interactions have been reported with TPV.
Vincent Soriano - One of the best experts on this subject based on the ideXlab platform.
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drug resistance mutations in hiv infected patients in the spanish drug resistance database failing Tipranavir and darunavir therapy
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Eva Poveda, Lourdes Anta, Jose L Blanco, Jose L Casado, Felix Gutierrez, Federico Garcia, J L Gomezsirvent, Jose Antonio Iribarren, Vincent Soriano, Carmen De MendozaAbstract:The presence of resistance mutations in patients failing Tipranavir or darunavir was examined at the national drug resistance database of the Spanish AIDS Research Network. Although mutations emerging during Tipranavir and darunavir failures differed considerably, cross-resistance was found in up to half of the patients tested. Interestingly, mutation 54L, which is associated with Tipranavir hypersusceptibility, was selected in half of the darunavir failures. Thus, resistance testing seems mandatory to ensure the benefit of the sequential use of these drugs.
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the benefit of simplification from Tipranavir ritonavir 500 200 bid to 500 100 bid guided by therapeutic drug monitoring
Therapeutic Drug Monitoring, 2010Co-Authors: Judit Morello, Sonia Rodrigueznovoa, Inmaculada Jimeneznacher, F J Blanco, Gema Gonzalezpardo, Eugenia Vispo, Pablo Barreiro, Juan Gonzalezlahoz, Vincent SorianoAbstract:: Despite being among the most potent protease inhibitors, the use of Tipranavir (TPV) is hampered by a high pill burden and frequent side effects compared with other boosted protease inhibitors. A total of 10 patients receiving TPV/ritonavir (TPV/RTV) 500/200 for longer than 6 months were randomized to stay on the same dosing schedule or switch to TPV/RTV 500/100. Although all patients on TVP/RTV 500/200 remained stable for the next 12 weeks, 3 out of 5 patients who switched doses experienced benefits in terms of reducing aminotransferases and total cholesterol. Fasting triglycerides were also reduced in 2 of them. Plasma HIV-RNA remained undetectable in all patients, despite the observed decline in TPV trough concentrations.
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The benefit of simplification from Tipranavir/ritonavir 500/200 bid to 500/100 bid guided by therapeutic drug monitoring.
Therapeutic Drug Monitoring, 2010Co-Authors: Judit Morello, Gema González-pardo, Francisco J. Blanco, Inmaculada Jiménez-nácher, Juan González-lahoz, Sonia Rodriguez-novoa, Eugenia Vispo, Pablo Barreiro, Vincent SorianoAbstract:: Despite being among the most potent protease inhibitors, the use of Tipranavir (TPV) is hampered by a high pill burden and frequent side effects compared with other boosted protease inhibitors. A total of 10 patients receiving TPV/ritonavir (TPV/RTV) 500/200 for longer than 6 months were randomized to stay on the same dosing schedule or switch to TPV/RTV 500/100. Although all patients on TVP/RTV 500/200 remained stable for the next 12 weeks, 3 out of 5 patients who switched doses experienced benefits in terms of reducing aminotransferases and total cholesterol. Fasting triglycerides were also reduced in 2 of them. Plasma HIV-RNA remained undetectable in all patients, despite the observed decline in TPV trough concentrations.
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use of different inhibitory quotients to predict early virological response to Tipranavir in antiretroviral experienced human immunodeficiency virus infected patients
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Judit Morello, Lourdes Anta, Vincent Soriano, Carmen De Mendoza, Inmaculada Jimeneznacher, Angélica Corral, F J Blanco, Gema Gonzalezpardo, Juan Gonzalezlahoz, Sonia RodrigueznovoaAbstract:Information about the relationship between pharmacological parameters and an early virological response to Tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of ≥1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (Ctrough)/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores (from the International AIDS Society—USA [IAS-USA], Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir [RESIST], and Agence Nationale de Recherches sur le Sida et les Hepatites Virales [ANRS] trials). The sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and likelihood ratios for a positive result (LHR+) and a negative result (LHR−) [LHR+ = sensitivity/(1 − specificity); LHR− = (1 − sensitivity)/specificity] were calculated. A total of 57 HIV-infected patients were analyzed. A virological response was achieved by 77% of the patients. TPV resistance mutations, TPV Ctrough, vIQs, and gIQs were all significantly associated with a virological response. The vIQ had the best PPV and NPV (97% and 78%, respectively). The values of the LHR+ were 7.8 for vIQ, 3.4 for the RESIST gIQ, 3.3 for the IAS-USA gIQ, 3.1 for the ANRS gIQ, 2.2 for TPV Ctrough, and 1.3 for the IAS-USA and RESIST scores. The values of LHR− were 0 for the RESIST score, 0.07 for vIQ, 0.09 for the IAS-USA score, 0.27 for the RESIST gIQ, 0.32 for the IAS-USA gIQ, 0.37 for the ANRS gIQ, and 0.48 for TPV Ctrough. HIV-infected patients who initiate a salvage regimen based on TPV may benefit from baseline drug resistance testing and TPV plasma concentration determination, as vIQ is the best predictor of a virological response.
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Use of Different Inhibitory Quotients To Predict Early Virological Response to Tipranavir in Antiretroviral-Experienced Human Immunodeficiency Virus-Infected Patients
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Judit Morello, Lourdes Anta, Vincent Soriano, Carmen De Mendoza, Gema González-pardo, Angélica Corral, Francisco J. Blanco, Inmaculada Jiménez-nácher, Juan González-lahoz, Sonia Rodriguez-novoaAbstract:Information about the relationship between pharmacological parameters and an early virological response to Tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of ≥1 log unit or to
Douglas Mayers - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of Tipranavir boosted with ritonavir in hiv 1 infected patients failing multiple protease inhibitor regimens 80 week data from a phase 2 study
Journal of Acquired Immune Deficiency Syndromes, 2007Co-Authors: Martin Markowitz, Douglas Mayers, Dietmar Neubacher, Leonard N Slater, Robert Schwartz, Powel Kazanjian, Bruce Hathaway, David Wheeler, Mitchell Goldman, Hernan ValdezAbstract:Background: BI 1182.2, an open-label, randomized, multicenter, phase 2 study, evaluated efficacy and tolerability of the protease inhibitor (PI) Tipranavir (TPV; 500 mg twice daily or 1000 mg twice daily) administered with ritonavir (100 mg twice daily) in combination with 1 nucleoside reverse transcriptase inhibitor and 1 non-nucleoside reverse transcriptase inhibitor in multiple PI-experienced HIV-1-infected patients. Methods: Forty-one patients were evaluated in 2 arms: low-dose (19 patients) or high-dose (22 patients) ritonavir-boosted Tipranavir (TPV/r). Primary endpoints were change from baseline in HIV-1 RNA concentrations at weeks 16, 24, 48, and 80 and percentage of patients with plasma HIV-1 RNA levels lower than the limit of quantitation. Safety was evaluated by adverse events (AEs), grade 3/4 abnormalities, and serious AEs. Results: Of all patients, 59% were still receiving TPV/r (14 in low-dose arm and 10 in high-dose arm) at week 80. Patients in both arms had a median >2.0-log 10 reduction in plasma viral load. Intent-to-treat analysis demonstrated that a similar proportion of patients in the high-dose and low-dose groups achieved plasma HIV-1 RNA levels <50 copies/mL at week 80 (43% vs. 32%; P = 0.527). The most frequently observed AEs were diarrhea, headache, and nausea. Conclusion: TPV/r combined with other active antiretroviral agents can provide a durable treatment response for highly treatment-experienced patients.
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genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor Tipranavir
Journal of Virology, 2006Co-Authors: John D Baxter, Jonathan M Schapiro, Charles A Boucher, Veronika Kohlbrenner, David B Hall, Joseph Scherer, Douglas MayersAbstract: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-log10 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.
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durable efficacy of Tipranavir ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment experienced hiv 1 infected patients at 48 weeks in the randomized evaluation of strategic intervention in multi drug re
The Lancet, 2006Co-Authors: Charles B Hicks, Christine Katlama, Dietmar Neubacher, Bonaventura Clotet, Pedro Cahn, Adriano Lazzarin, David A Cooper, Sharon Walmsley, Margaret Johnson, Douglas MayersAbstract:Summary Background Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor Tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. Methods We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log 10 copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). Findings 3324 patients were screened; 746 received Tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65·1%) patients on Tipranavir-ritonavir and 192 (26·1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the Tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33·6%] vs 113 [15·3%]; p vs 0 days; p Interpretation Compared with CPI-ritonavir, Tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.
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non peptidic protease inhibitors nppis Tipranavir
Advances in Antiviral Drug Design, 2003Co-Authors: Douglas Mayers, Veronika Kohlbrenner, Kevin Curry, Scott MccallisterAbstract:Publisher Summary Tipranavir is a potent, highly selective, orally bioavailable, non-peptidic protease inhibitor (NPPI). Tipranavir suppresses the replication of laboratory and clinical HIV-1 strains in primary peripheral blood mononuclear cells. Tipranavir acts additively or synergistically with other licensed antiretroviral (ARV) drugs, including other protease inhibitors (PIs). The majority (90%) of 105 HIV-1 isolates that were highly cross resistant to other PIs were sensitive to Tipranavir when tested in vitro. The observed incidence of cross-resistance to Tipranavir following treatment with currently available peptidomimetic PIs is low. Tipranavir has demonstrated potent anti-retroviral activity both clinically and in vitro , and has a distinct and robust resistance profile. It is active both in treatment-naive and highly treatment-experienced patients and has a generally well-tolerated safety profile.
Joseph Scherer - One of the best experts on this subject based on the ideXlab platform.
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improving the prediction of virological response to Tipranavir the development and validation of a Tipranavir weighted mutation score
Antiviral Therapy, 2010Co-Authors: Jonathan M Schapiro, John D Baxter, Charles A Boucher, Joseph Scherer, Clemens Tilke, Carlo Federico Perno, Franco Maggiolo, Maria Mercedes Santoro, David B HallAbstract:Background: The purpose of this study was to develop a Tipranavir-weighted mutation score that provides guidance to treating physicians on the relative effect of specific protease mutations on Tipranavir activity. Methods: Weights were developed using data from RESIST Tipranavir-treated patients based on regressions of virological response at weeks 8 and 24, accounting for baseline CD4 + T-cell count and background regimen activity. The resulting weighted score and cutoffs were validated using a set of cohort patients external to the Tipranavir development programme. Response rates were tabulated for the new weighted score and compared with other Tipranavir mutation scores used in clinical practice. Results: The final weights were 74P, 82L/T, 83D and 47V (+4), 58E and 84V (+3), 361, 43T and 54A/M/V (+2), 10V, 33F and 46L (+1), 241 and 76V (-2), 50L/V (-4), and 54L (-6). Tipranavir-weighted score susceptibility categories were susceptible ≤3, partially susceptible >3 but ≤10, and resistant ≥11. Week 48 response rates for RESIST patients were 34.6%, 15.9% and 5.9%, respectively. Using the external cohort data (n=150), the weighted score was highly associated with week 8 viral load reduction (P=0.0027). Only one other score achieved statistical significance. Conclusions: The Tipranavir-weighted score developed and externally validated here, in three datasets representing a broad population of treatment-experienced patients, can be used to make clinical decisions about whether to consider Tipranavir in a treatment-experienced patient who has limited treatment options.
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multidrug experienced hiv 1 infected women demonstrated similar virological and immunological responses to Tipranavir ritonavir compared with men
AIDS, 2009Co-Authors: Sharon L Walmsley, Michael Kraft, Kathleen Squires, Laurence Weiss, Philippa Easterbrook, Anna Orani, Joseph SchererAbstract:: Gender-related differences in the efficacy and safety of ritonavir-boosted Tipranavir [Tipranavir/ritonavir (TPV/r) 500/200 mg twice daily (b.i.d.)] were evaluated in a subanalysis of the Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients with Tipranavir (RESIST) trials. Data from HIV-1-infected women (203; TPV/r = 117) and men (1280; TPV/r = 629) showed no significant gender-related differences in HIV RNA response rates (at 48 weeks) and safety (at 96 weeks) despite higher mean steady-state plasma TPV trough concentrations in women. Significantly greater increases in CD4 cell count (+81.2 vs. +48.6; P = 0.0012) were observed in women at week 48.
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Multidrug-experienced HIV-1-infected women demonstrated similar virological and immunological responses to Tipranavir/ritonavir compared with men.
AIDS, 2009Co-Authors: Sharon L Walmsley, Michael Kraft, Kathleen Squires, Laurence Weiss, Philippa Easterbrook, Anna Orani, Joseph SchererAbstract:: Gender-related differences in the efficacy and safety of ritonavir-boosted Tipranavir [Tipranavir/ritonavir (TPV/r) 500/200 mg twice daily (b.i.d.)] were evaluated in a subanalysis of the Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients with Tipranavir (RESIST) trials. Data from HIV-1-infected women (203; TPV/r = 117) and men (1280; TPV/r = 629) showed no significant gender-related differences in HIV RNA response rates (at 48 weeks) and safety (at 96 weeks) despite higher mean steady-state plasma TPV trough concentrations in women. Significantly greater increases in CD4 cell count (+81.2 vs. +48.6; P = 0.0012) were observed in women at week 48.
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genotypic susceptibility to Tipranavir tpv and darunavir drv in a cohort of treatment experienced patients tep
Journal of the International AIDS Society, 2008Co-Authors: John D Baxter, Joseph Scherer, Laveeza Bhatti, M Mcdonough, Peter J PilieroAbstract:Purpose of the study TPV and DRV are ritonavir-boosted HIV protease inhibitors (PI) indicated for use in TEPs with PI resistance. Both agents have shown superior virologic and immunologic responses in TEPs compared with first-generation PIs. In the Utilization of HIV Drug Resistance in Treatment-Experienced Patients (UTILIZE) study, we assessed the presence of resistance to Tipranavir, darunavir, and other antiretroviral agents among HIV-1 isolates in treatmentexperienced patients.
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genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor Tipranavir
Journal of Virology, 2006Co-Authors: John D Baxter, Jonathan M Schapiro, Charles A Boucher, Veronika Kohlbrenner, David B Hall, Joseph Scherer, Douglas MayersAbstract: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-log10 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.
Charles A Boucher - One of the best experts on this subject based on the ideXlab platform.
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improving the prediction of virological response to Tipranavir the development and validation of a Tipranavir weighted mutation score
Antiviral Therapy, 2010Co-Authors: Jonathan M Schapiro, John D Baxter, Charles A Boucher, Joseph Scherer, Clemens Tilke, Carlo Federico Perno, Franco Maggiolo, Maria Mercedes Santoro, David B HallAbstract:Background: The purpose of this study was to develop a Tipranavir-weighted mutation score that provides guidance to treating physicians on the relative effect of specific protease mutations on Tipranavir activity. Methods: Weights were developed using data from RESIST Tipranavir-treated patients based on regressions of virological response at weeks 8 and 24, accounting for baseline CD4 + T-cell count and background regimen activity. The resulting weighted score and cutoffs were validated using a set of cohort patients external to the Tipranavir development programme. Response rates were tabulated for the new weighted score and compared with other Tipranavir mutation scores used in clinical practice. Results: The final weights were 74P, 82L/T, 83D and 47V (+4), 58E and 84V (+3), 361, 43T and 54A/M/V (+2), 10V, 33F and 46L (+1), 241 and 76V (-2), 50L/V (-4), and 54L (-6). Tipranavir-weighted score susceptibility categories were susceptible ≤3, partially susceptible >3 but ≤10, and resistant ≥11. Week 48 response rates for RESIST patients were 34.6%, 15.9% and 5.9%, respectively. Using the external cohort data (n=150), the weighted score was highly associated with week 8 viral load reduction (P=0.0027). Only one other score achieved statistical significance. Conclusions: The Tipranavir-weighted score developed and externally validated here, in three datasets representing a broad population of treatment-experienced patients, can be used to make clinical decisions about whether to consider Tipranavir in a treatment-experienced patient who has limited treatment options.
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treatment response to ritonavir boosted Tipranavir versus ritonavir boosted lopinavir in hiv 1 patients with higher lopinavir mutation scores
AIDS, 2007Co-Authors: Sharon L Walmsley, Stefano Rusconi, Laurent Cotte, Douglas J Ward, Charles B Hicks, Ulrich Meier, Hernan Valdez, Charles A BoucherAbstract:: Week 48 HIV-RNA treatment response to the protease inhibitor Tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the Tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.
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genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor Tipranavir
Journal of Virology, 2006Co-Authors: John D Baxter, Jonathan M Schapiro, Charles A Boucher, Veronika Kohlbrenner, David B Hall, Joseph Scherer, Douglas MayersAbstract: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-log10 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.
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prevention of mother to child transmission of multi drug resistant hiv 1 using maternal therapy with both enfuvirtide and Tipranavir
AIDS, 2006Co-Authors: Annemarie M J Wensing, Charles A Boucher, Marjo Van Kasteren, Pieter J Van Dijken, Sybil P Geelen, Job R JuttmannAbstract:The management of multi-drug resistant HIV is a complex challenge in daily practice. Of particular concern is the presence of these strains in pregnant females as drug resistance does not only limit therapeutic options for the mother but may also reduce the effectiveness of perinatal prophylaxis. In order to avoid mother-to-child transmission clinicians may feel compelled to prescribe recently approved drugs for which there is none or only limited experience in pregnancy. We present a case of a pregnant female with drug-resistant HIV who received a mega-HAART regimen including the recently approved drugs enfuvirtide and Tipranavir. Only limited information is available on perinatal prescription of enfuvirtide and the use of Tipranavir in pregnancy has not yet been reported. (excerpt)