Antiretroviral drug summary: Tipranavir/r (TPV/r; Aptivus)
Last updated on Nov 10, 2008
In vitro TPV has selected for the following major PI-resistance mutations: V32I, I54V, V82L, and I84V (Doyon et al. 2005). V82L, V82T, and I84V have been the most common major PI-resistance mutations to emerge during TPV/r salvage therapy (Naeger and Struble 2007). V82L occurs in viruses that were wildtype at baseline; whereas V82T occurs in viruses with V82A at baseline (Baxter et al. 2006).
In addition to V82L/T which are associated with the greatest decreases in TPV susceptibility in vitro, I47V, I54A/V/S/M, I84V have also been associated with reduced TPV susceptibility (Baxter et al. 2006; Parkin and Chappey 2006; Scherer et al. 2007).
In a weighted genotypic susceptibility score (GSS) based on the RESIST study, T74P (weight=7), I47V (6), V82L/T (5), Q58E (5), N83D (4) were the best predictors of poor virological response; whereas I54A/M/V (3), I84V (2), M36I (2), K43T (2), L10V (1), and M46V (1) were weaker predictors whereas L24I (-2), I50L/V (-4), I54L (-7), and L76V (-2) were predictors of virological response.
L90M was once considered a primary TPV-resistance mutation. However, in subsequent analyses it has shown to have only a weak effect on TPV susceptibility (Piliero et al. 2006; Scherer et al. 2007; Vermeiren et al. 2007).
L33F/I are among the most commonly occurring mutations to emerge during TPV/r treatment and are associated with decreased virologic response when combined with other major mutations (Vermeiren et al. 2007).
E35G, K43T, Q58E, T74P, N83D, and L89V are nonpolymorphic mutations that have been associated with decreased virologic response to TPV/r in multivariate analyses (Baxter et al. 2006; Naeger and Struble 2007; Scherer et al. 2007).
L24I, I50V, I50L, I54L, and L76V are associated with increased TPV susceptibility (Elston et al. 2006; Schapiro et al. 2007; Scherer et al. 2007). This effect is particularly large for I50V/L and I54L.
TPV/r is not recommended for initial HAART because it is associated with increased toxicity relative to other first line PIs against wildtype viruses (Cooper et al. 2006; Temesgen and Feinberg 2007).
In the RESIST studies, TPV/r outperformed APV/r, IDV/r, LPV/r, and SQV/r in treating persons with multiple past PI failures (Cahn et al. 2006; Gathe et al. 2006; Hicks et al. 2006). However, the difference between LPV/r and TPV/r did not reach statistical significance among LPV/r-naïve persons. Although it has not been compared directly to DRV/r, one analysis suggests that DRV/r is superior (Hill and Moyle 2007).
Several mutations have been associated with increased susceptibility to TPV relative to other PIs. However, because the genotypic correlates of reduced TPV susceptibility and reduced virologic response to TPV/r-containing salvage therapy regimens are complicated, phenotypic testing should be done to confirm the superior activity of TPV relative to that of other PIs before TPV/r is used for salvage therapy.
- Baxter, J.D., J.M. Schapiro, C.A. Boucher, V.M. Kohlbrenner, D.B. Hall, J.R. Scherer, and D.L. Mayers. 2006. Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir. J Virol 80: 10794-10801.
- Cahn, P., J. Villacian, A. Lazzarin, C. Katlama, B. Grinsztejn, K. Arasteh, P. Lopez, N. Clumeck, J. Gerstoft, N. Stavrianeas, S. Moreno, F. Antunes, D. Neubacher, and D. Mayers. 2006. Ritonavir-Boosted Tipranavir Demonstrates Superior Efficacy to Ritonavir-Boosted Protease Inhibitors in Treatment-Experienced HIV-Infected Patients: 24-Week Results of the RESIST-2 Trial. Clin Infect Dis 43: 1347-1356.
- Cooper, D., R. Zajdenverg, K. Ruxrungtham, J. Scherer, and R. Chaves. 2006. Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naive patients: results of BI 1182.33. 8th International Congress on Drug Therapy in HIV Infection (Glasgow, Scotland).
- Doyon, L., S. Tremblay, L. Bourgon, E. Wardrop, and M.G. Cordingley. 2005. Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antiviral Res 68: 27-35.
- Elston, R., J. Scherer, D. Hall, J. Schapiro, R. Bethell, V. Kohlbrenner, and D. Mayers. 2006. De-selection of the I50V mutation ocurs in clinical isolates during aptivus/r (tipranavir/ritonavir)-based therapy [abstract 92]. Antivir Ther 11: S102.
- Gathe, J., D.A. Cooper, C. Farthing, D. Jayaweera, D. Norris, G. Pierone, Jr., C.R. Steinhart, B. Trottier, S.L. Walmsley, C. Workman, G. Mukwaya, V. Kohlbrenner, C. Dohnanyi, S. McCallister, and D. Mayers. 2006. Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial. Clin Infect Dis 43: 1337-1346.
- Hicks, C.B., P. Cahn, D.A. Cooper, S.L. Walmsley, C. Katlama, B. Clotet, A. Lazzarin, M.A. Johnson, D. Neubacher, D. Mayers, and H. Valdez. 2006. 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 reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 368: 466-475.
- Hill, A. and G. Moyle. 2007. Relative antiviral efficacy of ritonavir-boosted darunavir and ritonavir-boosted tipranavir vs. control protease inhibitor in the POWER and RESIST trials. HIV Med 8: 259-264.
- Naeger, L.K. and K.A. Struble. 2007. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS 21: 179-185.
- Parkin, N. and C. Chappey. 2006. Protease mutations associated with higher or lower than expected tipranavir (TPV)susceptibility based on the TPV mutation score [abstract 637]. CROI2006.
- Piliero, P., N. Parking, and D. Mayers. 2006. Impact of protease mutations L33F, V82A, I84V, and L90M on ritonavir (RTV)-boosted protease inhibitor susceptibility. ICAAC 2006.
- Schapiro, J., J. Scherer, R. Vinisko, V. Kohlbrenner, J. Baxter, C. Boucher, R. MacArthur, and D. Hall. 2007. Genotypic tipranavir scores as predictors of response. 11th European AIDS Conference.
- Scherer, J., V. Kohlbrenner, D. Hall, J. Baxter, J. Schapiro, and C. Boucher. 2007. Mutations associated with cross-resistance to tipranavir in patients previously treated with two or more protease inhibitors [abstract 100]. 5th European HIV Drug Resistance Workshop.
- Temesgen, Z. and J. Feinberg. 2007. Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis 45: 761-769.
- Vermeiren, H., E. Van Craenenbroeck, P. Alen, L. Bacheler, G. Picchio, and P. Lecocq. 2007. Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods 145: 47-55.