Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens

Abstract

The virological response (VR) to a tipranavir-ritonavir (TPV-RTV)-based regimen had been shown to be associated with a number of mutations in the protease gene, the use of enfuvirtide (T20), and the TPV phenotypic inhibitory quotient (IQ). The role of the TPV genotypic IQ (gIQ) has not yet been fully investigated. The aim of our study was to evaluate the relationship between the TPV gIQ and the VR at 48 weeks to TPV-based salvage regimens. Patients placed on regimens containing two nucleoside reverse transcriptase inhibitors plus TPV-RTV 500/200 mg twice a day with or without T20 were prospectively studied. Regular follow-up was performed over the study period. VR, considered a viral load (VL) decrease of >1 log unit and/or the achievement of <50 copies/ml with no VL rebound of >0.5 log unit compared to the maximal VL decrease at week 48, was assessed. Thirty-eight patients who had received multiple drugs were included. At week 48 the VL decrease was ؊1.48 (interquartile range [IQR], ؊2.88 to ؊0.48), 15 patients (39.5%) had VLs of <50 copies/ml, and the CD4 ؉ cell count increase was 37 cells/mm 3 (IQR, ؊30 to ؉175). Twenty subjects (52.6%) achieved VRs. The TPV gIQ and optimized background score (OBS) were independently associated with higher VL decreases. The TPV gIQ and OBS were also independent predictors of a VR at week 48. TPV gIQ and OBS cutoff values of 14,500 and 2, respectively, were associated with a higher rate of VR. The TPV gIQ was shown to be able to predict the VR at 48 weeks to TPV-containing salvage regimens better than the TPV trough concentration or TPV-associated mutations alone. A possible TPV gIQ cutoff value of 14,500 for reaching a VR at week 48 was suggested. Further studies are needed in order to evaluate the calculation of TPV gIQ as a new tool for the optimization of TPV-based salvage therapy.Tipranavir (TPV) is a nonpeptidic protease inhibitor with potent in vitro activity against most human immunodeficiency virus (HIV) type 1 (HIV-1) strains resistant to other protease inhibitors (PIs) (1,14,15). In vitro data have shown that resistance to TPV develops slowly (5). When TPV is coadministered with ritonavir (RTV) as a booster, TPV has been shown to have potent antiviral activity in multidrug-experienced patients (3,6,9,12). In the RESIST-1 and the RESIST-2 studies, the efficacy and safety of TPV-RTV (500 mg/200 mg twice daily) in 1,509 highly treatment-experienced HIV-1-positive patients were assessed. Analysis at 48 weeks showed that the TPV-RTV-containing regimens significantly improved the immune and virological responses (VRs) compared to the responses to an RTV-boosted comparator PI plus an optimized background (OB) regimen (3,6,8).Different factors have been found to be associated with the virological and immunological responses: a lower viral load (VL) at the baseline, the use of enfuvirtide (T20) as a part of the OB regimen, the presence of two or more active drugs in the OB regimen (OB score [OBS], Ն2) (3,6,8), and the baseline numbers of specific TPV-associated resistance mu...

Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure

“…Genotypic inhibitory quotients (GIQ) were calculated for each PI by dividing the C trough by the number of specific DRM detected in the GRT1 [13,14] and classified as therapeutic/subtherapeutic on the basis of GIQ efficacy thresholds extrapolated from the literature (C0.220 lg/ml/ mutation for atazanavir; C1.800 lg/ml/mutation for darunavir; C0.300 lg/ml/mutation for fosamprenavir; C1.000 lg/ml/mutation for lopinavir; C0.040 lg/ml/ mutation for saquinavir; C14.501 lg/ml/mutation for tipranavir) [15][16][17][18][19][20].…”

Role of tipranavir in treatment of patients with multidrug-resistant HIV

“…The genotypic sensitivity score, sometimes referred to as an optimized background score considers the number of drugs in the optimized background regimen which have been shown to be active through genotypic testing 65–67. For adult patients with a genotypic sensitivity score of ≥2, 64.2% achieved a virologic response, compared with a 20% virologic response rate for those with a score <2 66. This trend was not observed in pediatric patients, possibly due to the small number of patients enrolled, and very few having a genotypic sensitivity score of ≥2 67.…”

“…When correlating gIQ, tipranavir trough, tipranavir mutation score, use of enfuvirtide, and genotypic sensitivity score with virologic response in adult patients using logistic regression, gIQ was found to be the most significant predictor of virologic response ( P = 0.03) 63. At 48 weeks, a significantly greater reduction in viral load was observed in adult patients who had a gIQ > 14,500 ng/mL/mutation (83.3% versus 38.4%) 66. At 48 weeks, pediatric patients with a gIQ above the first quartile (0.56–7.19) were more likely to achieve a viral load of <400 copies/mL (8% versus 52–68%) 67.…”

“… 65 – 67 For adult patients with a genotypic sensitivity score of ≥2, 64.2% achieved a virologic response, compared with a 20% virologic response rate for those with a score <2. 66 This trend was not observed in pediatric patients, possibly due to the small number of patients enrolled, and very few having a genotypic sensitivity score of ≥2. 67 An inhibitory quotient is calculated by dividing the tipranavir trough by the tipranavir IC 50 .…”

“…The genotypic inhibitory quotient (gIQ) is calculated by dividing the tipranavir serum trough concentration by the number of tipranavir resistance conferring mutations genotyped from the patient’s HIV strain 62,63,66,67,70. The measure of gIQ had the highest correlation with virologic success in both children and adults.…”