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Protease Inhibitors and Utility Of Inhibitory Quotients: high dose Kaletra may overcome PI resistance; Reyataz Expanded Access; Lipids & Kaletra Drug levels
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Written for NATAP by Ronald Reisler, MD, MPH, Institutes of Human Virology, University of Maryland Medical School
11th Annual Retrovirus Conference, Feb 8-11, 2004, San Francisco
Oral abstract 134 (Bertz et al) demonstrated that lopinavir Inhibitory Quotient (IQ) predicted virologic response in highly antiretroviral-experienced patients receiving high-dose Lopinavir/Ritonavir. Multiple PI- and NNRTI-experienced HIV+ patients (n = 33) were randomized to and received 1 of 2 twice daily high-dose LPV/r regimens with food: 667/167 mg (5 x 133/33 mg LPV/r caps, n = 19) or 400/300 mg (3 x 133/33 mg LPV/r caps + 2 x 100 mg ritonavir caps, n = 14). NRTI (2 to 3) were selected by the care provider. High dose Kaletra may overcome protease inhibitor and Kaletra resistance.
Pharmacokinetics findings of studying high dose Kaletra (lopinavir/ritonavir): A wide range of LPV phenotypic susceptibility was noted; the median fold IC50 was 4.1 (range 0.6 to 273). LPV Ctrough values were similar for both regimens, 60 to 70% higher compared with LPV/r 400/100 mg twice weekly. The median LPV inhibitory quotient was 27 (range 0.7 to 438). In correlation analyses, lower LPV fold IC50 (p <0.01), lower number of PI mutations (p £0.04), more active NRTI (p £0.04), and higher LPV inhibitory quotient (p =0.002) were associated with a better virologic response (TAD). In contrast, LPV PK parameters alone were not associated with virologic response (p_0.17). In a multiple regression analysis, higher LPV inhibitory quotient (p = 0.007) and more active NRTI (p = 0.04) were associated with improved virologic response. Similarly, a higher LPV inhibitory quotient (p = 0.026) and lower baseline HIV RNA (p = 0.027) were associated with a higher probability of achieving an HIV RNA <400 copies/mL in a multiple logistic regression analysis. A higher number of active NRTIs was marginally significantly associated (p = 0.052) with achieving an HIV RNA <400 copies/mL.
Conclusions: LPV inhibitory quotient is a significant predictor of antiviral response in multiple PI- and NNRTI-experienced patients. Higher doses of LPV/r may provide LPV concentrations sufficient to overcome certain degrees of reduced LPV phenotypic susceptibility, resulting in a significant treatment effect.
Genotypic Inhibitory Quotient, Lopinavir Blood Levels & Number of Resistance Mutations Predict Viral Response; Increases in Lipids & Drug Blood Levels
Gonzalez de Requena et al. report in abstract 610 on the predictive power of genotypic inhibitory quotient and LPV plasma levels in both efficacy and lipid elevations of LPV/r based salvage regimens at 48 weeks. The genotypic inhibitory quotient was calculated as LPV Ctrough/ number of protease mutations. They analysed 126 patients: virological response was observed in 85/126 (68%), 74/120 (62%), and 65/113 (58%) at 12, 24, and 48 weeks, respectively. At baseline, the median (IQR) number of resistance mutations was 4 (2 to 7); 48 weeks responders had 2 (2 to 5) vs. 7 (3 to 8) in non-responders (p = 0.02). The median (IQR) LPV Ctrough was 6.2 (2.2 to 8.7) _g/mL: 6.4 (4 to 9.2) in responders vs. 4.9 (0.36 to 7.3) in non-responders (p = 0.03). In the multivariate analysis, both LPV Ctrough >5 _g/mL and £6 resistance mutations were independent predictors of 48 weeks responders (p = 0.02; OR 6; 95%CI: 1.3 to 28.8; and p = 0.002; OR 21.5; 95%CI: 4,3 to 105, respectively). Logistic regression analysis showed that a genotypic inhibitory quotient >1.2 was a predictor of 48 weeks response (p = 0.0001; OR 13, 95%CI 3.4 to 48.7). genotypic inhibitory quotient was closely related to viral load drop at 48 weeks (r = -0.52; p <0.0001); CD4 count increased +114 cells/_L (p <0.0001). Patients with both higher LPV Ctrough and genotypic inhibitory quotient showed greater CD4 increases at 48 weeks (r = 0.23, p = 0.025; and r = 0.315, p = 0.019, respectively). In patients with neither diet nor lipid lowering drugs, triglyceride and cholesterol percentage of increase at 48 weeks was correlated with LPV and RTV plasma levels, respectively (r = 0.28, p = 0.04; and r = 0.314, p = 0.018).
Conclusions: Baseline HIV protease genotyping and LPV Ctrough independently predict response to LPV/r-based salvage therapy at 48 weeks. Nevertheless, genotypic inhibitory quotient offers the best predictor of virological response to Kaletra as well as a good estimator of viral load decrease. LPV Ctrough was also predictive of both CD4+ T-cell recovery and triglyceride elevations. In contrast, cholesterol elevations seem to be driven by RTV Ctrough instead of LPV Ctrough
Atazanavir Experience in Expanded Access Program in Madrid
Abstract 606 reported by Barrios et al. describes the use of Atazanavir in Madrid in the expanded access program there. Performance of ATV was examined in PI-experienced patients included in the expanded access program in Madrid. ATV plasma levels (C12h; estimated Cmin) were measured (HPLC-UV) at week 12. The genotypic inhibitory quotient was defined as C12h/number of protease resistance mutations.
Results: Data from 92 and 52 patients followed for 12 and 24 weeks, respectively, were analyzed: median age, 42 years; male, 68%; time on prior HAART, 72 months; in patients with baseline viral load >50 copies/mL (65%), the median plasma HIV-RNA was 3.9 log10; median CD4 count, 395 cells/_L; HCV co-infection, 45%; ATV was prescribed as rescue (45%), simplification (11%), or to ameliorate dyslipemia (24%) or other toxicities (16%); concomitant tenofovir (TDF), 78%; none received ritonavir boosting. At 24 weeks, virologic response (≥1 log drop in HIV-RNA or to <50 copies/mL) was recorded in 64% (OT-analysis) or 57% (ITT). In patients with baseline detectable viral load, median HIV-RNA drop was 0.7 log. Median CD4 gain was 38 cells/__L. Median ATV Cmin was 0.12 ug/mL (IQR, 0.05-0.22 ug/mL).
Immunologic and virologic responses did not correlate with ATV Cmin. Neither the efficacy of ATV nor Cmin significantly varied according to TDF use. The number of protease resistance mutations (IAS-USA list) tended to be associated with the VR: median of 5 protease resistance mutations in failing patients vs. 1 in responders (p = 0.07). In subjects with baseline viral load >50 copies/mL, a higher viral load drop was associated with a higher genotype inhibitory quotient (p = 0.02; _ -0.6; 95%CI -0.9, -0.2). At 24 weeks, only 4 patients (4%) discontinued treatment due to ATV-related toxicity (1 hyperbilirubinemia). Although bilirubin increased overall in up to 66% of subjects, grade 4 only developed in 10%. Increases in bilirubin at week 12 were associated with higher ATV plasma levels (p = 0.01; _ 0.4; 95%CI 0.3 to 1.1). No significant liver enzyme elevations were observed. There were no significant differences in bilirubin nor transaminases according to HCV status. Hypertriglyceridemia and hypercholesterolemia significantly decreased.
Conclusions: ATV-based regimens provide a significant virologic response in PI-experienced patients, particularly in subjects lacking protease resistance mutations. The genotype inhibitory quotient predicts accurately the virologic response to ATV. Hyperbilirubinemia is associated with ATV plasma levels.
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