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• W2316652275 abstract "Twice-daily indinavir/ritonavir regimens of 400/400 mg and 800/100 mg are usually effective in diminishing the viral load but are poorly tolerated by HIV-1-infected patients [1,2]. The efficacy and safety of the combination of low-dose indinavir/ritonavir (400/100 mg twice a day) with two nucleoside reverse transcriptase inhibitors (NRTI) have also been reported [3]. These two drugs are extensively biotransformed by hepatic pathways, and their respective pharmacokinetic profiles are affected by liver disease. We have analysed this combination in patients co-infected with HIV and either hepatitis B virus (HBV; HBs antigen-positive) or hepatitis C virus (HCV; HCV RNA-positive) in the GENOPHAR Study. The objective of the GENOPHAR Study was to evaluate, in the context of expert committee advice, the benefit of therapeutic drug monitoring in association with genotypic resistance testing to optimize treatment in multi-experienced patients failing antiretroviral therapy [4]. A total of 134 patients have been enrolled in the study, including 24 patients who were co-infected with HIV-1 and either HBV (n = 10) or HCV (n = 14). In five patients with HCV, one with HBV, and 16 without chronic hepatitis (control group), treatment with a low-dose indinavir/ritonavir (400/100 mg twice a day) combination plus two NRTI was selected upon the results of the resistance genotyping test, treatment history and drug tolerance. For all patients, a month after starting the new regimen, the plasma HIV-1-RNA level was measured and indinavir minimal plasma concentrations (Cmin) were performed using a specific and validated high performance liquid chromatographic assay (limit of quantification of 5 ng/ml) [5]. Steady-state indinavir Cmin were interpreted according to the algorithm previously described [6]. We considered plasma concentrations as adequate if values of indinavir Cmin determined 12 h after the last intake were in the therapeutic range of 150–675 ng/ml [7]. The lower limit of this therapeutic range was defined according to the probability of plasma HIV-1-RNA levels reaching an undetectable level, and the upper limit was defined according to the probability of the smallest possible incidence of adverse effects [7,8]. In the six patients with chronic hepatitis, indinavir plasma concentrations were very high and all Cmin but one (values non-corrected for the delay between dosing and sampling) were above 675 ng/ml (median value 1440 ng/ml; range 650–2310). None of the patients had been on a concomitant medication known to affect indinavir exposure significantly (i.e. either enzymatic inducers or inhibitors except ritonavir). In all patients, a viral load below 200 copies/ml was achieved. Despite high indinavir Cmin in the patients who had biological renal parameters within normal values, no severe side-effects, such as symptomatic nephrolithiasis were noted. After a therapeutic adjustment within a month (indinavir/ritonavir 200/100 mg twice a day), adequate indinavir Cmin were obtained and remained stable in five patients until the end of the study (at week 24: median value 277 ng/ml; range 150–320). The patient with HCV, who had an adequate Cmin, was lost to follow-up. Plasma HIV-1-RNA levels remained undetectable until the end of the study. In the control group without chronic hepatitis (n = 16), all but three patients had indinavir Cmin within adequate values (median value 422 ng/ml; range 150–2512). After treatment adjustment (indinavir/ritonavir 200/100 mg twice a day) adequate plasma concentrations were also obtained in the remaining three patients. The results of this study suggest that the low-dose indinavir/ritonavir (200/100 mg twice a day) combination plus two NRTI appears to be effective and safe in patients co-infected with HIV and HCV or HBV. Non-boosted indinavir had an unfavourable pharmacokinetic profile, with a short half-life and high maximal plasma concentrations that create a risk of adverse effects. On the other hand the low Cmin may induce viral resistance if it remains near or below the in-vitro 95% inhibitory concentration for HIV-1 (100 ng/ml) [9]. Ritonavir, the most potent inhibitor of cytochrome P450 3A4, improves the pharmacokinetic exposure of most associated protease inhibitors, including indinavir, allowing their daily dose to be reduced while at the same time improving their antiviral efficacy [10–13]. Previous reports have suggested that the incidence of indinavir-associated nephrolithiasis is increased in HBV/HCV-infected patients [14]. Renal, cutaneous, gastrointestinal and metabolic side-effects that usually occur during indinavir treatment are associated with elevated indinavir plasma concentrations [6,15]. We did not observe any side-effects in our patients with high indinavir plasma concentrations, which may have been due to the swiftness of the therapeutic intervention to decrease the indinavir dosage based on the high indinavir Cmin determined within one month of starting the regimen. In this study, the optimal doses of the indinavir/ritonavir combination were 200/100 mg twice a day in HIV-positive patients co-infected with HCV or HBV, respectively. The benefit of therapeutic drug monitoring in association with genotypic resistance testing and expert advice to optimize subsequent therapy in HCV or HBV co-infected patients receiving the indinavir/ritonavir combination appeared to be crucial in this GENOPHAR substudy." @default.
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• W2316652275 title "High indinavir plasma concentrations in HIV-positive patients co-infected with hepatitis B or C virus treated with low doses of indinavir and ritonavir (400/100 mg twice a day) plus two nucleoside reverse transcriptase inhibitors" @default.
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