Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomes
Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 μg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results: Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p = 0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p = 0.013], 0.27 vs. 0.11 day-1 [p = 0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p = 0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p = 0.114). Genotype 1 had a significantly lower δ compared to genotype 3 (median 0.14 vs. 0.23 day-1 [p = 0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC50) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p = 0.034]). Conclusions: Both the HCV-infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.
|Keywords||Hepatitis C virus, Human immunodeficiency virus infection, Mathematical modeling, Viral kinetics, adult, area under the curve, article, cell loss, clinical article, controlled study, drug absorption, drug blood level, drug efficacy, drug elimination, drug withdrawal, female, genotype, hepatitis C, human, male, mixed infection, nonhuman, peginterferon alpha2a, priority journal, prognosis, ribavirin, steady state, treatment duration, treatment outcome, treatment response, validation process, virus RNA|
|Persistent URL||dx.doi.org/10.1016/j.jhep.2010.03.019, hdl.handle.net/1765/21168|
Dahari, H., Affonso De Araujo, E.S., Haagmans, B.L., Layden, T.J., Cotler, S.J., Barone, A.A., & Neumann, A.U.. (2010). Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomes. Journal of Hepatology, 53(3), 460–467. doi:10.1016/j.jhep.2010.03.019