Pharmacodynamics of PEG-IFN-α-2a and HCV Response as a Function of IL28B Polymorphism in HIV/HCV-Coinfected Patients

Abstract

We examined the association between IL28B single-nucleotide-polymorphism rs12979860, hepatitis C virus (HCV) kinetic and pegylated-interferon-alpha-2a pharmacodynamic parameters in HIV/HCV-co-infected patients from South America. Twenty-six subjects received PEG-IFN-alpha-2a+ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12-weeks of therapy and analyzed using mathematical models. African Americans and Whites had a similar distribution of IL28B genotypes (p=0.5). The CC genotype was overrepresented (p=0.015) in patients infected with HCV genotype-3 compared to genotype-1. In both genotype-1 and genotype-3, the first-phase-viral decline and the average PEG-IFN-alpha-2a effectiveness during the first week of therapy were larger (trend P≤0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second-slower phase of viral decline (days 2–29) and infected-cells-loss rate, δ, were larger (p=0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

“…13,27,29,33 Finally, we found no significant influence of donor/recipient IL28B rs12979860 allele combinations, although the small number of patients analysed may preclude confirming the significant associations found in other studies. 40,41 The fact that treatment efficacies during the first few days of treatment were significantly lower (0-26%) than those reported in immunocompetent patients is consistent with previous observations on other monoinfected 30,37 and, especially, on HIV-coinfected individuals. 33,34,42,43 The low efficacy found in our 3 immunocompetent controls (20-22%) may also indicate a role for drug levels and pharmacokinetics.…”

“…However, studies on HCV dynamics typically include a small number of patients. 11,21,27,30,33,34,37,[39][40][41][42][52][53][54][55][56][57][58] Despite this limitation, we identified a delayed early HCV kinetics pattern in LT patients that should be further investigated in larger studies before drawing any definitive conclusion.…”

Association between IL28B polymorphisms and first-phase viral load decrease in chronic hepatitis C virus-infected patients treated with peginterferon alfa-2b/ribavirin

“…A similar observation has been recently reported in HIV/HCV co-infected patients [13] and in HCV monoinfected patients with a first phase defined as the first 4 days after the start of therapy [9]. Although the function of the different IL28B SNPs still needs to be clarified, they have been associated with upregulation of interferon-stimulating genes (ISGs) [14].…”

Pegylated Interferon Fractal Pharmacokinetics: Individualized Dosing for Hepatitis C Virus Infection

“…There are several limitations to our study. Previous attempts to determine the role of drug concentrations for interferon-based compounds in the treatment of HCV have generally met with limited success (28)(29)(30). Reasons for previous lack of predictive insights from others' data might be due to limited precision of pharmacokinetic parameter estimates, use of a single-time-point drug concentration, the type of viral kinetic measurements utilized, or the statistical methods to determine the relationship (26,27).…”