Uwe Naumann

Randomized, double‐blind, placebo‐controlled trial of interferon Alfa2a with and without amantadine as initial treatment for chronic hepatitis C

Although the antiviral effects of amantadine sulphate (1‐aminoadamantan sulphate) have not been characterized for the hepatitis C virus (HCV), previous pilot studies have suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the efficacy, safety, and health‐related quality of life (HRQOL) of interferon alfa (IFN‐α) alone or in combination with oral amantadine for treatment of chronic hepatitis C. One hundred nineteen previously untreated patients with chronic hepatitis C were randomly allocated to treatment with IFN‐α2a at a dose of 6 megaunits 3 times a week subcutaneously for 24 weeks, followed by 3 megaunits thrice weekly for an additional 24 weeks plus amantadine sulphate administered orally 100 mg twice a day for 48 weeks or the same IFN regimen plus a matched placebo. The primary endpoint was undectable serum HCV RNA (<1,000 copies/mL) at week 24 after treatment. At the end of treatment and the 24‐week follow‐up period serum HCV RNA was undetectable in 20 (34%) and 6 (10%) of the 59 patients treated with the combination IFN‐α plus amantadine and in 20 (33%) and 13 (22%) of the 60 patients treated with IFN‐α alone, respectively (P = n.s.). Discontinuation of therapy for adverse events was similar in both treatment groups. Although treatment with IFN‐α worsened HRQOL, combination with amantadine showed a substantial trend to improve fatigue and vigor. In conclusion, combination therapy IFN‐α plus amantadine is as effective as IFN‐α monotherapy in previously untreated patients with chronic hepatitis C.

Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C.

Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatitis C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C.

The cytotoxic lymphocyte antigen 4 polymorphisms affect response to hepatitis C virus-specific therapy in HIV(+) patients with acute and chronic hepatitis C virus co-infection.

Objective:Cytotoxic lymphocyte antigen 4 (CTLA4), a co-receptor expressed on T lymphocytes, is involved in the regulation of T-cell functions. Here, we analyzed the potential impact of the CTLA4 polymorphisms on response to hepatitis C virus (HCV)-specific treatment in HIV(+) patients co-infected with HCV. Patients and methods:A total of 184 HIV/HCV co-infected Caucasian patients were enrolled into this study, including 109 patients with chronic and 75 patients with acute hepatitis C. CTLA4 genotypes were determined by LightCycler PCR. Results:We found the CTLA4 −318 C/C genotype to be associated with sustained virological response in HCV/HIV co-infection (P = 0.035). Moreover, response rates were significantly higher in patients with a +49G/G genotype [23/29 (79.3%)] than in carriers of other +49 genotypes [59/155 (38.1%); OR 6.2; P = 0.00005]. Of note, the CTLA4 +49G/G genotype was confirmed as an independent predictor for treatment response in both patients with acute and chronic hepatitis C. Conclusion:CTLA4 polymorphisms are associated with treatment-induced resolution of HCV infection in HIV co-infected patients. These findings underline the impact of genetic host factors for successful treatment.

Treatment of naive patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10–20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.

Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting.

Background SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. Methods We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). Results Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). Conclusion IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.

Su1072 Treatment of Chronic Hepatitis C Genotype 1 (G1) Infection With Boceprevir (Victrelis®) in German Real-Life: Impact of Hemoglobin Decline on Virologic Response

Treatment of Chronic Hepatitis C Genotype 1 (G1) Infection With Boceprevir (Victrelis®) in German Real-Life: Impact of Hemoglobin Decline on Virologic Response Gerlinde Teuber, Peter Buggisch, Hanns Lohr, Hermann Steffens, Michael Kraus, Christine John, Peter Geyer, Bernd Weber, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl, Uwe Naumann, Tarek Dahhan, Dagmar Hartmann, Bernd Dreher, Manfred Bilzer