U. Mihm

Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function

Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral efficacy and a high genetic barrier to viral resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited. Here, we report on 16 patients with liver cirrhosis and chronic hepatitis B who were treated with entecavir. Five of these patients developed lactic acidosis during entecavir treatment. All patients who developed lactic acidosis had highly impaired liver function (Model for End‐Stage Liver Disease [MELD] score ≥ 20). Lactic acidosis (lactate 26‐200 mg/dL, pH 7.02‐7.40, base excess −5 mmol/L to −18 mmol/L) occurred between 4 and 240 days after treatment initiation with entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18. The MELD score correlated with the development of lactic acidosis (P < 0.005) as well as its single parameters bilirubin, international normalized ratio, and creatinine. In contrast, Child‐Pugh Score did not correlate with the development of lactic acidosis. Our data indicate that entecavir should be applied cautiously in patients with impaired liver function. (HEPATOLOGY 2009;50:2001–2006.)

Comparison of conventional PCR with real-time PCR and branched DNA-based assays for hepatitis C virus RNA quantification and clinical significance for genotypes 1 to 5

ABSTRACT The key parameter for diagnosis and management of hepatitis C virus (HCV) infection is HCV RNA. Standardization of HCV RNA assays to IU is mainly based on genotype 1 panels. Little is known about the variability of commercially available HCV RNA assays for quantification of different genotypes. Two real-time reverse transcription (RT)-PCR assays (COBAS TaqMan HCV Test for use with the High-Pure System [HPS/CTM] and COBAS Ampliprep/COBAS TaqMan HCV Test [CAP/CTM]), one standard RT-PCR assay (COBAS Amplicor HCV Monitor 2.0 [CAM]), and one signal amplification assay (Versant Quantitative 3.0 [branched DNA {bDNA}]) were compared for quantification of genotypes 1 to 5 (n = 108). Using CAM as a reference assay for genotype 1-infected patients, the mean interassay differences compared with CAP/CTM, HPS/CTM, and bDNA were 0.16, −0.13, and −0.48 log10 IU/ml HCV RNA, respectively. Comparison of CAM with CAP/CTM, HPS/CTM, and bDNA for the remaining genotypes showed the following results, respectively: 2a/c, −0.24, −0.78, and −0.49; 2b, −0.21, −0.18, and −0.64; 3a, 0.13, −1.04, and −0.55; 4, −0.52, −1.51, and −0.05; and 5, −0.28, −1.00, and −0.24 log IU/ml HCV RNA. A correct decision for treatment discontinuation in genotype 1 patients at week 12 was possible only when the same assay was used at baseline and week 12. Comparison of CAM with the CAP/CTM assay showed equal quantifications of genotype 1, 2, 3, and 5 samples, while genotype 4 samples were slightly underestimated. For the HPS/CTM assay, a significant underestimation of the HCV RNA concentrations of genotypes 2a/c, 3, 4, and 5 was observed. For the bDNA assay, a constant lower quantification of genotypes 1 to 3 was detected.

Deep Sequencing Reveals Mutagenic Effects of Ribavirin during Monotherapy of Hepatitis C Virus Genotype 1-Infected Patients

ABSTRACT The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy (n = 6) in comparison to placebo (n = 6). Baseline HCV RNA levels maximally declined on average by −0.8 or −0.1 log10 IU/ml in ribavirin- versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.

Review article: predicting response in hepatitis C virus therapy

The introduction of combination therapy with ribavirin and of pegylated interferons has improved treatment results in patients with chronic hepatitis C. However, overall rates of sustained virologic response following antiviral therapy of chronic hepatitis C still do not exceed 54–63%. Because of several virus‐ and patient‐related factors, treatment is even less successful in some patient subpopulations.

Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C

Summary.  In patients with chronic hepatitis C, alanine aminotransferase (ALT) levels do not accurately reflect the extent of liver inflammation. The discrepancy between ALT level and liver damage could be related to the mode of cell death. In the present study, we quantified serum levels of apoptotic cytokeratin 18 (CK‐18) neoepitopes that are generated by activated caspases during apoptosis. Apoptotic CK‐18 neoepitopes were quantified by enzyme linked immunosorbent assay in sera from patients with chronic hepatitis C and elevated ALT levels (n = 72), patients with chronic hepatitis C and persistently normal ALT levels (n = 27) and healthy controls (n = 19). Serum CK‐18 neoepitope levels were strongly correlated with ALT (r = 0.659, P < 0.0001) and the histology activity index (r = 0.374, P < 0.001). Patients with chronic hepatitis C and persistently normal ALT levels had higher apoptotic CK‐18 neoepitope levels than healthy controls (P = 0.03) but lower levels than patients with chronic hepatitis C and elevated ALT levels (P < 0.001). Highest serum CK‐18 neoepitope levels were observed in patients with cirrhosis (P = 0.002). Hence apoptotic CK‐18 neoepitopes in serum of patients with chronic hepatitis C are associated with ALT level and histological liver damage. Serum apoptotic CK‐18 neoepitope levels are elevated both in patients with chronic hepatitis C and elevated ALT levels as well as in patients with normal ALT levels indicating that also patients with chronic hepatitis C and normal ALT have an increased hepatocyte loss by apoptosis.

Cost-effectiveness analysis of roadmap models in chronic hepatitis B using tenofovir as the rescue therapy

BACKGROUND The roadmap approach is recommended to guide chronic hepatitis B treatment. We evaluated the cost-effectiveness of various treatment strategies in the global market. METHODS Lamivudine and telbivudine were tested in roadmap models with switch-to tenofovir if HBV was detectable at week 24 or add-on tenofovir if resistance developed at year 1. Tenofovir and entecavir were tested as continuous monotherapy. In the reference arm, lamivudine was used with add-on tenofovir if resistance developed at year 1. The primary measure of effectiveness was undetectable HBV DNA at year 2. Cost-effectiveness was measured by incremental cost-effectiveness ratio (ICER) in US dollars against the reference arm. RESULTS In the US and Germany, costs of the reference arms were US

Prospective study of bone mineral density and metabolism in patients with chronic hepatitis C during pegylated interferon α and ribavirin therapy

14,486 and US

Portal vein thrombosis as complication of romiplostim treatment in a cirrhotic patient with hepatitis C-associated immune thrombocytopenic purpura

9,998 for hepatitis B e antigen (HBeAg)-positive and US

Optimal therapy in genotype 1 patients.

11,398 and US

Clinical Significance of In Vitro Replication–Enhancing Mutations of the Hepatitis C Virus (HCV) Replicon in Patients with Chronic HCV Infection

7,531 for HBeAg-negative patients, respectively. In HBeAg-positive patients, the lamivudine roadmap was most cost-effective (ICER US