H Wedemeyer

The German Hep-Net acute hepatitis C cohort: impact of viral and host factors on the initial presentation of acute hepatitis C virus infection.

INTRODUCTION The impacts of viral load, genotype, age, sex and BMI on the clinical course of acute hepatitis C are poorly defined. Here we studied 259 patients with acute HCV infection recruited in the German Hep-Net data base between 1998 and 2008. Antiviral treatment with interferon alpha was initiated in 171 patients (66 %) within 4 months after the diagnosis of acute hepatitis C. RESULTS In this cohort (i) the mode of infection was associated with age as iv-drug users were significantly younger than non-iv-drug users while the proportion of patients who acquired HCV by medical procedures increased with age; (ii) patients younger than 30 years were more often infected with genotype 3 (26 % versus 8 % for patients older than 50 years; p = 0.03); (iii) 51 % of patients were icteric and 28 % presented with a 30-fold elevation of liver enzymes, however, no fulminant hepatic failure occurred; (iv) HCV genotype was not associated with disease severity and time to onset of symptoms; (v) low HCV viremia was associated with lower serum AST levels and a longer time from exposure to onset of symptoms; (vi) disease severity was independent from the mode of infection, age, sex and body mass index (BMI). CONCLUSIONS In this large cohort of patients admitted for antiviral therapy, acute hepatitis C took a rather mild course of disease in the majority of patients. Disease severity was not associated with HCV genotype, viral load, age, sex and BMI.

Pneumococcal Meningitis during Antiviral Treatment with Interferon and Ribavirin in a Splenectomized Patient with Chronic Hepatitis C – Do Not Miss Vaccination before Starting Therapy

We report on a 35-year-old man who developed pneumococcal meningitis while receiving antiviral therapy with interferon (consensus interferon, CIFN) and ribavirin for chronic hepatitis C. Antibiotic therapy was started four days after the onset of symptoms. Unfortunately, the patient developed a persisting right-sided cochlear hearing impairment. Antiviral therapy led to sustained viral response of hepatitis C. At the age of 14 years he had experienced a hemorrhagic shock after a traffic accident, received multiple blood transfusions and undergone a splenectomy. He had not received vaccination against Streptococcus pneumoniae. This case report reminds us that splenectomized patients without previous pneumococcal vaccination should receive such vaccination before immunomodulatory treatment.

Irreversible impact of chronic hepatitis C virus infection on human natural killer cell diversity

Diversity is crucial for the immune system to efficiently combat infections. Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to the control of viral infections. NK cells were for long thought to be a homogeneous population of cells. However, recent work has instead revealed NK cells to represent a highly diverse population of immune cells where a vast number of subpopulations with distinct characteristics exist across tissues. However, the degree to which a chronic viral infection affects NK cell diversity remains elusive. Hepatitis C virus (HCV) is effective in establishing chronic infection in humans. During the last years, new direct-acting antiviral drugs (DAA) have revolutionized treatment of chronic hepatitis C, enabling rapid cure in the majority of patients. This allows us to study the influence of a chronic viral infection and its subsequent elimination on the NK cell compartment with a focus on NK cell diversity. In our recent study (Nat Commun, 9:2275), we show that chronic HCV infection irreversibly impacts human NK cell repertoire diversity.

Early on treatment detection of nucelos(t)ide analogue resistant minor variants of Hepatitis B virus (HBV) with ultra deep-pyrosequencing (UDPS) in chronic hepatitis B(CHB) patients

Introduction: UDPS allows the detection of minor viral variants during the natural course and antiviral treatment in HBV-infected patients. It could be shown that double infections with two HBV genotypes and minor strains carrying resistance mutations not detected by clonal sequencing could be analyzed. Here we tested a method for analyzing multiple HBV genotypes in a single sample as well as its potential to identify resistance mutations in patients months before viral breakthrough. Patients and methods: A custom HBV sample was constructed by equimolar pooling of PCR amplicons derived from viral nucleic acid extracts from the serum of three different CHB patients. They had been identified as HBV genotypes B and D. Two samples were described as genotype D (one as wild-type, one as carrier of the resistance mutation rtM204V), and one sample as genotype B (wild-type). The genotype D wild-type developed lamivudine (LMV) and adefovir (ADV) resistance later on treatment. UDPS was performed on a GS Flx 454 sequencer (Roche). Sequencing data was analyzed using GenomiX Workbench (CLC Bio). Results: Sequence analysis showed 37,07% of reads mapping to HBV genotype B (subtype adw), 61.99% to genotype D (subtypes w3 and ayw3) while the remaining 0,96% where scattered among other genotypes. Single nucleotide polymorphism (SNP) analysis of the sequences mapped to distinct genotypes clearly discriminated between wild-type and mutated HBV strains. For one patient, previously described as infected with wild-type HBV genotype D, a minor variant (coverage 35, frequency 100%) in the viral quasi species showed mutations at position rtM204 and rtI233, mediating viral resistance to LMV and ADV. Follow-up of this patient revealed a viral breakthrough with a major species resistant to LMV and ADV (rtM204V, rtI233V) 14 months later. Conclusions: UDPS is a feasible method for the identification of HBV viral sequences including genotype and resistance mutations. The detection of minor variants carrying resistance-bearing mutations more than a year prior to viral breakthrough could constitute a new tool for individualizing antiviral treatment, especially with low genetic barrier nucleos(t)ide analogues. Whether the occurrence of minor quasi-species with resistance mutations could also be reflected by serological parameters like serum HBsAg is currently investigated.