As acute hepatitis C virus (HCV) infection is clinically inapparent in most cases, the immunologic correlates of recovery are not well defined. The cellular immune response is thought to contribute to the elimination of HCV-infected cells and a strong HCV-specific T-helper-cell (Th) response is associated with recovery from acute hepatitis C (ref. 2). However, diagnosis of resolved hepatitis C is based at present on the detection of HCV-specific antibodies and the absence of detectable HCV RNA, and detailed comparison of the humoral and cellular immune response has been hampered by the fact that patient cohorts as well as HCV strains are usually heterogeneous and that clinical data from acute-phase and long-term follow-up after infection generally are not available. We studied a cohort of women accidentally exposed to the same HCV strain of known sequence and found that circulating HCV-specific antibodies were undetectable in many patients 18-20 years after recovery, whereas HCV-specific helper and cytotoxic T-cell responses with an interferon (IFN)-gamma-producing (Tc1) phenotype persisted. The data indicate these HCV-specific CD4 + and CD8+ T cells are biomarkers for a prior HCV exposure and recovery. Because of undetectable antibodies against HCV, the incidence of self-limited HCV infections and recovery may be underestimated in the general population.

batches of anti-D immune globulin contaminated with hepatitis C virus (HCV) genotype 1b (20,000-480,000 copies/dose) from a single erythrocyte donor had been administered for prophylaxis of rhesus isoimmunization throughout East Germany. All 2,867 women involved had been recalled after January 12, 1979 for repeated screening of alanine transaminase (ALT). They were prospectively followed in regional centers. We have reexamined a cohort of 1,018 women (median age 24, range 16-38 years at infection) on follow-up for 20 years in 9 representative centers. Within 6 months after anti-D administration, 10% of these women had no evidence of disease and 90% had acute hepatitis C (n ‫؍‬ 917) including 49% with symptomatic and 22% with icteric course. After 20 years, 85% of the 917 affected women still tested positive for HCV antibodies (among them 3% responded to interferon treatment) and 55% were positive for HCV RNA (among them 7% were nonresponders to interferon and 3% were apparent HCV carriers). Only 4 (0.4%) had overt cirrhosis. Two (0.2%) died of superinfected fulminant hepatitis B or alcoholism and cirrhosis, respectively. Histology obtained in 44% of the viremic women showed hepatitis of minimal to moderate grade in 96%, portal fibrosis in 47%, and septal fibrosis in 3% of the cases.

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Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

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The high incidence of hepatitis C virus (HCV) persistence raises the question of how HCV interferes with host immune responses. Studying a single-source HCV outbreak, we identified an HCV mutation that impaired correct carboxyterminal cleavage of an immunodominant HLA-A2-restricted CD8 cell epitope that is frequently recognized by recovered patients. The mutation, a conservative HCV nonstructural protein 3 (NS3) tyrosine to phenylalanine substitution, was absent in 54 clones of the infectious source, but present in 15/21 (71%) HLA-A2-positive and in 11/24 (46%) HLA-A2-negative patients with chronic hepatitis C. In order to analyze whether the mutation affected the processing of the HLA-A2-restricted CD8 cell epitope, mutant and wild-type NS3 polypeptides were digested in vitro with 20S constitutive proteasomes and with immunoproteasomes. The presence of the mutation resulted in impaired carboxyterminal cleavage of the epitope. In order to analyze whether impaired epitope processing affected T cell priming in vivo, HLA-A2-transgenic mice were infected with vaccinia viruses encoding either wild-type or mutant HCV NS3. The mutant induced fewer epitope-specific, IFN-γ-producing and fewer tetramer + cells than the wild type. These data demonstrate how a conservative mutation in the flanking region of an HCV epitope impairs the induction of epitope-specific CD8 + T cells and reveal a mechanism that may contribute to viral sequence evolution in infected patients. IntroductionHepatitis C virus (HCV) is a 9.6 kb positive-stranded RNA virus of the flavivirus family and the leading cause of chronic hepatitis worldwide. Whereas recovery from acute HCV infection has been associated with multispecific T cell responses that protect upon reexposure to the virus (1, 2), these responses are either not induced or not maintained in the large number of patients who develop chronic infection (3-5).We have therefore asked whether HCV interferes with the induction of antigen-specific T cells. Induction of CD8 + T cells depends on the generation of MHC class I ligands by the proteasome, the major cytosolic proteinase. The proteasome cleaves short peptides from longer polypeptide precursors that are then translocated into the endoplasmic reticulum and bind to newly synthesized MHC class I molecules (6). 26S proteasomes contain a 20S catalytic core, arranged as 2 heptameric outer rings with 7 α-subunits each and 2 heptameric inner rings with 7 β-subunits each. Proteasome activity is closely regulated by cytokines that are produced in viral infections (7-12). In response to IFN-γ, for example, the constitutive catalytic subunits β1, β2, and β5 are replaced by low molecular weight protein 2 (LMP2) (iβ1), LMP7 (iβ5), and multicatalytic endopeptidase complex-like-1 (MECL-1) (iβ2) to form immunoproteasomes with altered cleavage properties (13).HCV circulates in an abundant number of quasispecies because of its high replication rate (14) and its lack of polymerase proof-

IntroductionNon-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a head-to-head comparison between both methods.MethodsFifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34–66%, S3 ≥67%.ResultsSteatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiver-operating characteristics curves were 0.93 vs. 0.88 for steatosis ≥S1 and 0.94 vs. 0.88 for ≥S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2–4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa.ConclusionOur data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.

The immunogenicity of hepatitis B vaccine is unknown for patients with chronic hepatitis C, although hepatitis B vaccination is highly recommended in these patients. We therefore studied in a prospective open trial of 59 patients with chronic hepatitis C (mean age 42 years, hepatitis C for G10 years, Child-Pugh score I5) and 58 healthy hospital staff persons the rate of nonresponse (anti-HBs F10 mIU/mL at 9 months) to recombinant hepatitis B vaccine (Gen H-B-Vax R ,10g intradeltoidal at month 0, 1, and 6). Nonresponse was observed in 18/59 (31%) patients with chronic hepatitis C and 5/58 (9%) healthy staff persons (P F .005) (vs. 7% in historical controls; P F .005), low response (anti-HBs 10-99 mIU/mL) in 19% of patients with chronic hepatitis C and 17% of staff persons. High-dose booster vaccination led to seroconversion in 12/15 (80%) of primary nonresponders. Primary nonresponse to HB vaccine was related neither to presence of early-stage liver cirrhosis nor magnitude of serum hepatitis C virus (HCV) RNA concentration, nor explained by the presence of human leukocyte antigen (HLA) types (B8 DR3, B44, DR7, DQ2) predisposing to low antibody response to hepatitis B surface antigen. The rate of primary nonresponse to the standard regimen of recombinant hepatitis B vaccine is surprisingly high in patients with longstanding chronic hepatitis C. Therefore, the antibody to HBV surface antigen (anti-HBs) titer response should be determined in these patients. Depending on the response titer, higher booster doses may be required to achieve and maintain seroprotection in these patients. (HEPATOLOGY 2000;31:230-234.)