Virushepatitis [Viral hepatitis].

Viral hepatitis is associated with significant morbidity and mortality worldwide. Hepatitis A and E viruses are enterally transmitted and lead to usually self-limited acute hepatitis. Hepatitis B, C and D viruses are transmitted by parenteral routes and can lead to chronic hepatitis with progression to liver cirrhosis and hepatocellular carcinoma. Here, we briefly review current understanding and new developments in the virology and epidemiology, diagnosis, natural history, therapy and prevention of viral hepatitis.

Three cases of neonatal herpes simplex virus infection presenting as fulminant hepatitis.

We report three cases of neonatal herpes simplex virus (HSV) infection presenting as fulminant hepatitis. None of the patients had clear risk factors for HSV infection and they all died. Antiviral treatment for HSV is currently available but must be administered early in the course of the disease before irreversible liver tissue damage is present. Since the diagnosis may be difficult to establish, we wish to draw the attention of clinicians to the presentation of neonatal HSV infection and suggest that in such cases viral cultures, including culture of liver tissue, should be obtained early and antiviral treatment administered while awaiting the culture results.

Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma.

OBJECTIVE: To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with hepatitis C and B viruses. DESIGN: A case-control study nested in the Swiss HIV Cohort Study. METHODS: Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrollment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression. RESULTS: All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count [Odds ratio (OR) per 100 cells/mul decrease = 1.33, 95% confidence interval (CI) 1.06-1.68] and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01-2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18-1.91). CONCLUSION: Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.

MHC-genotype of progeny influenced by parental infection.

In a previous series of in vitro fertilization experiments with mice we found non-random combination of major histocompatibility complex (MHC) haplotypes in the very early embryos. Our results suggested that two selection mechanisms were operating: (i) the eggs selected specific sperm; and (ii) the second meiotic division in the eggs was influenced by the type of sperm that entered the egg. Furthermore, the proportion of MHC-heterozygous embryos varied over time, suggesting that non-random fertilization was dependent on an external factor that changed over time. As a higher frequency of heterozygous individuals correlated with an uncontrolled epidemic by MHV (mouse hepatitis virus), we suggested that MHV-infection might have influenced the outcome of fertilization. Here, we present an experiment that tests this hypothesis. We infected randomly chosen mice with MHV and sham-infected control mice five days before pairing. We recovered the two-cell embryos from the oviduct, cultured them until the blastocyst stage, and determined the genotype of each resulting blastocyst by polymerase chain reaction. We found the pattern that we expected from our previous experiments: virus-infected mice produced more MHC-heterozygous embryos than sham-infected ones. This suggests that parents are able to promote specific combinations of MHC-haplotypes during fertilization according to the presence or absence of a viral infection.

Interleukin-28B polymorphisms, IP-10, viral load and age predict the outcome of therapy in genotype 1 hepatitis C virus under real-life conditions

Background and Aims: IL28B polymorphisms, interferon (IFN)-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score have been reported to predict rapid (RVR) and sustained (SVR) virological response in chronic hepatitis C (CHC), but it is not known whether these factors represent independent, clinically useful predictors. The aim of the study was to assess factors (including IL28B polymorphisms, IP-10 levels and HOMA-IR score) independently predicting response to therapy in CHC under real life conditions.Methods: Multivariate analysis of factors predicting RVR and SVR in 280 consecutive, treatment-naive CHC patients treated with pegylated IFN alpha and ribavirin in a prospective multicenter study.Results: Independent predictors of RVR were HCV RNA < 400,000 IU/ml (OR11.37; 95% CI 3.03-42.6), rs12980275 AA (vs. AG/GG) (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR = 0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age < 40 yrs (OR = 4.79; 1.50-15.34) and HCV RNA < 400,000 IU/ml (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR = 6.26; 1.98-19.74) and age < 40 yrs (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (32 of 33, 97%; OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99; p=0.009) or 3 patients (OR 7.8, 1.43-42.67; p=0.01).Conclusions: In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pretreatment prediction of SVR. HOMA-IR score is not associated with viral response.

Is carbohydrate-deficient transferrin a specific marker for alcohol abuse? A study in patients with chronic viral hepatitis.

Carbohydrate-deficient transferrin, a transferrin isoform, is hailed as a new marker of chronic alcohol abuse, but its specificity is, however, not unequivocally accepted. The aim of the present study was therefore to determine carbohydrate-deficient transferrin levels in patients with chronic hepatitis B and C with or without documented chronic alcohol intake. Carbohydrate-deficient transferrin was measured using a double-antibody radioimmunoassay (CDTect, Pharmacia) in serum samples from 66 patients (45 males and 21 females; mean age: 39 years) with chronic viral hepatitis B (n = 20) or C (n = 46). Diagnosis of the underlying liver disease was established by liver biopsy. Carbohydrate-deficient transferrin levels were raised in 15 patients [23%; hepatitis B (n = 2) and hepatitis C (n = 13)]. In patients with chronic hepatitis B, the carbohydrate-deficient transferrin level was raised in two abstainers. In the 46 patients with chronic hepatitis C, 10 (22%) patients with an alcohol consumption of < 60 g/day for the men and 30 g/day for the women had raised carbohydrate-deficient transferrin levels. The overall specificity of carbohydrate-deficient transferrin for chronic alcohol abuse was thus 78%, suggesting an association between elevated carbohydrate-deficient transferrin levels and the presence of chronic viral hepatitis. Carbohydrate-deficient transferrin levels were not correlated with the histological grading or staging of chronic hepatitis B and C, or with biological markers of hepatic synthesis and cellular damage. Thus, an increased carbohydrate-deficient transferrin level may occur in patients with chronic viral hepatitis in the absence of chronic alcohol abuse. This fact should be kept in mind by physicians when using this marker to detect alcohol abuse.

IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C.

Aliment Pharmacol Ther 2011; 33: 1162-1172 SUMMARY: Background  Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue. Aim  To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC). Methods  Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study. Results  Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03-42.6), rs12980275 AA (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR = 0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age <40 years (OR = 4.79; 1.50-15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR = 6.26; 1.98-19.74) and age <40 years (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99) or genotype 3 patients (OR 7.8, 1.43-42.67). Conclusions  In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.

Hepatitis B and C virus coinfection: a novel model system reveals the absence of direct viral interference.

Coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) has been associated with severe liver disease and frequent progression to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests reciprocal replicative suppression of the two viruses, or viral interference. However, interactions between HBV and HCV have been difficult to study due to the lack of appropriate model systems. We have established a novel model system to investigate interactions between HBV and HCV. Stable Huh-7 cell lines inducibly replicating HBV were transfected with selectable HCV replicons or infected with cell culture-derived HCV. In this system, both viruses were found to replicate in the same cell without overt interference. Specific inhibition of one virus did not affect the replication and gene expression of the other. Furthermore, cells harboring replicating HBV could be infected with cell culture-derived HCV, arguing against superinfection exclusion. Finally, cells harboring replicating HBV supported efficient production of infectious HCV. Conclusion: HBV and HCV can replicate in the same cell without evidence for direct interference in vitro. Therefore, the viral interference observed in coinfected patients is probably due to indirect mechanisms mediated by innate and/or adaptive host immune responses. These findings provide new insights into the pathogenesis of HBV-HCV coinfection and may contribute to its clinical management in the future.

Bridging basic science and clinical research - The EASL Monothematic Conference on Translational Research in Viral Hepatitis.

The EASL Monothematic Conference on Translational Research in Viral Hepatitis brought together a group of leading scientists and clinicians working on both, basic and clinical aspects of viral hepatitis, thereby building bridges from bench to bedside. This report recapitulates the presentations and discussions at the conference held in Lyon, France on November 29-30, 2013. In recent years, great advances have been made in the field of viral hepatitis, particularly in hepatitis C virus (HCV) infection. The identification of IL28B genetic polymorphisms as a major determinant for spontaneous and treatment-induced HCV clearance was a seminal discovery. Currently, hepatologists are at the doorstep of even greater advances, with the advent of a wealth of directly acting antivirals (DAAs) against HCV. Indeed, promising results have accumulated over the last months and few years, showing sustained virological response (SVR) rates of up to 100% with interferon-free DAA combination therapies. Thus, less than 25years after its identification, HCV infection may soon be curable in the vast majority of patients, highlighting the great success of HCV research over the last decades. However, viral hepatitis and its clinical complications such as liver cirrhosis and hepatocellular carcinoma (HCC) remain major global challenges. New therapeutic strategies to tackle hepatitis B virus (HBV) and hepatitis D virus (HDV) infection are needed, as current therapies have undeniable limitations. Nucleoside/nucleotide analogues (NUC) can efficiently control HBV replication and reduce or even reverse liver damage. However, these drugs have to be given for indefinite periods in most patients to maintain virological and biochemical responses. Although sustained responses off treatment can be achieved by treatment with (pegylated) interferon-α, only about 10-30% of patients effectively resolve chronic hepatitis B. It was the goal of this conference to review the progress made over the last years in chronic viral hepatitis research and to identify key questions that need to be addressed in order to close the gap between basic and clinical research and to develop novel preventive and treatment approaches for this most common cause of liver cirrhosis and HCC.

Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis.

BACKGROUND & AIMS: Steatosis is a prominent feature of hepatitis C, especially in patients infected with genotype 3. The analysis of genetic polymorphisms influencing steatosis in chronic hepatitis C has been limited by the studies' small sample size, and important single nucleotide polymorphisms (SNPs), such as those in the patatin-like phospholipase family 3 protein (PNPLA3), were never evaluated. METHODS: We analyzed the role of SNPs, from 19 systematically selected candidate genes, on steatosis in 626 Caucasian hepatitis C virus (HCV) infected patients. SNPs were extracted from a genome-wide association-generated dataset. Associations of alleles with the presence and/or different severity of steatosis were evaluated by univariate and multivariate logistic regression, accounting for all relevant covariates. RESULTS: The risk of steatosis was increased by carriage of I148M in PNPLA3, but only in patients with HCV genotypes non-3 (odds ratio [OR]=1.9, 95% confidence interval [CI]=1.6-2.3, p<0.001) and similar, albeit weaker associations were found for SNPs in peroxisome proliferator-activated receptor-γ (PPARG) and interleukin-28B (IL28B). Carriage of a SNP in the microsomal triglyceride transfer protein (MTTP) increased the risk of steatosis, but only in patients with HCV genotype 3 (rs1800803, OR=3.4, 95% CI=2.4-4.9, p=0.001). CONCLUSIONS: The rs738409 SNP in PNPLA3 is associated with an increased risk of steatosis in patients infected with HCV genotypes non-3. Host genes affect steatosis depending on the infecting HCV genotype, suggesting their interaction with viral factors.

Spontaneous viral clearance, viral load, and genotype distribution of hepatitis C virus (HCV) in HIV-infected patients with anti-HCV antibodies in Europe.

BACKGROUND: Variables influencing serum hepatitis C virus (HCV) RNA levels and genotype distribution in individuals with human immunodeficiency virus (HIV) infection are not well known, nor are factors determining spontaneous clearance after exposure to HCV in this population. METHODS: All HCV antibody (Ab)-positive patients with HIV infection in the EuroSIDA cohort who had stored samples were tested for serum HCV RNA, and HCV genotyping was done for subjects with viremia. Logistic regression was used to identify variables associated with spontaneous HCV clearance and HCV genotype 1. RESULTS: Of 1940 HCV Ab-positive patients, 1496 (77%) were serum HCV RNA positive. Injection drug users (IDUs) were less likely to have spontaneously cleared HCV than were homosexual men (20% vs. 39%; adjusted odds ratio [aOR], 0.36 [95% confidence interval {CI}, 0.24-0.53]), whereas patients positive for hepatitis B surface antigen (HBsAg) were more likely to have spontaneously cleared HCV than were those negative for HBsAg (43% vs. 21%; aOR, 2.91 [95% CI, 1.94-4.38]). Of patients with HCV viremia, 786 (53%) carried HCV genotype 1, and 53 (4%), 440 (29%), and 217 (15%) carried HCV genotype 2, 3, and 4, respectively. A greater HCV RNA level was associated with a greater chance of being infected with HCV genotype 1 (aOR, 1.60 per 1 log higher [95% CI, 1.36-1.88]). CONCLUSIONS: More than three-quarters of the HIV- and HCV Ab-positive patients in EuroSIDA showed active HCV replication. Viremia was more frequent in IDUs and, conversely, was less common in HBsAg-positive patients. Of the patients with HCV viremia analyzed, 53% were found to carry HCV genotype 1, and this genotype was associated with greater serum HCV RNA levels.