Natural History Of Hepatitis Research Articles

Unified semicompeting risks analysis of hepatitis natural history through mediation modeling.

Natural history of hepatitis B or C is comprised of multiple milestones such as liver cirrhosis and liver cancer. To fully characterize its natural course, semicompeting risks represent a common problem where liver cirrhosis and liver cancer are both of interest, but only the former may be censored by the latter. Copula, frailty and multistate models serve as well-established analytics for semicompeting risks. Here, we cast the semicompeting risks in a mediation framework, with liver cirrhosis as a mediator and liver cancer as an outcome. We define the indirect and direct effects as the effects of an exposure on the liver cancer incidence mediated and not mediated through liver cirrhosis, respectively. With the estimands derived as conditional probabilities, we derive respective expressions under the copula, frailty, and multistate models. Next, we propose estimators based on nonparametric maximum likelihood or U-statistics and establish their asymptotic results. Numerical studies demonstrate that the efficiency of copula models leads to potential bias due to model misspecification. Moreover, the robustness of frailty models is accompanied by a loss in efficiency, and multistate models balance the efficiency and robustness. We demonstrate the utility of the proposed methods by a hepatitis study, showing that hepatitis B and C lead to a higher incidence of liver cancer by increasing liver cirrhosis incidence. Thus, mediation modeling provides a unified framework that accommodates various semicompeting risks models.

Hepatocellular Carcinoma Incidence Threshold for Surveillance in Virologically Cured Hepatitis C Individuals

Guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in hepatitis C individuals with cirrhosis if the HCC incidence rate is above 1.5 per 100 person-years (PY). However, the incidence threshold for surveillance in individuals who achieve a virologic cure is unknown. We estimated the HCC incidence rate above which routine HCC surveillance is cost-effective in this growing population of virologically cured hepatitis C individuals with cirrhosis or advanced fibrosis. We developed a Markov-based microsimulation model of the natural history of HCC in individuals with hepatitis C who achieved virologic cure with oral direct-acting antivirals. We used published data on the natural history of hepatitis C, competing risk post virologic cure, HCC tumor progression, real-world HCC surveillance adherence, contemporary HCC treatment options and associated costs, and utilities of different health states. We estimated the HCC incidence above which biannual HCC surveillance using ultrasound and alpha-fetoprotein would be cost-effective. In virologically cured hepatitis C individuals with cirrhosis or advanced fibrosis, HCC surveillance is cost-effective if HCC incidence exceeds 0.7 per 100 PY using $100,000 per quality-adjusted life year willingness-to-pay. At this HCC incidence, routine HCC surveillance would result in 2650 and 5700 additional life years per 100,000 cirrhosis and advanced fibrosis persons, respectively, compared with no surveillance. At $150,000 willingness-to-pay, surveillance is cost-effective if HCC incidence exceeds 0.4 per 100 PY. Sensitivity analysis showed that the threshold mostly remained below 1.5 per 100 PY. The contemporary HCC incidence threshold is much lower than the previous 1.5% incidence value used to guide HCC surveillance decisions. Updating clinical guidelines could improve the early diagnosis of HCC.

Differential Expression of the Host Lipid Regulators ANGPTL-3 and ANGPTL-4 in HCV Infection and Treatment.

Host lipid metabolism reprogramming is essential for hepatitis C virus (HCV) infection and progression to severe liver disease. Direct-acting antivirals (DAAs) achieve a sustained virological response (SVR) in most patients, but virus eradication does not always protect against hepatocellular carcinoma (HCC). Angiopoietin-like protein-3 (ANGPTL-3) and angiopoietin-like protein-4 (ANGPTL-4) regulate the clearance of plasma lipids by inhibiting cellular lipase activity and possess emerging roles in tumourigenesis. We used ELISA and RT-qPCR to investigate ANGPTL-3 and ANGPTL-4 expression in HCV patients with characterised fibrosis throughout the natural history of hepatitis C and in long-term HCV infection in vitro, before and after DAA treatment. ANGPTL-3 was decreased in patients with advanced fibrosis compared to other disease stages, while ANGPTL-4 was progressively increased from acute infection to cirrhosis and HCC, peaking at the advanced fibrosis stage. Only ANGPTL-3 mRNA was down-regulated during early infection in vitro, although both ANGPTLs were increased later. DAA treatment did not alter ANGPTL-3 levels in advanced fibrosis/cirrhosis and in HCV infection in vitro, in contrast to ANGPTL-4. The association between ANGPTLs and fibrosis in HCV infection was underlined by an inverse correlation between the levels of ANGPTLs and serum transforming growth factor- β (TGF-β). Collectively, we demonstrate the pivotal role of advanced fibrosis in defining the expression fate of ANGPTLs in HCV infection and after treatment and propose a role for ANGPTL-3 as a contributor to post-treatment deregulation of lipid metabolism that could predispose certain individuals to HCC development.

Viral hepatitis in haemophilia: historical perspective and current management.

The introduction of clotting factor concentrates has substantially improved the lives of people with clotting factor deficiencies. Unfortunately, the transmission of blood-borne viral infections through these plasma-derived products led to a huge epidemic of human immunodeficiency virus and viral hepatitis in people with haemophilia (PWH). In a significant proportion of PWH exposed to these viruses, the ensuing decades-long chronic infection resulted in excess morbidity and mortality. Fortunately, developments in the safety of blood products, as well as vaccination and highly effective antiviral treatments have improved the prospects of PWH. The present article reviews the background of the viral hepatitis epidemic in PWH, the natural history of hepatitis B and C infections and their long-term management.

Natural history of hepatitis C virus infection in a large national seroconversion cohort in the direct-acting antiviral agent era: Results from ERCHIVES.

Hepatitis C virus (HCV) natural history studies are limited by not knowing the time of infection, small numbers and non-representative populations. No studies are available from the direct-acting antiviral agents (DAA) era. We created the largest known cohort of persons with HCV with a known window of seroconversion in the DAA era. We compared the annual cumulative incident events and incidence rate/1000 person-years of follow-up for liver cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC) and mortality from the time of seroconversion among untreated and those treated and attaining a sustained virologic response (SVR). Among 12,881 persons in the final analyses, 10,417 had never been treated for HCV, 2464 (23.6%) were treated with a DAA regimen and 1836 (74.5%) attained SVR. After 9years of follow-up, cirrhosis was diagnosed in 17.4% of untreated and 13.6% of the SVR group. Overall, 29.5% in the untreated versus 3.5% in the SVR group died. Incidence rates/1000 person-years of follow-up (95% CI) for untreated versus SVR group were 22.7 (21.6, 23.9) versus 19.5 (17.0, 21.9) for cirrhosis (p=0.03), 0.1 (0.03, 0.2) versus 0.07 (-0.07, 0.2) for HCC (p=0.74) and 35.4 (34.0, 36.8) versus 4.53 (3.4, 5.7) for mortality (p<0.0001). After excluding those with alcohol-related diagnoses at baseline, the difference in cirrhosis was not statistically significant. Cirrhosis and mortality occur early and steadily increase over the first decade after acquiring HCV infection, while HCC is rarely observed. Those treated with a DAA regimen have sharply lower cirrhosis and mortality rates, particularly among those without alcohol abuse or dependence.

Pregenomic HBV RNA and Hepatitis B Core-Related Antigen Predict Outcomes in Hepatitis B e Antigen-Negative Chronic Hepatitis B Patients Suppressed on Nucleos(T)ide Analogue Therapy.

A dichotomous separation of hepatitis B viral DNA and hepatitis B surface antigen (HBsAg) concentrations occurs during the natural history and treatment of chronic hepatitis B. We have evaluated the ability of hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) as surrogates of silencing of covalently closed circular DNA (cccDNA), to characterize this dissociation, and virological outcomes. Three cohorts of hepatitis B e antigen (HBeAg)-negative patients were studied: cohort A: 66 HBeAg-negative patients on long-term nucleos(t)ide analogue (NA) therapy; cohort B: 23 antibodies against hepatitis B e antigen (anti-HBe)-positive patients who stopped treatment; and Cohort C: 19 anti-HBe-positive patients on long-term NA treatment who achieved HBsAg loss and in whom treatment was withdrawn. Concentrations of HBV serological/virological biomarkers (HBV DNA, HBsAg, HBcrAg, and HBV RNA) were measured in sequential samples at different time points on/off therapy. Cohort A: After 3years of antiviral therapy, 33% and 30% had detectable HBcrAg and HBV RNA, respectively, despite all being HBV-DNA negative. After 5years' therapy with NA, 27% and 14% had detectable HBcrAg and HBV RNA. Detectable HBcrAg and HBV RNA at the time of treatment withdrawal was only observed in those patients who developed a severe aminotransferase flare. Only those patients with HBV reactivation in cohort C had detectable HBV RNA at treatment withdrawal, but HBcrAg and HBV DNA were not detected. HBcrAg and HBV RNA are sensitive biomarkers of continued transcription of cccDNA in HBeAg-negative patients despite marked HBV-DNA suppression by NA. These markers were predictors of severe alanine transaminase flares, after treatment withdrawal, and HBV-DNA reactivation. Their measurement during the natural history of hepatitis B, and on treatment with current and new agents, could characterize residual HBV-RNA transcription from cccDNA and assist drug development and disease management.

Association of NTCP polymorphisms with clinical outcome of hepatitis B infection in Thai individuals

BackgroundSingle nucleotide polymorphisms (SNPs) in the sodium taurocholate co-transporting polypeptide (NTCP) have been showed to be associated with natural history of hepatitis B virus (HBV) infection. However, it is unclear whether the SNPs are related to the clinical outcome of HBV infection in Thai individuals.MethodsThe rs2296651 and rs4646287 polymorphisms of NTCP were determined by allelic discrimination using commercial TaqMan probes in blood samples of 1021 Thai individuals. These subjects included 610 patients with chronic HBV infection [CHB, 305 with hepatocellular carcinoma (HCC) and 305 without HCC], 206 subjects with spontaneous HBV clearance and 205 healthy controls who were age and gender-matched.ResultsThe frequencies of rs2296651 A minor allele in the CHB group, the HBV clearance group and healthy controls were 7.8, 7.3 and 13.9%, respectively. For rs4646287, the frequencies of T minor allele of the corresponding groups were 10.4, 8.0 and 9.5%, respectively. Compared with healthy controls, the frequencies of rs2296651 GA + AA genotypes were significantly lower in the CHB group (P < 0.001) and in the HBV clearance group (P = 0.001). There was no difference in their distribution between the HBV clearance and CHB groups. Among the CHB group, the distribution of GA + AA genotypes in patients with HCC were significantly lower than in patients without HCC (P = 0.014). The frequencies of HBeAg positivity in patients harboring GG and GA + AA genotypes were 39.8 and 23.5%, respectively (P = 0.004). Among patients with HCC, the mean HBV DNA of the corresponding genotypes were 4.9 ± 1.3 vs. 2.7 ± 1.0 log10 IU/mL, respectively (P < 0.001). There was no difference in genotype and allele frequencies of rs4646287 polymorphism among all studied groups.ConclusionsOur results showed that rs2296651 polymorphism was associated with a decreased risk of susceptibility to HBV infection and the development of HCC. These data suggest that the NTCP polymorphism might have an influence on natural history of HBV infection in Thai individuals.This abstract was partly presented at the American Association for the Study of Liver Diseases (AASLD) Meeting 2018, November 9–13, 2018, in San Francisco, CA, USA and was published in Hepatology 2018; 68:1237A-1238A.

Epidemiology and natural history of hepatitis C virus infection among children and young people

Chronic hepatitis C virus (HCV) infection is a global health burden. Although HCV infection rarely contributes to morbidity during childhood, most HCV-infected children develop chronic HCV with a lifetime risk of liver disease. Little is known about the development of long-term liver disease and the effect of treatment in patients infected with HCV in childhood. This study was a retrospective review of patients infected with HCV in childhood enrolled in HCV Research UK. A total of 1,049 patients were identified and included. The main routes of infection were intravenous drug use (53%), blood product exposure (24%) and perinatal infection (11%). Liver disease developed in 32% of patients, a median of 33 years after infection, irrespective of the mode of infection. Therefore, patients with perinatal exposure developed cirrhosis at an earlier age than the rest of the risk groups. The incidence of hepatocellular carcinoma (HCC) was 5%, liver transplant 4% and death occurred in 3%. Overall, 663 patients were treated (55% with interferon/pegylated interferon and 40% with direct-acting antivirals). Sustained virological response (SVR) was achieved in 406 (75%). There was a higher mortality rate among patients without SVR vs. those with SVR (5% vs. 1%, p = 0.003). Treatment was more effective in patients without cirrhosis and disease progression was less frequent (13%) than in patients with cirrhosis at the time of therapy (28%) p < 0.001. Patients with cirrhosis were more likely to develop HCC, require liver transplantation, or die. HCV infection in young people causes significant liver disease, which can now be prevented with antiviral therapy. Early treatment, especially before development of cirrhosis is essential. Detection of HCV should be aimed at relevant risk groups and antiviral therapy should be made available in childhood to prevent long-term liver disease and spread of HCV. Chronic hepatitis C virus (HCV) infection is a global health problem, which can now be treated with potent direct-acting antiviral drugs. This study demonstrates that HCV infection in childhood causes serious liver disease in 32% of patients, a median of 33 years after infection, irrespective of age, mode and route of infection. Disease outcomes were better in patients treated before the development of advanced liver disease. Antiviral therapy should be made available in childhood to prevent long-term liver disease and the spread of HCV.

Clinical manifestations of hepatitis a virus infection in Kyrgyzstan children

Background: Acute hepatitis is one of the more common causes of hepatitis A virus (HAV). Humans appear to be the only reservoir for this virus. Clinical manifestations, and natural history of hepatitis A virus. The relative frequency of hepatitis A virus in Western country.Objectives: Hepatitis A infection developing countries where sanitation is still a public health issue. In Kyrgyzstan, there is no epidemiological data on children for this infection.Materials &amp; Methods: A community based cross sectional study was carried in occurs around the southern city of Osh (Osh region) state in Kyrgyzstan in one of the smaller country central Asia. Total 260 children aged 1-18 years. Blood samples were analysed for anti-HAV total antibody (IgM and IgG) using a ELISA.Results: One hundred and forty four subjects tested positive for anti-HAV total antibody giving a prevalence rate of 55.4%. The median age for those positive was 9 years and for those without evidence of HAV infection was 4 years. 65 (45.1%) males and 79 (54.9) females were positive. The study population was mainly of the low social class with 94.1%.Conclusion: In the study population was HAV infection. Educational campaign is imperative and vaccine provision is advocated to further curb the spread of this infection.KYAMC Journal Vol. 9, No.-2, July 2018, Page 73-75

Pharmacogenetics and the treatment of HIV-/HCV-coinfected patients.

This review will summarize the role of pharmacogenetics in the natural history of hepatitis C, particularly in patients with HIV/HCV and will take the perspective of pharmacogenetics and its influence on the response to antiviral therapy and the susceptibility to develop adverse effects. This review will also devote a section to host genetics in other clinical situations, such as disease progression and acute HCV infection, which may determine whether treatment of HIV-/HCV-coinfected patients is implemented or deferred.

HBeAg positive chronic HBV with persistent normal ALT: Not treat now

Chronic hepatitis B virus infection is a major cause of cirrhosis and hepatocellular carcinomaworldwide. Antiviral treatment can safely and effectively suppress viral replication and reduce riskof disease progression but need long term therapy. However, understanding the natural history ofhepatitis B virus infection is important when deciding whether to treat or not to treat the patients.On the basis of virus-host interaction, the natural course of HBV infection can be divided into four phases.The elevation of alanine aminotransferase (ALT) level is an important indicator of immune-mediatedinflammation to eliminate HBV infected hepatocyte. The individual patients with normal ALTare assume to be the immune tolerance phase and low risk to disease progression.&#x0D; &#x0D; Figure 1 ระยะของการติดเชื้อไวรัสตับอักเสบบีชนิดเรื้อรัง&#x0D; &#x0D; &#x0D; Keywords: chronic hepatitis B, HBV, ALT

Economic evaluation of a population strategy for the treatment of chronic hepatitis C with direct-acting antivirals.

The high initial cost of antivirals against hepatitis C prompted development of the "Strategic Plan for Tackling Chronic Hepatitis C in the Spanish National Health System". The objective of this study was the economic evaluation of the first two years of its application in Navarre, Spain. The change in the natural history of hepatitis C produced by the sustained virological response (SVR) was compared to an alternative without treatment and modeled with patient-level data. By means of a discrete events simulation model, the cost-effectiveness and the budget impact analysis of the treatment program were measured from the perspective of the Navarre Health Service. Of 656 patients treated, 98% had SVR. The average cost of the treatments was 18,743 euros per patient. The incremental cost-effectiveness ratio (ICER) with discount was 5,346 euros per quality-adjusted life years, which became more efficient as the stage of fibrosis increased until it reached levels of dominance in stage 4 fibrosis. The associated costs for chronic liver disease decreased as the benefit of the treatment was expressed. The implementation of the Strategic Plan is cost-effective, with an ICER well below the threshold, since the cost of treatment is largely compensated by savings in long-term health expenditure. The budgetary impact foresees a net saving from the third year on. The two key parameters were the decrease in the price of the treatment and the SVR in nearly 100% of the patients.

Language support for linguistic minority chronic hepatitis B/C patients: an exploratory study of availability and clinicians\u2019 perceptions of language barriers in six European countries

BackgroundLanguage support for linguistic minorities can improve patient safety, clinical outcomes and the quality of health care. Most chronic hepatitis B/C infections in Europe are detected among people born in endemic countries mostly in Africa, Asia and Central/Eastern Europe, groups that may experience language barriers when accessing health care services in their host countries. We investigated availability of interpreters and translated materials for linguistic minority hepatitis B/C patients. We also investigated clinicians’ agreement that language barriers are explanations of three scenarios: the low screening uptake of hepatitis B/C screening, the lack of screening in primary care, and why cases do not reach specialist care.MethodsAn online survey was developed, translated and sent to experts in five health care services involved in screening or treating viral hepatitis in six European countries: Germany, Hungary, Italy, the Netherlands, Spain and the United Kingdom (UK). The five areas of health care were: general practice/family medicine, antenatal care, health care for asylum seekers, sexual health and specialist secondary care. We measured availability using a three-point ordinal scale (‘very common’, ‘variable or not routine’ and ‘rarely or never’). We measured agreement using a five-point Likert scale.ResultsWe received 238 responses (23% response rate, N = 1026) from representatives in each health care field in each country. Interpreters are common in the UK, the Netherlands and Spain but variable or rare in Germany, Hungary and Italy. Translated materials are rarely/never available in Hungary, Italy and Spain but commonly or variably available in the Netherlands, Germany and the UK. Differing levels of agreement that language barriers explain the three scenarios are seen across the countries. Professionals in countries with most infrequent availability (Hungary and Italy) disagree strongest that language barriers are explanations.ConclusionsOur findings show pronounced differences between countries in availability of interpreters, differences that mirror socio-cultural value systems of ‘difference-sensitive’ and ‘difference-blindness’. Improved language support is needed given the complex natural history of hepatitis B/C, the recognised barriers to screening and care, and the large undiagnosed burden among (potentially) linguistic minority migrant groups.

Predictive Value of Hepatitis B Core-Related Antigen (HBcrAg) During the Natural History of Hepatitis B Virus Infection.

The natural history of HBV infection includes immune tolerance (IT), immune clearance (IC), HBeAg-negative inactive/quiescent carrier (ENQ), and HBeAg-negative hepatitis (ENH) phases. As the current biomarkers for discriminating the four phases still have some weaknesses, additional serological indicators are needed. Hepatitis B core-related antigen (HBcrAg) encoded with the precore/core gene contains denatured HBeAg, HBV core antigen (HBcAg), and a 22-KDa precore protein (p22cr) and has been demonstrated to have a close association with the natural history of hepatitis B infection. However, no specific cutoff values and diagnostic parameters have been identified to evaluate the diagnostic efficacy. This study aimed to clarify the distribution of HBcrAg levels and evaluate the diagnostic performance during the natural history of HBV infection in a Western Chinese population. In this study, 294 samples were collected from treatment-naive HBV infection patients in different phases (IT = 64; IC = 72; ENQ = 100, and ENH = 58). We detected the HBcrAg values and analyzed the relationship between HBcrAg and HBV DNA. HBsAg and other clinical parameters were quantitatively detected. The HBcrAg levels of IT, IC, ENQ, and ENH were 9.30 log U/mL, 8.80 log U/mL, 3.00 log U/mL, and 5.10 log U/mL, respectively (p < 0.0001). Receiver operating characteristic curve analysis demonstrated that the areas under the curves (AUCs) for HBcrAg and quantitative HBsAg at cutoff values of 9.25 log U/mL and 4.355 log IU/mL for distinguishing the IT phase from the IC phase were 0.704 and 0.694, with a sensitivity of 53.13% and 79.69% and specificity of 76.39% and 59.72%, respectively. AUCs of HBcrAg and quantitative HBsAg at cutoff values of 4.15 log U/mL and 2.395 log IU/mL for discriminating between the ENQ and ENH phases were 0.931 and 0.653, with a sensitivity of 87.93% and 91.38% and specificity of 84.00% and 39.00%, respectively. HBcrAg levels varied significantly among the four natural phases of HBV infection and had higher predictive performance than quantitative HBsAg for distinguishing between ENQ-patients and ENH-patients and a similar performance as HBsAg for the discrimination between IT and IC phases, which indicated that HBcrAg could be a potential serological marker for HBV infection.

Clinical Significance of Quantitative HBsAg Titres and its Correlation With HBV DNA Levels in the Natural History of Hepatitis B Virus Infection

Quantification of serum hepatitis B antigen (HBsAg) is an important test that marks active infection with hepatitis B and helps in the prediction of the clinical outcome and management of hepatitis B virus (HBV) infection. Correlation with HBV DNA quantitative levels may help in developing strategies for antiviral treatment. This study is aimed to evaluate HBsAg titres in various phase of HBV infection in HBsAg positive patients, and its correlation with HBV DNA viral load levels. 976 HBV related patients were analysed in this retrospective cross-sectional study. Patients were categorised on the basis of the phase of HBV infection: immune tolerant phase (IT, n=123), immune clearance phase (IC, n=192), low-replicative phase (LR, n=476), and HBeAg-negative hepatitis (ENH, n=185). HBsAg titres were quantified and correlated with HBV-DNA levels and clinical parameters. Median HBsAg titres were different between each phases of HBV infection (P<0.001): (4.62log10IU/ml), IC (3.88log10IU/ml), LR (2.76log10IU/ml) and ENH (2.94log10IU/ml). HBsAg and HBV DNA levels showed significant correlation in the whole group (r=0.694, P<0.001), and this was also observed in different phases of HBV infection. Strong correlation in IT phase (r=0.603, P<0.001) and IC phase (r=0.523, P<0.001), moderate in LR phase (r=0.362, P<0.001) and weak in ENH (r=0.110, P=0.04). No correlation was observed between serum HBsAg levels and biochemical parameters. The study demonstrated significant difference in the median baseline values of serum HBsAg titres in different phases of HBV infection and provides additional information in understanding the natural history of HBV-infection.

Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis.

In the natural history of hepatitis B virus (HBV) chronic infection, the hepatocellular carcinoma (HCC) risk is unclear. We assessed incidence and predictors of HCC by a systematic review and meta-analysis. We included longitudinal studies and randomized controlled trials assessing HCC incidence in untreated patients with HBV chronic infection. Incidence rates and their 95% confidence intervals were extracted by each study and pooled together in random effects models. Sixty-six studies were included with a total of 347859 patients. According to liver disease status, the summary incidence rates were in Europe, North America and East Asia, respectively: (a) asymptomatic carriers: 0.07 (95% confidence interval: 0.05-0.09), 0.19 (0.07-0.31) and 0.42 (0.21-0.63) per 100 person-years, respectively; (b) inactive carriers: 0.03 (0.0-0.10), 0.17 (0.02-0.62) and 0.06 (0.02-0.10), respectively; (c) chronic hepatitis: 0.12 (0.0-0.27), 0.48 (0.22-0.91) and 0.49 (0.32-0.66), respectively; (d) compensated cirrhosis (Child-Pugh A): 2.03 (1.30-2.77), 2.89 (1.23-4.55) and 3.37 (2.48-4.26) respectively. Multivariate meta-regression showed a significant increase in incidence rates for age, and for status of a symptomatic carrier, chronic hepatitis and compensated cirrhosis compared to inactive carrier, but not for geographical area after adjusting for age. An increase in the incidence rates was also observed for alcohol intake ≥60g/dl, HBV genotype C with respect to B and HBV-DNA serum levels >2000IU/ml, in Asian studies. Hepatocellular carcinoma risk in untreated subjects with HBV chronic infection is strongly related with age and liver disease status.

New insights into the natural history of hepatitis E virus infection through a longitudinal study of multitransfused immunocompetent patients in France.

Little is known about the natural history of Hepatitis E virus (HEV) infection in immunocompetent individuals. The prevalence, the course of infection and the occurrence of transmission by transfusion were investigated in multitransfused immunocompetent patients/blood donor pairs included in a longitudinal sample repository collection and followed up between 1988 and 2010. Ninety-eight subjects aged 6-89 years and suffering from acquired haemoglobinopathies were tested for HEV markers (IgM, IgG and RNA) in serial samples collected every 2 or 3 years. Eighteen patients (18.4%) were positive for HEV-IgG at baseline with a prevalence increasing from 12.5% below 26 years to 32% above 56 years. Nine patients remained IgG positive along the study and nine lost their antibodies after a mean follow-up of 7.4 years (1-22 years). One seropositive patient showed an increase of IgG level and RNA-HEV reappearance 1 year after inclusion, suggesting a reinfection and one seroconversion, probably acquired through blood transfusion was observed. This first longitudinal study including immunocompetent individuals confirms that HEV infection is common in Western Europe and that transfusion transmission occurs probably less frequently than expected. In addition, seroreversion and reinfection seem to be common. This suggests that the anti-HEV may not persist overtime naturally. However, repeat exposure to the virus related to the high prevalence of HEV infection may result in a sustainable specific IgG response.

Chronic Inactive Hepatitis B Virus: More Benign Than We Think!

Introduction: Hepatitis B virus (HBV) is one of the most common viral infections worldwide, the natural history of which does not always progress in a linear fashion. We aimed to identify the natural history of chronic inactive hepatitis B virus over the course of 15 years, and to describe the changes in the liver condition using AST platelet ratio index (APRI) score as a measure of liver fibrosis. Methods: This is a prospective cohort study following 69 patients aged 30-60 years who have had inactive hepatits B virus for 15 years. APRI score was calculated at the time of diagnosis and 15 years later. Inactive hepatitis B virus was identified as PCR < 2000 with normal liver enzymes and no clinical symptoms regardless of their HBe Ag status. APRI score was used as a non-invasive measure of liver fibrosis. Results: Of the 69 patients, 37 were females (54%), and 32 were males (46%). Upon diagnosis, 87% percent of patients were Hepatitis e Ag negative, while only 13% were positive. At the end of the 15 year follow-up, 93% of patients were Hepatitis e Ag negative. At the time of diagnosis, the mean APRI score was 0.33 ± 0.17 suggestive of minimal fibrosis and the mean bilirubin was 9.6 ± 6.8 μmol/L. However, 15 years later, the mean APRI score remained 0.33 ± 0.36. (P=.12) while the mean bilirubin decreased to 8.5 ± 4.5 μmol/L (P= < .001). Conclusion: The natural history of hepatitis B is variable and multifactorial; the main component is the activity level of the virus. There is limited data on the natural history of inactive hepatitis B virus, and our study is one of the few long-term prospective studies to be done on this category of hepatitis B patients. Based on these results, we believe that inactive hepatitis B virus is more benign than what is commonly thought, with minimal risk of liver damage, even long term. Additional large scale prospective studies are needed to validate these results and to improve our overall understanding of the nature of the inactive form of this virus.Figure 1

Natural History of Hepatitis B Virus: Initial Analysis of 1,200 Patients From the SOLID Registry

Introduction: There are currently 400 million people worldwide who are infected with Hepatitis B Virus (HBV), imposing a substantial economic burden on healthcare systems. The Systematic Observatory Liver-Diseases Registries (SOLID) is a multi-national, multi-center, observational, open-label group of medical registries designed to electronically collect data, manage, monitor, and report different liver diseases. We aim to describe the clinical characteristics and natural history of Hepatitis B virus, and to show the benefit of using the SOLID registries in describing and investigating major liver diseases, including HBV. Methods: We performed a retrospective analysis of patients with HBV using the SOLID registry, and included 1198 patients from multiple medical centers who were diagnosed with HBV in the last 10 years. We analyzed the clinical characteristics of HBV in terms of viral activity, liver condition, and fibrosis assessment. Results: The overall duration of the disease since the initial diagnosis was 35.5 ± 23.1 months. Inactive virus was detected in 848 (70.8%) patients, and active virus in 270 (22.5%) patients. Cirrhosis was found in 80 (6.7%) patients in which 27 (33.8%) had decompensated cirrhosis. Of the 13 (1.1%) patients who developed hepatocellular carcinoma over the course of the disease, 12 (92.3%) of them had cirrhosis and 1 (7.7%) patient was an inactive virus carrier. Liver fibrosis stage was determined through biopsy in 151 (12.6%) patients, the remaining 1047 (87.4%) patients were assessed using Transient Elastography (Fibroscan) or APRI score. Multivariate analysis of patients with cirrhosis compared to active disease patients alkaline phosphatase showed an OR of 1.016 (95% CI, 1.007-1.024; P < .001) and platelet count showed an OR of 0.982 (95% CI, 0.974-0.990; P< .001). Multivariate analysis of patients with cirrhosis compared to inactive disease patients alkaline phosphatase showed OR of 1.011 (95% CI, 1.006-1.015; P < .001) and a platelet count showed an OR of 0.980 (95% CI, 0.975-0.985; P < .001). Conclusion: Based on this initial analysis, high alkaline phosphatase and low platelets are significant predictors of cirrhosis development in patient with active or inactive HBV. SOLID registries are very efficient in facilitating research by providing sufficient data that will help estimating the precise burden of major liver diseases such as HBV.

Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence

Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.