Natural History Of Chronic Hepatitis Research Articles

Treatment of HBeAg‐positive chronic hepatitis B with nucleos(t)ide analogues

HBeAg seropositivity is a marker for active viral replication. In the natural history of chronic hepatitis B infection, HBeAg marks the first two of the four phases, namely the immune tolerant phase and the immune clearance phase, and is associated with highly replicative activity of the hepatitis B virus (HBV). Most HBV consensus reports and guidelines recommend antiviral therapy if the immune clearance phase is prolonged and if there is evidence of significant necroinflammation and fibrosis. Two main types of antiviral agents have been approved for treating patients in the immune clearance phase: interferon and nucleos(t)ide analogues (NUCs). The endpoints of therapy are viral suppression with HBeAg seroconversion, undetectable serum HBV DNA, normalization of serum alanine transaminase and improvement in the histological necroinflammatory and fibrosis scores. The ultimate goal of therapy is to obtain clinical benefit for the patient by reducing complications including hepatocellular carcinoma (HCC). The choice between interferon-based immune modulators or NUCs that target the HBV DNA polymerase must be carefully weighed on an individual basis. Therapy with NUCs is often preferred by doctors and patients because it is easy to administer, with predictable efficacy and minimal side-effects. In specific patient subgroups such as those with decompensated disease, poor predictors of response or lack of response to interferon-based therapy and/or significant comorbidities that cannot tolerate interferon-induced side effects, NUCs therapy is the obvious choice. Entecavir and tenofovir are the treatments of choice because their efficacy and safety profile are better than lamivudine, adefovir and telbivudine. More importantly, there is a minimal risk of drug resistance during long-term therapy with these agents.

Natural history of chronic HBV infection: special emphasis on the prognostic implications of the inactive carrier state versus chronic hepatitis

The evaluation of the natural history of chronic hepatitis B virus (HBV) infection requires the precise definition of the various clinical conditions that can be encountered (i.e. inactive carrier state or subject with liver disease activity). This can be achieved by repeat monitoring of ALT, serum HBV-DNA levels (over a period of at least 1 year, according to international guidelines) and/or evaluation of HBsAg titre. Liver biopsy may offer additional information although it is not mandatory. Overall, the natural history of the true inactive carrier is benign: reactivation of hepatitis, especially in Western countries, is rare and is usually due to co-factors (like alcohol or drugs); spontaneous HBsAg loss is frequent (around 1% per year) and HCC development rare. On the other hand, in patients with chronic hepatitis B or cirrhosis, the risk of reactivation, of HCC development and of liver-related mortality is much higher, especially in Eastern countries, and should therefore lead to antiviral therapy.

Hepatitis C virus‐induced oxidative stress and mitochondrial dysfunction: A focus on recent advances in proteomics

The natural history of chronic hepatitis C virus (HCV) infection presents two major aspects. On one side, the illness is by itself benign, whereas, on the other side, epidemiological evidence clearly identifies chronic HCV infection as the principal cause of cirrhosis, hepatocellular carcinoma, and extrahepatic diseases, such as autoimmune type II mixed cryoglobulinemia and some B cell non-Hodgkin's lymphomas. The mechanisms responsible for the progression of liver disease to severe liver injury are still poorly understood. Nonetheless, considerable biological data and studies from animal models suggest that oxidative stress contributes to steatohepatitis and that the increased generation of reactive oxygen and nitrogen species, together with the decreased antioxidant defense, promotes the development of hepatic and extrahepatic complications of HCV infection. The principal mechanisms causing oxidative stress in HCV-positive subjects have only been partially elucidated and have identified chronic inflammation, iron overload, ER stress, and a direct activity of HCV proteins in increasing mitochondrial ROS production, as key events. This review summarizes current knowledge regarding mechanisms of HCV-induced oxidative stress with its long-term effects in the context of HCV-related diseases, and includes a discussion of recent contributions from proteomics studies.

Do interleukin‐28B single nucleotide polymorphisms influence the natural history of chronic hepatitis B?

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Long-Term Effects of Antiviral Therapy in Patients with Chronic Hepatitis C

Chronic hepatitis C is a major cause of chronic liver disease globally, and the natural history of progression may lead to cirrhosis with liver failure, hepatocellular carcinoma, and premature liver-related death. Emerging data demonstrates that interferon-based therapy, particularly among those achieving a sustained virologic response (SVR), is associated with long-term persistence of SVR, improved fibrosis and inflammation scores, reduced incidence of hepatocellular carcinoma, and prolonged life expectancy. This reduction in the rate of progression has also been demonstrated in patients with chronic hepatitis C and cirrhosis in some but not all studies. The majority of these results are reported with standard interferon therapy, and long-term results of peginterferon plus ribavirin therapy with a higher likelihood of SVR should have a yet greater impact on the population of treated patients. The impact on slowing progression is greatest in patients with an SVR, less in relapsers, and equivocal in nonresponders. Thus, the natural history of chronic hepatitis C after completion of antiviral therapy is favorable with achievement of an SVR, although further data are needed to determine the likely incremental impact of peginterferon plus ribavirin, late long-term effects of therapy, and the benefit of treatment in patients with advanced hepatic fibrosis.

Profile of pre‐S deletions in the natural history of chronic hepatitis B infection

It have been suggested that hepatitis B virus (HBV) pre-S deletions may play a role in hepatocarcinogenesis. The aim of the study was to determine the prevalence of pre-S deletions in chronic hepatitis B patients in Hong Kong, the factors associated with the deletions and its relationship with hepatitis B e antigen (HBeAg) seroconversion. HBV pre-S deletions were determined by nucleotide sequence analysis in 178 patients with chronic HBV (cross-sectional study). Eighty-four patients had paired samples before and after HBeAg seroconversion (longitudinal study). The prevalence of pre-S deletions was 12.9% (23/178). A majority of the pre-S deletions (73.9%) occurred in the 5' terminus of pre-S2 region whereas deletions in the pre-S1 region appeared less frequently (47.8%). There was no relationship between age and pre-S deletions. Male gender [odds ratio (OR) =10.88; 95% confidence interval (CI) =1.37-86.52; P=0.024] and HBV genotype C (OR=13.85; 95% CI=3.05-62.92; P=0.001) were independent factors associated with pre-S deletions. Only 17 out of the 84 patients with paired samples before and after HBeAg seroconversion had pre-S deletions. The patterns of pre-S deletions before and after HBeAg seroconversion were variable. Compared with genotype B, HBV genotype C was associated with earlier emergence of pre-S deletions. In conclusion, 12.9% of chronic HBV carriers had pre-S deletions (predominantly pre-S2 deletions) in a geographical area highly endemic for chronic hepatitis B. Male gender and HBV genotype C were associated independently with the development of pre-S deletion mutations. There was no clear relationship between HBeAg seroconversion and pre-S deletions.

Natural history of chronic hepatitis C: Genotype 1 versus genotype 6

Data on the natural history of chronic hepatitis C virus (HCV) genotype 6 is lacking. We compared the natural history of 138 HCV genotype 1 patients (median age: 50) with 78 HCV genotype 6 patients (median age: 46.5). Baseline demographic data including gender, route of transmission, liver biochemistry, HCV RNA levels, and serial alanine aminotransferase (ALT) levels were compared. The rate of development of complications and mortality were also analyzed. A total of 71.7% and 8.7% of genotype 1 patients were infected through blood transfusion and intravenous drug addiction, respectively, compared with 56.4% and 28.2% for genotype 6 patients, respectively (p<0.05). There were no differences in the baseline liver biochemistry in terms of ALT, albumin, bilirubin, alpha-fetoprotein (AFP), and HCV RNA levels between the two groups. Comparison of the proportion of normal and abnormal ALT levels between the two groups showed no statistical difference (p=0.121). There was also no statistical difference in the cumulative rate of development of cirrhotic complications and hepatocellular carcinoma (p=0.358) and mortality (p=0.649) between the two groups. HCV genotype 1 patients were largely infected through blood transfusion, while a statistically larger proportion of genotype 6 patients were infected through intravenous drug injection. Both genotypes have comparable liver biochemistry, HCV viral load, and similar rates of development of cirrhotic complications and mortality.

Natural history of chronic hepatitis B: extending the REVEAL study

Natural history of chronic hepatitis B: extending the REVEAL study

Hepatitis B: treatment strategies and resistance

More than 350 million people worldwide are chronically infected with HBV. The prevalence is particularly high in South East Asia, Sub-Saharan Africa and South America. In developed regions, the rate of chronic hepatitis B is declining mainly as result of universal HBV vaccine programs, although immigration from HBV endemic areas represents a continuous source of incident cases. Viral load and HBV genotype influences the natural history of chronic hepatitis B and progression of liver fibrosis. Treatment must be considered for individuals with serum HBV-DNA above 2000 IU/ml, given their increased risk of cirrhosis and liver cancer. Non-invasive tools for assessing liver fibrosis, such as elastometry (FibroScan) are rapidly replacing liver biopsy to guide treatment decisions. Besides peginterferon, five nucleos(t)ide analogues (lamivudine, adefovir, telbivudine, entecavir and tenofovir) have been approved for the treatment of chronic hepatitis B; it is unlikely that any more will be available in the near future. Cross-resistance is common between all these drugs, although in different extent. Therefore, an adequate design of effective therapeutic strategies is crucial for long-term benefit using these drugs. Patients that experience virologic breakthrough or partial response to their primary therapy can often be successfully treated with a second nucleos(t)ide analogue, preferentially when the rescue intervention is done at early stages of failure. However, best strategies for preventing drug resistance include first-line use of the most potent antivirals with a high barrier to resistance (namely tenofovir or entecavir) and/or combination therapy. At this time, the use of lamivudine or adefovir as single agents in first-line therapy is no longer recommended, given their low-genetic barrier to resistance and weak activity, respectively. The genes that encode the polymerase and envelope proteins of HBV overlap, so resistance mutations in polymerase usually affect the hepatitis B surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of liver disease, and transmission throughout the population. Primary lamivudine resistance-associated mutations in HBV are now being seen in 10% of new HBV infections in Western Europe and North America. A particular considerations merit the coinfection with HIV or the superinfection by delta virus. Specific guidelines for managing HBV in HIV+ individuals have been released (AIDS 2008, 22:1399–1410). The fixed combination of tenofovir plus emtricitabine (Truvada) is the preferred option in most HIV-HBV coinfected patients. The role of entecavir or telbivudine in this setting is hampered by the recognition of low anti-HIV activity and possibility of selecting resistance mutations in HIV. With respect to hepatitis delta, preliminary data suggest that potent nucleotide analogues as tenofovir may exert some benefit in a subset of individuals with chronic hepatitis delta, although data are too preliminary.

Histologic Disease in Patients with Chronic Hepatitis B, High HBV DNA, and Normal Alanine Aminotransferase Levels

Recent advances in the treatment of hepatitis B virus (HBV) infection have presented new options as well as challenges. Serum alanine aminotransferase (ALT) continues to be one of the three principal parameters used by all existing treatment guidelines to identify candidates for antiviral therapy. Although there is little controversy that inactive carriers and young immune tolerant patients can be monitored without antiviral therapy, and that antiviral therapy should be initiated in immune active patients with elevated HBV DNA ant ALT levels, not all guidelines agree on the management of older individuals with elevated HBV DNA but normal ALT levels who may no longer be immune tolerant and who have significant histologic disease. These patients may benefit from antiviral therapy, but distinguishing them from the true immune tolerant patient is challenging. This article reviews the natural history of chronic hepatitis B, the evolving concept of a “normal”ALT level, and recent studies examining liver histology in patients with chronic HBV infection, high HBV DNA levels, and normal ALT levels.

Analysis on clinical features and immunity in chronic hepatitis B virus infected patients with low-level HBsAg

To understand clinical features and immunity of chronic HBV-infected patients with high or low level HBsAg, the differences of serum two-component-determined circulating immune complexes (TCIC) and peripheral blood lymphocyte subsets between these patients were analyzed. 126 patients with chronic hepatitis B virus infection were divided into two groups including 44 with low-level HBsAg and 82 with high-level HBsAg, and three phases including non-active phase, immune active phase and immune tolerant phase by level of HBsAg and natural history of chronic hepatitis B virus infection. Antibody capture-ELISA method and flow cytometry were used to assay serum TCIC and peripheral blood lymphocyte subsets in 44 patients with low-level HBsAg (Group A), 82 patients with high-level HBsAg (Group B) and 22 healthy volunteers (Group C), respectively, and the results were analyzed and compared. Among these 44 patients in Group A, 40 patients (90.9%) were stable in non-active phase and the positive rate of HBsAg/IgG-CIC was the highest, accounting for 15.9% (7/44), while the positive rate of HBsAg/C3-CIC was the highest in Group B, accounting for 46.3% (38/82). The positive rates of serum TCIC, A value and non-active CD3+CD8+ percentages in Group A were all lower than those in Group B with corresponding phases (P<0.01-0.05), however, the percentages of CD4+/CD8+were higher than those in the corresponding phases of Group B(P<0.01). Patients with low-level HBsAg were correlated to low capability of TCIC synthesis and elimination and there was a low dose-induced immunotolerance phenomenon. Key words: Immune complex, chronic HBV infection, HBsAg, lymphocyte subsets, immunotolerance.

Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: A perspective on Asia

Data from clinical trials suggest a potential role for on-treatment monitoring of serum HBsAg titres during interferon-alpha (pegIFN) therapy in predicting virological responses. However, baseline HBsAg titres during the natural history of chronic hepatitis B (CHB) have not been well-characterized. We aimed to define the serum HBsAg titres during the different phases of CHB in a cohort of Asian patients infected with either genotype B or C HBV. Two-hundred and twenty patients were classified into immune-tolerant (IT), immune-clearance (IC), non/low-replicative (LR) or hepatitis B e antigen negative hepatitis (ENH) phases. Serum HBsAg was quantified using the ARCHITECT platform (Abbott Laboratories, Chicago, USA). Correlation of HBsAg titre with HBV DNA and serum ALT within each phase of infection was performed. Median HBsAg titres were different between each phase of CHB (p=0.001): IT (4.53 log(10)IU/ml), IC (4.03 log(10)IU/ml), LR (2.86 log(10)IU/ml), and ENH (3.35 log(10)IU/ml). HBsAg titres were highest in the IT phase, and lowest in the LR phase. In general, median HBsAg titres were similar between genotypes B and C HBV. Serum HBsAg titres only correlated with HBV viral load in the IC phase. No correlation between the serum HBsAg level and ALT was observed. This study demonstrated significant differences in median baseline serum HBsAg titres across the different phases of CHB. These results provide further insight into the HBV viral life cycle in the setting of the various phases of CHB. Baseline HBsAg quantification may help refine future treatment algorithms for both immune-modulator therapy and oral nucleos(t)ide analogue therapy.

Growing attention to an old marker, hepatitis B surface antigen, in the natural history of chronic hepatitis B

Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers.

Sustained virological response to interferon plus ribavirin reduces liver‐related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus†

Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, thus promoting more rapid progression to cirrhosis and end-stage liver disease. The objective of our study was to determine whether hepatitis C virus (HCV) clearance is associated with improved clinical outcomes in patients positive for HIV and HCV. It was an ambispective cohort study carried out in 11 HIV units in Spain and involved 711 consecutive patients positive for HIV/HCV who started interferon plus ribavirin therapy between 2000 and 2005. We measured sustained virologic response (SVR), i.e., undetectable HCV RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver decompensation, hepatocellular carcinoma, and liver transplantation. Of 711 patients who were positive for HIV/HCV, 31% had SVR. During a mean follow-up of 20.8 months (interquartile range: 12.2-38.7), the incidence rates per 100 person-years of overall mortality, liver-related mortality, and liver decompensation were 0.46, 0.23, and 0.23 among patients with SVR and 3.12, 1.65, and 4.33 among those without SVR (P = 0.003, 0.028, and <0.001 by the log-rank test), respectively. Cox regression analysis adjusted for fibrosis, HCV genotype, HCV RNA viral load, Centers for Disease Control and Prevention clinical category, and nadir CD4+ cell count showed that the adjusted hazard ratio of liver-related events was 8.92 (95% confidence interval, 1.20; 66.11, P = 0.032) for nonresponders in comparison with responders and 4.96 (95% confidence interval, 2.27; 10.85, P < 0.001) for patients with fibrosis grade of F3-F4 versus those with F0-F2.Because this was not a prospective study, selection and survival biases may influence estimates of effect. Our results suggest that the achievement of an SVR after interferon-ribavirin therapy in patients coinfected with HIV/HCV reduces liver-related complications and mortality.

HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B

During the natural history of chronic hepatitis B virus (HBV) infection, the loss of serum hepatitis B e antigen (HBeAg) and the development of anti-HBe antibodies (HBeAg seroconversion) mark a transition from the immune-active phase of disease to the inactive carrier state. This review examines the evidence from natural history and cohort studies on the relationship between HBeAg seroconversion and disease progression. The role of HBeAg seroconversion as an important milestone in the management of HBeAg-positive patients with chronic hepatitis B (CHB), as well as the advantages and disadvantages of administering a finite course of therapy for HBeAg-positive CHB, is also discussed. The evidence from natural history and cohort studies indicates that spontaneous or treatment-induced HBeAg seroconversion is associated with lower rates of disease progression to cirrhosis and hepatocellular carcinoma, a potential of hepatitis B surface antigen seroconversion, and improved survival rates. Updated guidelines developed by major liver associations recommend stopping oral therapy for HBeAg-positive patients who achieve sustained HBeAg seroconversion with polymerase chain reaction-undetectable HBV-DNA on two separate occasions for 6 or more months apart, taking into consideration the individual's clinical and virologic response to therapy, as well as the severity of liver disease. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogues has important clinical and socioeconomic implications for the management of CHB.

The impact of hepatic steatosis on the natural history of chronic hepatitis C infection

Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39-51 years), who had two liver biopsies performed (median biopsy interval 50, 34-74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5-33% = S1, 33-66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis (n = 59), declined therapy (n = 48), or had co-existing disease precluding treatment (n = 5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3-16.7, P = 0.02). Twenty-three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by > or =1 stage. On univariate analysis, fibrosis progression was associated with older age (P = 0.004), higher AST (P = 0.04), and steatosis (P = 0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1-111.1, P = 0.006). Kaplan-Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak > or =F3) and cirrhosis (Ishak F5-6) (P = 0.001 and P = 0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti-viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.

Indications for therapy in hepatitis B #

Increased treatment options that are more efficacious and safe and new knowledge on the natural history of chronic hepatitis B virus (HBV) infection have expanded the indications for therapy in hepatitis B. The question is no longer "Who should be treated?" but "When should treatment be initiated?" Treatment is clearly indicated in patients with life-threatening liver disease (acute liver failure, decompensated cirrhosis, or severe hepatitis flare) and in those with compensated cirrhosis and high levels of serum HBV DNA. For patients with precirrhotic liver disease, treatment indications should be based on clinical, biochemical, or histological evidence of liver disease, such as elevated alanine aminotransferase (ALT) levels, abnormal histology, and high levels of serum HBV DNA. The cutoff for ALT and HBV DNA values are constantly being revised and should be set at a lower level for older patients who may have been infected for a longer period of time. High serum HBV DNA levels persisting for a few decades are associated with increased risk of clinical outcomes, but there is insufficient data to support the initiation of treatment based on high serum HBV DNA alone, particularly in young patients, those with persistently normal ALT levels, and those with a single high HBV DNA level. The decision to initiate treatment at the time of assessment or to defer treatment should take into consideration other factors such as desire to start a family, occupational requirement, family history of hepatocellular carcinoma, access to care and insurance coverage, and commitment to long-term treatment and medication compliance. All patients who are not initiated on treatment should continue to be monitored so treatment can be started if and when the indication arises.

The natural history of chronic hepatitis B virus infection #

Chronic hepatitis B virus (HBV) infection has a complicated course. Three phases are identified: an immune tolerant phase with high HBV DNA and normal alanine aminotransferase (ALT) levels associated with minimal liver disease; an immune active phase with high HBV DNA and elevated ALT levels with active liver inflammation; and an inactive phase with HBV DNA levels < 2000 IU/mL and normal ALT levels with minimal inflammation and fibrosis on liver biopsy. Affected persons can move progressively from one phase to the next and may revert backward. The primary adverse outcomes of chronic HBV infection are hepatocellular carcinoma (HCC) and cirrhosis. Published natural history studies were reviewed and ranked by the strength of evidence regarding the study design. Factors with the highest evidence of risk for development of HCC or cirrhosis from population-based prospective cohort studies include male sex, family history of HCC, HBV DNA level above 2000 IU/mL in persons above age 40, HBV genotypes C and F, and basal core promoter mutation. Those with the next highest level of evidence include aflatoxin exposure, and heavy alcohol and tobacco use. Improved methods to identify persons at highest risk of developing HCC or cirrhosis are needed to allow intervention earlier with antiviral therapy in appropriate patients. Future studies should include prospective follow-up of established population-based cohorts as well as new cohorts recruited from multiple centers stratified by HBV genotypes/subgenotypes and clinical phase to determine the incidence of the various HBV phases, HCC, and cirrhosis. Also, nested case-control studies assessing immunological and host genetic factors among persons with active and inactive disease phases, HCC, and cirrhosis could be conducted using these types of cohorts.

Sustained viral response after interferon‐based therapy in chronic hepatitis C: more evidence to support a life‐long cure

Sustained viral response after interferon‐based therapy in chronic hepatitis C: more evidence to support a life‐long cure

Cirrhosis Regression in Chronic Hepatitis C: An Old Tale With a New Ending

Cirrhosis Regression in Chronic Hepatitis C: An Old Tale With a New Ending