Natural history of chronic hepatitis B virus infection

In chronic hepatitis B virus (HBV) infection acquired during adulthood, which is the type mostly seen in the Caucasian population, there is biochemical and histologic regression after HBeAg seroconversion, and the risk of death from hepatitis B‐related causes is low. In chronic HBV infection acquired during birth or early childhood, which is the type most commonly seen in the Asian population, there is a prolonged phase of immunotolerance. The immune clearance phase is characterized by multiple acute exacerbations preceeded by elevations in serum HBV DNA levels, HBeAg concentration and HBeAg/anti‐HBe immune complexes. Of these patients, 2.4% may develop hepatic decompensation during the stage of HBeAg seroconversion. The development of cirrhosis occurs more frequently in patients with episodes of decompensation and with repeated severe acute exacerbations. However progression to cirrhosis can be relatively silent and can occur even in children. After HBeAg seroconversion, precore and core promotor mutations occur frequently in the Asian population. However, there is little correlation between the occurrence of these mutations and alanine aminotransferase elevation in patients who are positive for anti‐HBe. Although cirrhosis develops during the process of HBeAg seroconversion, 68% of the complications of cirrhosis and of hepatocellular carcinoma occur after HBeAg seroconversion. These complications may still occur even after HBsAg seroclearance.     

Natural history of hepatitis B virus infection in children

Hepatitis B virus (HBV) infection during childhood can cause acute, fulminant or chronic hepatitis, liver cirrhosis, and liver cancer. Approximately 90% of the infants of hepatitis B e antigen (HBeAg) seropositive mothers become hepatitis B surface antigen (HBsAg) carriers. Children chronically infected are mostly asymptomatic. Although liver damage is usually mild during childhood, severe liver disease, including cirrhosis and hepatocellular carcinoma, may develop insidiously for 2–7 years. Spontaneous HBeAg seroconversion occurs gradually as the age of the child increases. Viral replication is reduced during this process, which is usually preceded by an elevation of aminotransferases. In a long‐term follow‐up study, the annual HBeAg seroconversion rate was 4–5% in children older than 3 years of age and less than 2% in children under 3 years. The annual seroconversion rate of HBsAg was very low (0.56%). Age at infection, maternal HBsAg and HBeAg status, host immune status, and possibly the HBV strain are the main factors determining the course of HBV infection in children.     

Natural history of hepatitis B virus infection: pediatric perspective

Hepatitis B virus (HBV) infection is an important disease globally. Chronic HBV infection may result in serious complications. Its transmission may be either perinatal or horizontal. Perinatal transmission is particularly important after the implementation of a universal vaccination program. Through either route, chronic carrier status is usually established in early childhood. The course of the disease course is determined by the host–virus interaction. The host’s immune system initially tolerates the virus, and then gradually attempts to clear it. The virus, on the other hand, tries to avoid host immune system attack by a strategy involving targeted epitope mutations. By generating mutants, the virus can survive attacks from the host’s immune system, enabling the infection to persist. Different individuals have different responses to HBV infection; genetic polymorphisms in cytokines, hormones, and other immune modulators may affect the final outcome of chronic HBV infection. Due to the implementation of a universal infant HBV vaccination program, HBV infection is now under control. Unfortunately, there still are some cases of vaccination failure. Very high maternal viremia, in utero infection, or escape mutants are possible reasons for vaccination failure. Immunocompromised hosts also risk vaccination failure. Blood or organ donors with occult HBV infection are possible sources for immunocompromised hosts. These victims of vaccination failure may exhibit a different disease course due to chronic HBV infection from those who acquired the infection before the universal vaccination era. The achievement of our ultimate goal of HBV elimination depends on a globally effective universal vaccination program, as well as the application of some novel successful medications to control those who are already infected.     

Natural history of hepatitis C virus infection

Hepatitis C is a heterogeneous disease whose natural history is controversial and perplexing. However, it can be a pernicious disease and is responsible for considerable mortality and morbidity. More than 80% individuals infected with the hepatitis C virus (HCV) develop chronic infection; the remaining 10–20% develop spontaneous clearance with natural immunity. The majority of patients who develop chronic HCV infection are asymptomatic; but 60–80% develop chronic hepatitis as indicated by elevated ALT; around 30% maintain normal ALT. One‐third of chronically infected patients develop progressive liver injury, fibrosis and cirrhosis over a period of 20–30 years, and 15% develop hepatocellular carcinoma. Acquiring infection after the age of 40 years, male sex, excessive alcohol consumption, HBV or HIV co‐infection and the immunosuppressive state have been identified as factors associated with progression of fibrosis and development of cirrhosis. The relationship between virus load, HCV genotype I and quasispecies variability and progression of live disease is controversial. In the present study on 141 patients with chronic HCV infection and established chronic liver disease, the median time to develop cirrhosis was 20 years. Progression to cirrhosis was faster (16 vs 20 years) in those who acquired infection after the age of 35 years, and in immunosuppressed patients (8 vs 21 years), whereas diabetes, sex and HBV co‐infection were not associated with faster progression.     

Natural history and clinical management of chronic hepatitis B virus infection in children

Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon α and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon α, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.     

Natural history of chronic hepatitis C virus infection

The natural history of chronic Hepatitis C Virus (HCV) infection is still poorly understood. The main reason is the asymptomatic onset and course in the majority of infected subjects. Moreover, in the presence of the very effective therapies now available it is impossible to follow people untreated in order to analyse the events and their timing and type of evolution. For these reasons, most studies are mainly retrospective, although studies on post-transfusion hepatitis could help in understanding the natural course of the infection. Another important phenomenon that makes this issue problematic is that chronic HCV infection is not linear in time, probably because many co-factors can change the speed of development of fibrosis, cirrhosis and hepatocellular carcinoma.Data now available show that this disease can persist for about two decades with limited morbidity and mortality; problems may arise between the third and fourth decade after infection. Alcohol consumption is a very important factor of additional risk of progression, but there are several other factors (iron, steatosis, metabolic problems, etc.) that must be better analysed. In conclusion, only in a small group (no more than 15%) of all HCV-infected patients does the disease reduce quality and/or quantity of life.     

Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum

Hepatitis B virus DNA (HBV DNA) in serum was measured by a Spot hybridization technique in a consecutive series of 79 cases with chronic HBV infection from Taiwan. HBV DNA was found in 96.3% (52/54) of HBeAg-positive, 66% (2/3) with neither HBeAg or anti-HBe and in 63.6% (14/22) of anti-HBe positive patients. The levels of HBV DNA in the HBe-Ag-positive patients were significantly higher than in the anti-HBe positive patients (median, 944 vs. 58 pg per ml, p less than 0.001). The mean ages increased from 28.7 years for the cases with high levels of HBV DNA, to 34.7 years for those with low levels (p less than 0.01) and to 41.0 years in those without HBV DNA in serum (p less than 0.05 when compared with those with low level of HBV DNA). Ninety per cent of patients (27/30) with high levels of HBV DNA showed only minor hepatic inflammatory activity, as did 91% (10/11) of those without HBV DNA. In contrast, histologic signs of chronic active hepatitis or chronic lobular hepatitis were demonstrated in 76% of cases (29/38) with low levels of HBV DNA. These data are consistent with the hypothesis that liver damage occurs during the period of clearance of hepatocytes supporting HBV replication, and are inconsistent with the view that HBV may be directly cytopathic. Thus, the natural history of chronic HBV infection may be divided into three phases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Natural history of hepatitis B virus infection in renal transplant recipients--a fifteen-year follow-up

Hepatitis B virus (HBV) markers were measured in 83 immunosuppressed renal transplant patients who were followed for periods of 2 to 15 years. Sixty-nine patients were negative for HBsAg before transplantation, of whom 14 were positive for anti-HBs. The remaining 14 patients were HBsAg positive prior to transplantation. Eighteen patients were identified as being HBsAg positive during the follow-up period. Four patients acquired primary type B hepatitis; one died of submassive hepatic necrosis and the remaining three became chronic HBV carriers with positive HBeAg, DNA polymerase, and HBV DNA. Several patterns of HBV expression were observed in HBsAg-positive patients. Four patients were HBsAg, HBeAg, DNA polymerase, and HBV DNA positive prior to transplantation, and these markers persisted. Reactivation of HBV replication occurred in eight patients, seven of whom were HBsAg positive and HBeAg and anti-HBe negative originally; one patient was anti-HBc positive. A single patient was HBsAg and anti-HBe positive and remained so for 22 months. The remaining previously HBsAg-positive patient is currently HBsAg negative. These serological data suggest that reactivation of HBV replication or continued hepatitis B virion replication occurs as commonly or more commonly than de novo infection in renal transplant recipients. The presence of HBeAg in serum predisposes to long-term Dane particle expression in immunosuppressed patients, whereas anti-HBe-positive carriers may not always be susceptible to reactivation of HBV replication despite immunosuppression.     

Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy

Abstract

Objectives. In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. Methods and subjects. A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. Results. The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (<10⁴ copies/ml) was observed in 43 and 29 patients, respectively. The sustained effects of IFN therapy were evaluated by comparison between 43 hepatitis B e-antigen (HBeAg)-positive patients treated with IFN and 67 patients with chronic hepatitis B observed without IFN therapy. A Cox’s proportional hazard analysis showed a higher seroconversion rate in the IFN group than in the untreated group (p = 0.003). Similarly, there were higher rates of ALT normalization and lower viral levels in the IFN group than in the untreated group (p = 0.001 for both). Conclusion. IFN therapy showed sustained effects for achieving ALT normalization and HBeAg seroconversion and for reducing the viral load in children with chronic hepatitis B.     

Global control of hepatitis B virus infection

Worldwide about 350 million people are chronic carriers of the hepatitis B virus (HBV). The infection can cause acute and chronic liver disease including cirrhosis and hepatocellular carcinoma (HCC). Hepatocellular injuries of HBV infection are predominantly immune-mediated, and the natural history of chronic infection can be divided into three phases based on virus-host interactions-namely, immune tolerance, immune clearance, and viral integration phases. Four serotypes (adw, ayw, adr, and ayr) and seven genotypes (A to G) of HBV have been identified, and they show some distinct geographic distributions. The HBV genotypes may have clinical relevance and are currently under investigation. On the basis of disease burden and the availability of safe and effective vaccines, the WHO recommended that by the end of the 20th century hepatitis B vaccine be incorporated into routine infant and childhood immunisation programmes for all countries. The efficacy of universal immunisation has been shown in different countries, with striking reductions of the prevalence of HBV carriage in children. Most important, hepatitis B vaccination can protect children against HCC and fulminant hepatitis, as has been shown in Taiwan. Nevertheless, the implementation of worldwide vaccination against HBV requires greater effort to overcome the social and economic hurdles. Safe and effective antiviral treatments are available but are still far from ideal, a situation that, hopefully, will be improved soon. With hepatitis B immunisation, the global control of HBV infection is possible by the end of the first half of 21st century.     

The natural history of chronic hepatitis B virus infection

Three stages of chronic hepatitis B virus (HBV) infection are recognized: the immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis B carrier phase. Active liver disease is most often found in persons with elevated aminotransferase levels and HBV DNA levels >10(5) copies/mL. Possible risk factors for developing liver disease include older age, male gender, presence of hepatitis B e antigen (HBeAg), HBV genotype, mutations in the precore and core promoter regions of the viral genome, and coinfection with hepatitis D (delta) virus. All persons chronically infected with HBV should be followed every 6 to 12 months with aminotransferase levels. Those with elevated levels should be tested for HBeAg and its antibody (anti-HBe) as well as HBV DNA levels to determine if they are in need of further evaluation with a liver biopsy and are candidates for antiviral therapy. Future research will help clarify the outcome of chronic HBV infection.     

Natural history of chronic hepatitis B virus infection: New light on an old story

Chronic hepatitis B virus (HBV) infection is one of the most common persistent virus infection in man. It causes significant morbidity and mortality, and therefore is important. Extensive studies on clinicopathologic studies and long-term follow up on hepatitis B surface antigen (HBsAg) carriers have largely disclosed the natural history of chronic HBV infection. The infection easily becomes chronic when contracted in early infancy. As high as 90% of babies born to HBV carrier mothers will also become HBsAg carriers. Once chronic infection is established, it is refractory, and HBsAg carriage usually persists for life. However, the chronic infection is not monotonous, it actually evolves from an HBV replicative phase to a non-replicative phase. The host responds differently and with more complexity in different phases. The virus-host interactions, divided into three phases, virus tolerance, virus clearance and residual HBV integrated phases, result in a heterogeneous variety of hepatic lesions. The first two phases occur when HBV is actively replicating, and the last corresponds to the non-replicative phase. The high HBV level (and hence HBV gene products) renders the host's immune system tolerant to the virus, and the infected host does not exert an effort to get rid of the virus. At this stage, the liver is nearly normal, and the host is asymptomatic. However, later in the replicative phase, the HBV replication begins to wane, and the immune tolerance is no longer maintained. Hepatitis B core antigen/hepatitis B e antigen (HBcAg/HBeAg)-specific cellular immune responses result in lysis of the infected liver cells; the liver then begins to have active disease as revealed by the presence of lobular hepatitis. The asymptomatic carrier may then start to have symptoms of hepatitis. After a variable period, usually in years, the host eventually gets rid of active viral replication and only residual incomplete HBV genome integrated to host chromosomes is found. The carrier is now HBeAg negative/anti-HBe positive, serum HBV DNA decreases to very low levels, and the disease becomes qulescent at this stage. The outcome of the host is determined by the hepatic lesions caused by HBV-host interactions mentioned above, with cirrhosis and hepatocellular carcinoma (HCC) as the major sequelae of chronic HBV infection. Although HCC is usually preceded by HBV-induced cirrhosis, this is not always the case. Cirrhosis and HCC may develop independently, with cirrhosis as the most important precipitating factor or cofactor of HCC. A significant proportion of HBsAg carriers, particularly the males, will eventually die of these sequelae.     

Natural history of hepatitis B

The natural course of hepatitis B virus (HBV) chronic infection is variable, ranging from an inactive HBsAg carrier state to a more or less progressive chronic hepatitis, potentially evolving to cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis may present as typical HBeAg-positive chronic hepatitis B or HBeAg-negative chronic hepatitis B. HBeAg-positive chronic hepatitis is due to wild type HBV; it represents the early phase of chronic HBV infection. HBeAg-negative chronic hepatitis is due to a naturally occurring HBV variant with mutations in the precore or/and basic core promoter regions of the genome; it represents a late phase of chronic HBV infection. The latter form of the disease has been recognized as increasing in many countries within the last decade and it represents the majority of cases in many countries. HBeAg-negative chronic hepatitis B is generally associated with a more severe liver disease with a very low rate of spontaneous disease remission and a low sustained response rate to antiviral therapy. Longitudinal studies of patients with chronic hepatitis B indicate that, after diagnosis, the 5-year cumulative incidence of developing cirrhosis ranges from 8-20%. Morbidity and mortality in chronic hepatitis B are linked to evolution to cirrhosis or HCC. The 5-year cumulative incidence of hepatic decompensation is approximately 20%. The 5-year probability of survival is approximately 80-86% in patients with compensated cirrhosis. Patients with decompensated cirrhosis have a poor prognosis (14-35% probability of survival at 5 years). HBV-related end-stage liver disease or HCC are responsible for at least 500,000 deaths per year.     

HBV感染自然史研究进展

病毒复制与宿主免疫之间的动态平衡在HBV感染自然史进展和发病机制中起重要作用。多数免疫能力正常的成人感染HBV后呈自限性,而在婴幼儿则多发展成为慢性HBV感染。慢性HBV感染分为4期：免疫耐受期、HBeAg阳性慢性肝炎期、非复制的HBsAg携带期和HBeAg阴性慢性肝炎期。HBVDNA水平、HBeAg的状态以及ALT水平可以预测HBV感染的长期结局如肝硬化或肝细胞癌。本文对HBV感染自然史分期、慢性HBV感染的结局和预后进行了综述。     

Natural history of chronic persistent hepatitis B. Relationship between hepatitis B virus replication and the course of the disease

The status of viral replication at diagnosis and its relationship to the changes occurring during the natural history of the disease have been investigated in 26 patients with chronic persistent hepatitis (CPH) type B. Liver HBcAg and serum HBeAg were found in 73% of patients. During follow-up, serum transaminases normalized in 13/17 HBeAg-positive patients 1-6 years after diagnosis and 11 of them developed anti-HBe. HBe seroconversion was closely preceded by a transient elevation of transaminases in 5 patients in whom a repeated liver biopsy showed prominent lobular hepatitis and marked reduction of liver HBcAg. Such changes resulted in long-lasting biochemical normalization but only 1 patient became HBsAg-negative. These observations indicate that prolonged viral replication occurs in type B CPH. Termination of replication frequently implies a transient worsening caused by lysis of HBcAg-containing hepatocytes which leads to inactivation of the disease and to development of a healthy HBsAg carrier state.     

Natural history of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection can cause chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Chronic hepatitis B is characterized by an early replicative phase with hepatitis B e antigen (HBeAg) positivity, high serum HBV-DNA levels and disease activity (HBeAgpositive chronic hepatitis), and a late inactive phase with anti-HBe seroconversion, low or undetectable serum HBV-DNA, and liver disease remission (inactive carrier state). Another form is characterized by active disease due to HBV variants not expressing HBeAg (HBeAg-negative chronic hepatitis). Both types of chronic hepatitis B can lead to cirrhosis and its complications. The incidence of cirrhosis is two to five per 100 person-years, but may be as high as eight to 10 in HBeAg-negative cases. The incidence of HCC varies geographically and increases with the duration and severity of liver disease (0.1 to 8 per 100 person-years). The prognosis is reasonably good in compensated cirrhosis, but very poor following decompensation. Viral and environmental factors influence the natural history of chronic hepatitis B and explain the heterogeneity of its clinical outcomes.