| Abstract|| |
Despite the development of a number of antiviral agents for treatment of Chronic Hepatitis B, the treatment of chronic hepatitis B continues to be a challenge for physicians due to the high burden of the disease and the limited efficacy of available therapy. The primary goal of treatment is to eliminate or suppress HBV in order to decrease pathogenicity and infectivity, and reduce hepatic necroinflammation. Clinically, the short-term goal of treatment is to reduce hepatic activity, to prevent the development of hepatic decompensation, to ensure loss of HBeAg (with seroconversion to anti-HBe) and/or HBV-DNA with alanine aminotransferase (ALT) normalization at the end or 6-12 months after the end of treatment. The long-term goals are eradication of infection, prevent progression to cirrhosis, prevent development of HCC, and ultimately prolong survival. This review discusses the goals of therapy in patients with chronic hepatitis B.
Keywords: cccDNA, Chronic hepatitis B, Treatment, Hepatitis B e antigen, Hepatitis B s Antigen
|How to cite this article:|
Duseja A. Goals of therapy in patients with CHB. Hep B Annual 2010;7:16-27
Patients with chronic hepatitis B are at increased risk of disease progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). Effective therapy is necessary to reduce or prevent such disease progression. The treatment of chronic hepatitis B continues to be a challenge for physicians due to the high burden of the disease and the limited efficacy of available therapy. 
| Goals of Treatment|| |
It is then obvious that the primary goal of treatment is to eliminate or suppress HBV; that is, to decrease pathogenicity and infectivity, and thereby to stop or reduce hepatic necroinflammation. Clinically, the short-term goal of treatment is to reduce hepatic activity, to prevent the development of hepatic decompensation, to ensure loss of HBeAg (with seroconversion to anti-HBe) and/or HBV-DNA with alanine aminotransferase (ALT) normalization at the end or 6-12 months after the end of treatment. The long-term goals are eradication of infection, prevent progression to cirrhosis and prevent development of HCC, ultimately, prolong survival.  This kind of long-term goal would need really long time and may not be really applicable in a patient who actually comes for treatment. HBV infection cannot be completely eradicated due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. 
Two distinct patient populations:
- HBeAg-positive (wild-type)
- HBeAg loss ± seroconversion
- Durable suppression of HBV DNA to low or undetectable levels
- Therapy discontinued after seroconversion; durability of response ≈80%.
- HBeAg-negative (precore and core promoter mutants)
- HBeAg seroconversion not an endpoint
- Durable suppression of HBV DNA to low or undetectable levels
- Relapse common after stopping oral therapy; therapy usually administered long-term.
Numerous guidelines have been published for the treatment of chronic hepatitis B. Recommendations from the American Association for the Study of Liver Disease (AASLD) for the management of chronic hepatitis B are shown in [Figure 1] and [Figure 2]. When applying such treatment guidelines to patients with chronic hepatitis B, the following three clinical data are necessary: HBeAg status, ALT level, and HBV DNA level. Once this clinical information is available, clinicians can follow the treatment algorithm shown in [Figure 1] and [Figure 2]. The treatment algorithms published by Keeffe and colleagues in December 2008 and by Lok and McMahon  (AASLD guidelines) in September 2009 are similar in many respects. For patients with persistently elevated ALT and high viral load, regardless of HBeAg status, both publications recommend antiviral treatment. A high viral load is considered to be a value ≥20,000 IU/ml and ≥2,000 IU/ml for patients with HBeAg positive [Figure 1] and HBeAg-negative [Figure 2] chronic hepatitis B, respectively. Both guidelines agree that patients with HBeAg-negative chronic hepatitis B, low HBV DNA levels (< 2,000 IU/ml), and normal ALT values can be considered inactive carriers and do not require antiviral therapy.
|Figure 1: Treatment Algorithm for Patient with Chronic Hepatitis B and Positive HBeAg. Abbreviations: ALT = Alanine aminotransferase; ULN = Upper limit of normal. Figure Adapted from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-39|
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|Figure 2: Treatment Algorithm for Patient with Chronic Hepatitis B and Negative HBeAg. Abbreviations: ALT = Alanine aminotransferase; ULN = Upper limit of normal. Figure Adapted from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-39|
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| ALT Normalization|| |
Treatment is recommended for patients in the immune clearance and reactivation phases characterized by elevated serum ALT and HBV DNA levels. The aim of therapy in patients with HBeAg-positive CHB is loss of HBeAg and ⁄ or seroconversion to anti-HBe, normalization of ALT levels and maximum suppression of HBV DNA to low or undetectable levels. Accomplishing these goals will result in improvement in liver histology, reduction in disease progression and decreased incidence of HCC, as has been shown in patients with advanced hepatic fibrosis. 
For many years, ALT has been used as a standard surrogate for the activity of CHB. Thus, ALT level in combination with HBV DNA level and histological activity has been used as a determinant for HBV treatment. It is well accepted that elevated ALT should be used as one of the determinants for HBV treatment in patients with CHB. However, it remains controversial on at what level of ALT elevation a patient with CHB should be considered for HBV treatment also the level keeps fluctuating. Levels vary with BMI, gender, metabolic abnormalities etc. Xie et al. failed to show any significant correlation between HBV DNA viral load and ALT in HBeAg-neg chronic hepatitis patients.  Chun et al. reported that viral load was not related to aminotransferase.  Habersetzer et al. showed that in patients with chronic hepatitis B-eAg positive, HBV DNA, (detected by PCR) was not correlated with ALT value. ,
| HBsAg Seroconversion|| |
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. Loss of hepatitis B e antigen (HBeAg), either spontaneously or following alpha interferon (IFN) therapy, significantly improves the clinical outcome and survival in chronic hepatitis B virus (HBV) patients. Therefore, HBeAg loss with seroconversion to antibodies to hepatitis B e antigen (anti-HBe) has remained a major end point of antiviral therapy in chronic HBV infection.  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.
According to large-scale population study, the median age of HBeAg seroconversion for Asian CHB patients is approximately 34.5 years. The annual rate of HBeAg seroconversion is approximately 15-20%. Patients with higher ALT levels, which indicate more intense immune responses, have a higher chance of HBeAg seroconversion. For patients having hepatitis flares (ALT levels greater than 2 times upper limit of normal [ULN]), the chances of achieving HBeAg seroconversion are 28%, 45%, 58%, 67%, and 73% for the coming 5 years, while for patients with ALT levels >5x ULN, the corresponding chances are even higher (32%, 51%, 64%, 75%, and 78%, respectively). Therefore, HBeAg seroconversion is part of the natural process of CHB infection.
For disease progression, according to a study of 684 Taiwanese patients conducted by Liaw and colleagues,  6.9% of HBeAg-positive patients and 4.0% of anti-HBe-positive patients developed cirrhosis during a mean follow up of 35 months. There was no statistical difference in the annual incidence rate of development of cirrhosis between HBeAg-positive patients (2.4%) and anti-HBe-positive patients (1.3%, P = not significant [NS]). According to another Taiwanese study by Hsu and colleagues,  the median age of HBeAg seroconversion was 32 years, and 33% of the patients experienced exacerbation of CHB upon subsequent follow up. Importantly, 7.8% of the patients without evidence of cirrhosis at the time of HBeAg seroconversion developed HCC after a median follow up of 8.6 years. The authors concluded that although HBeAg seroconversion was associated with a more favorable prognosis, active hepatitis may still develop and lead to cirrhosis and HCC.
According to another recent study of 3233 Asian CHB patients conducted in Hong Kong  with a 10-year follow up, clinical cirrhosis-related complications, including HCC, developed in 8% of patients. The median age of HBeAg seroconversion was 35 years, whereas the median age for development of HCC- and/or cirrhosis-related complications was 57 years, that is at least two decades after HBeAg seroconversion. It was therefore not surprising that 73.5% of patients with clinical complications were already anti-HBe positive.
With all the above evidence, HBeAg seroconversion does not always protect Asian patients from the development of HCC and/or cirrhosis. This stresses the importance of continual monitoring of the HBeAg/anti-HBe status in studying the natural history of CHB.
| Serum HBV DNA Suppression|| |
Recent studies have supported an association between the level of viral replication and the risk for the development of cirrhosis and HCC. [Figure 3] illustrates the benefits of rapid and sustained suppression of HBV DNA to lowest possible level. A population-based prospective cohort study of 3,774 Taiwanese patients with CHB investigated the relationship between serum HBV DNA level and the risk for cirrhosis. A total of 560 individuals (15% of the study cohort) were HBeAg-positive at enrolment. Using individuals who were HBeAg-negative with undetectable HBV DNA as the reference, the relative risk for cirrhosis (adjusted for gender, age, anti-HCV, cigarette smoking, and alcohol consumption) in HBeAg-negative individuals rose from 1.9 to 4.9 in those with HBV DNA 10 4 and ≥ 10 5 copies/mL, respectively. In persons positive for HBeAg, the relative risk was 2.6 in those with HBV DNA ≤10 3 copies/mL, rising to 5.2 and 8.6 in individuals with HBV DNA 10 4 and ≥10 5 copies/mL, respectively.
A second study in Taiwan addressed the association between persistent elevation of HBV DNA and the risk for HCC. A total of 3,851 individuals with CHB were followed for 43,993 person-years, during which 176 patients were newly diagnosed with HCC (data obtained via the National Cancer Registry and the Death Certification System). A dose dependent relationship between HBV DNA level and HCC risk was reported. Relative risk was calculated in comparison to individuals with HBV DNA <10 4 copies/mL at study entry. In persons with HBV DNA levels ≥10 5 copies/mL at enrolment, the adjusted relative risk for development of HCC were 3.6, 6.9, and 9.1 for those with serum HBV DNA levels at follow-up examination of <10 4 , 10 4 -10 5 , and ≥10 5 copies/mL, respectively. Although patients with high levels of viral replication carry the greatest risk, the results from this study suggest that those with lower rates of viral replication (10 4 -10 5 copies/mL) are still at risk for the development of HCC. 
Spontaneous or drug-induced suppression of serum HBV-DNA is associated with biochemical and histological remission of liver disease.  Presence of cirrhosis and high levels of HBV replication influence the course of chronic hepatitis B. The cirrhotic patients with positive serum HBV-DNA had a higher risk of decompensation and death compared with those who were HBV-DNA negative. The relative risk for HCC is higher in men who are HBsAg and HBeAg positive compared with HBsAg-negative individuals.
| HBsAG Seroclearance|| |
To date, the best indicators for achieving this goal are HBV surface antigen (HBsAg) seroclearance, With or without the development of antibodies against HBsAg (anti-HBs), and the absence of detectable serum and intrahepatic HBV DNA, as indicated by sensitive assays. HBsAg seroclearance occurs spontaneously at around 1 to 1.7% per year in Caucasian patients and at 0.1 to 0.8% per year in Asian patients. Following alpha interferon treatment, 65% of Caucasian patients who lose the HBV e antigen (HBeAg) also become HBsAg negative upon subsequent follow-up. Spontaneous HBsAg seroclearance at an early age is advantageous since patients with HBsAg seroclearance before 50 years of age have better liver histology and reduced risk of development of hepatocellular carcinoma.
Patients with HBsAg seroclearance had favourable biochemical, virological, and histological parameters. Intrahepatic HBV DNA level was low and predominantly in the form of cccDNA. However, HCC could still develop, particularly in patients with cirrhosis who had HBsAg seroclearance at an older age. 
| Liver Histology|| |
Liver biopsy plays a central role in treatment algorithms in patients with hepatitis B and remains the gold standard for evaluating hepatic pathology. The pathology of hepatitis B is diverse and reflects the natural history of infection. An acute hepatitic pattern with lobular disarray is seen in acute infection, during acute flares of disease, and with acute hepatitis D superinfection. In chronic hepatitis B, inflammation is less pronounced in the immune-tolerant phase and is prominent during immune-mediated viral clearance. Active inflammation appears to be the driving force for development of fibrosis. Inflammatory grades and fibrosis stage are assigned as is done for hepatitis C. Although current management guidelines recommend liver biopsies only in select patients based on age, viral levels, and hepatitis B e antigen status, these clinical and biochemical parameters do not show consistent correlations with liver histology. Liver biopsy also helps identify preneoplastic lesions including large cell and small cell change. Unlike in other causes of chronic hepatitis, immunostains are widely used and can help determine the phase of infection. Liver biopsies can also identify additional pathology that may contribute to liver disease such as steatohepatitis, iron overload, autoimmune hepatitis, and drug-induced injury. Thus, liver biopsy can play an important role in staging and grading chronic hepatitis B and should be more widely used in assessing the need for therapy.  Histological activities can again fluctuate, can improve or worsen rapidly.
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a unique episomal replicative intermediate responsible for persistent infection of hepatocytes. HBV covalently closed circular (ccc DNA) is a critical intracellular replicative intermediate, which acts as the template for transcription of viral RNAs serving either as viral pregenome RNAs, or as mRNAs coding for the multifunctional polymerase, core, X and envelope (S) proteins. All the HBV proteins play crucial roles in HBV gene transcription, replication, viral packaging and recycling. Due to lack of proofreading functions of polymerase, HBV goes through a fast mutagenesis and creates drug resistant strains, which contributes to the viral cccDNA pool. Because cccDNA of HBV is resource of new HBV viruses and resistance to drug treatment, it is believed that cccDNA is the major reason for HBV reactivation after stopping the anti-HBV therapy. Monitoring of HBV viral load, antigenes, mutations and cccDNA levels will therefore provide a direct indication of HBV activity in the body.
The cccDNA level was correlated with viral load, which occurred earlier than ALT. Before the ALT value increased, both the cccDNA level and viral load rose to a high level. Once the ALT value increased, the cccDNA level dropped rapidly. These results suggest that patients whose sera contain cccDNA are at a high risk of HBV reactivation, and that HBV cccDNA develops in the sera earlier than ALT elevation.
Longitudinal studies revealed that the release of cccDNA to the sera was an early signal of liver damage, which is correlated with ALT and viral load in HBV reactivated patients. Therefore, measurement of the cccDNA level in the liver may provide an end-point of anti-HBV therapy, and detection of the cccDNA level in the sera may provide a better guidance to protect patients from HBV reactivation. 
| Conclusion|| |
The ideal goal in the management of Hepatitis B infection has to be complete eradication of the infection which looks little unrealistic. Practical goal includes
- Combination of two or more markers because none of the available markers ideal in isolation
- Sustained viral suppression/HBeAg seroconversion
- HBsAg titres/Non invasive hepatic fibrosis.
Chronic HBV is a significant public health concern worldwide. The natural history and outcome of the infection depend on several viral, host, and external factors. Individuals with chronic HBV are at increased risk of developing cirrhosis or HCC; effective treatment interventions need to be considered and if possible implemented before the development of decompensated cirrhosis or HCC.
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Conflict of interest
There are no conflicts of interest.
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Department of Hepatology, PGIMER, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]