Chronic hepatitis B therapy.
Chronic hepatitis B therapy
Nyoman Purwadi
Gastro-Hepatologi Division Sanglah Hospital Denpasar
It is estimated that 350 million of individuals are infected by hepatitis B virus (HBV)
worldwide. Major advances have been made in the treatment of chronic hepatitis B (CHB)
during the past several years. While increased available therapeutic agents improve efficacy of
HBV treatment, it is also CHB is one of the important public health problems worldwide. Major
advances have been made in the treatment of CHB during the past several years.
Clinical presentation of chronic HBV infection can be quite different ranging from inactive
carrier status to HBV-cirrhosis or hepatocellular carcinoma (HCC). Understanding the spectrum
and clinical presentation of chronic HBV infection is prerequisite for optimizing HBV treatment.
Chronic HBV infection is defined as positive HBsAg for > 6 months that has been traditionally
classified as the following subgroups.
Chronic Hepatitis B (CHB)
CHB is characterized by positive HBsAg for greater than 6 months, serum HBV DNA ≥1 x 106
copies/ml, and persistent or intermittent elevation of serum ALT/AST. A liver biopsy in most of
these patients shows chronic hepatitis. Depending on HBeAg status, these patients can be further
classified as following two subgroups:
1) HBeAg-positive CHB
Patients with HBeAg-positive CHB present with positive HBsAg and HBeAg in serum that is
associated with active HBV replication, infectivity, and hepatic inflammation. Depending on the
mode of HBV transmission, spontaneous seroconversion from HBeAg to anti-HBe is variable.
Most patients underwent seroconversion remain sustained remission of HBV infection that is
associated with normal transaminases and a low or undetectable level of serum HBV DNA
although serum HBsAg may remain positive.
2) HBeAg-negative CHB
Patients with HBeAg-negative CHB present with positive HBsAg, but negative HBeAg in serum
that is associated with active HBV replication, elevated transaminases, and hepatic inflammation.
Pathologically, it is secondary to mutant viral infection in HBV pre-core or pre-core promoter
region. The prevalence of HBeAg-negative CHB varies worldwide from 14% to 33%. In patients
with HBeAg-negative CHB, approximately half of the patients had serum HBV DNA < 105
copies/ml. HBeAg-negative CHB is usually progressive and less responsive to HBV treatment.
HBV-cirrhosis
Approximately 20% of patients with CHB develop HBV-cirrhosis. Although HBV-cirrhosis
represents a continued progression of CHB, we classify it as a different subgroup because of
different treatment approach. HBV load varies in this group of patients although it is usually low.
Like those with CHB, patients with HBV-cirrhosis can be either HBeAg or anti-HBe positive.
Although thrombocytopenia, splenomegaly, and hypoalubuminemia are indicative of cirrhosis, a
liver biopsy provides histological diagnosis. Patients with HBV-cirrhosis can be compensated or
decompensated. The later presents with esophageal bleeding, ascites, hepatic encephalopathy,
severe hyperbilirulinemia, and/or coagulopathy. Those with decompensated HBV-cirrhosis
should be referred for liver transplant evaluation.
The ultimate goal of CHB therapy is the prevention of cirrhosis, hepatic decompensation and/ or
HCC. This goal can be achieved if HBV replication can be suppressed in a sustained manner,
thus leading to biochemical remission, HBe seroconversion in HBeAg-positive patients,
histological improvement and prevention of cirrhosis and its complications. Several studies have
demonstrated that undetectable or low levels of HBV DNA are associated with a lower risk to
develop cirrhosis. Loss of HBsAg from serum with or without seroconversion to anti-HBs is
considered the ideal end-point of therapy, as it is associated with remission of chronic hepatitis B
activity and an improved long-term outcome. The loss of HBsAg, however, is infrequently
achieved with currently available anti-HBV agents. Hence, a more realistic end-point is the
induction of a sustained or maintained virological response. It must be emphasized that a
complete eradication of HBV infection is impossible to achieve due to the persistence of the socalled covalentlyclosed-circular DNA (cccDNA), the transcriptionally active HBV minicromosome in the nucleus of infected hepatocytes; that is to say, that an HBV infected patient
can be “cured” but the HBV infection cannot be eradicated and continues to persist as an occult
infection.
The indications for treatment are generally the same for both HBeAg-positive and HBeAgnegative CHB. This is based mainly on the combination of three criteria:Serum HBV DNA
levels, Serum ALT levels, Severity of liver disease. Patients should be considered for treatment
when they have HBV DNA levels above 2000 IU/ml, serum ALT levels above the upper limit of
normal (ULN) and severity of liver disease assessed by liver biopsy (or non-invasive markers
once validated in HBV infected patients) showing moderate to severe active necroinflammation
and/or at least moderate fibrosis using a standardised scoring system . In patients who fulfil the
above criteria for HBV DNA and histological severity of liver disease, treatment may be initiated
even if ALT levels are normal. Indications for treatment may also take into account age, health
status, family history of HCC or cirrhosis and extrahepatic manifestations.
At the present time, several drugs are licensed for the treatment of HBV infection: interferon
alfa, lamivudine, and the nucleotide analogue adefovir dipivoxil. Several newer nucleoside
analogues, such as entecavir, emtricitabine, and telbivudine, are in various phases of
study. Adefovir, tenofovir, and entecavir have been shown to have antiviral activity against
lamivudine resistant as well as wild-type HBV both in vitro and in vivo.
Nyoman Purwadi
Gastro-Hepatologi Division Sanglah Hospital Denpasar
It is estimated that 350 million of individuals are infected by hepatitis B virus (HBV)
worldwide. Major advances have been made in the treatment of chronic hepatitis B (CHB)
during the past several years. While increased available therapeutic agents improve efficacy of
HBV treatment, it is also CHB is one of the important public health problems worldwide. Major
advances have been made in the treatment of CHB during the past several years.
Clinical presentation of chronic HBV infection can be quite different ranging from inactive
carrier status to HBV-cirrhosis or hepatocellular carcinoma (HCC). Understanding the spectrum
and clinical presentation of chronic HBV infection is prerequisite for optimizing HBV treatment.
Chronic HBV infection is defined as positive HBsAg for > 6 months that has been traditionally
classified as the following subgroups.
Chronic Hepatitis B (CHB)
CHB is characterized by positive HBsAg for greater than 6 months, serum HBV DNA ≥1 x 106
copies/ml, and persistent or intermittent elevation of serum ALT/AST. A liver biopsy in most of
these patients shows chronic hepatitis. Depending on HBeAg status, these patients can be further
classified as following two subgroups:
1) HBeAg-positive CHB
Patients with HBeAg-positive CHB present with positive HBsAg and HBeAg in serum that is
associated with active HBV replication, infectivity, and hepatic inflammation. Depending on the
mode of HBV transmission, spontaneous seroconversion from HBeAg to anti-HBe is variable.
Most patients underwent seroconversion remain sustained remission of HBV infection that is
associated with normal transaminases and a low or undetectable level of serum HBV DNA
although serum HBsAg may remain positive.
2) HBeAg-negative CHB
Patients with HBeAg-negative CHB present with positive HBsAg, but negative HBeAg in serum
that is associated with active HBV replication, elevated transaminases, and hepatic inflammation.
Pathologically, it is secondary to mutant viral infection in HBV pre-core or pre-core promoter
region. The prevalence of HBeAg-negative CHB varies worldwide from 14% to 33%. In patients
with HBeAg-negative CHB, approximately half of the patients had serum HBV DNA < 105
copies/ml. HBeAg-negative CHB is usually progressive and less responsive to HBV treatment.
HBV-cirrhosis
Approximately 20% of patients with CHB develop HBV-cirrhosis. Although HBV-cirrhosis
represents a continued progression of CHB, we classify it as a different subgroup because of
different treatment approach. HBV load varies in this group of patients although it is usually low.
Like those with CHB, patients with HBV-cirrhosis can be either HBeAg or anti-HBe positive.
Although thrombocytopenia, splenomegaly, and hypoalubuminemia are indicative of cirrhosis, a
liver biopsy provides histological diagnosis. Patients with HBV-cirrhosis can be compensated or
decompensated. The later presents with esophageal bleeding, ascites, hepatic encephalopathy,
severe hyperbilirulinemia, and/or coagulopathy. Those with decompensated HBV-cirrhosis
should be referred for liver transplant evaluation.
The ultimate goal of CHB therapy is the prevention of cirrhosis, hepatic decompensation and/ or
HCC. This goal can be achieved if HBV replication can be suppressed in a sustained manner,
thus leading to biochemical remission, HBe seroconversion in HBeAg-positive patients,
histological improvement and prevention of cirrhosis and its complications. Several studies have
demonstrated that undetectable or low levels of HBV DNA are associated with a lower risk to
develop cirrhosis. Loss of HBsAg from serum with or without seroconversion to anti-HBs is
considered the ideal end-point of therapy, as it is associated with remission of chronic hepatitis B
activity and an improved long-term outcome. The loss of HBsAg, however, is infrequently
achieved with currently available anti-HBV agents. Hence, a more realistic end-point is the
induction of a sustained or maintained virological response. It must be emphasized that a
complete eradication of HBV infection is impossible to achieve due to the persistence of the socalled covalentlyclosed-circular DNA (cccDNA), the transcriptionally active HBV minicromosome in the nucleus of infected hepatocytes; that is to say, that an HBV infected patient
can be “cured” but the HBV infection cannot be eradicated and continues to persist as an occult
infection.
The indications for treatment are generally the same for both HBeAg-positive and HBeAgnegative CHB. This is based mainly on the combination of three criteria:Serum HBV DNA
levels, Serum ALT levels, Severity of liver disease. Patients should be considered for treatment
when they have HBV DNA levels above 2000 IU/ml, serum ALT levels above the upper limit of
normal (ULN) and severity of liver disease assessed by liver biopsy (or non-invasive markers
once validated in HBV infected patients) showing moderate to severe active necroinflammation
and/or at least moderate fibrosis using a standardised scoring system . In patients who fulfil the
above criteria for HBV DNA and histological severity of liver disease, treatment may be initiated
even if ALT levels are normal. Indications for treatment may also take into account age, health
status, family history of HCC or cirrhosis and extrahepatic manifestations.
At the present time, several drugs are licensed for the treatment of HBV infection: interferon
alfa, lamivudine, and the nucleotide analogue adefovir dipivoxil. Several newer nucleoside
analogues, such as entecavir, emtricitabine, and telbivudine, are in various phases of
study. Adefovir, tenofovir, and entecavir have been shown to have antiviral activity against
lamivudine resistant as well as wild-type HBV both in vitro and in vivo.