Describe the natural history of chronic hepatitis B infection
- The natural historyof chronic HBV infection can be schematically divided into five phases which are not necessarily sequential:
- (1) The ‘‘immune tolerant’’ phase
- (2) The ‘‘immune reactive HBeAg-positive phase
- (3) The ‘‘inactive HBV carrier state’’
- (4) ‘‘HBeAg-negative CHB’
- (5) HBsAg-negative phase
Describe the 'immune tolerant phase of chronic HBV Infection
- The ‘‘immune tolerant’’ phase is characterised by
- 2. High levels of HBV replication (reflected by highlevels of serum HBV DNA)
- 3. Normal or low levels of amino-transferases
- 4. Mild or no liver necroinflammation
- 5. No or slow progression of fibrosis
What is the rate of spontaneous HBeAg loss in the immunotollerant phase of chronic HBV infection?
When is the immune tollerant phase commonly seen?
This phase is more frequent and more prolonged in subjects infected perinatally or in the first years of life.
Are patients in the immune tollerant phase of chronic hepatitis B contagious?
Yes. They are highly contagious because of high levels of viremia.
What are the characteristics of the immune-reactive HBeAg-positive phase of chronic hepatitis B infection?
- The ‘‘immune reactive HBeAg-positive phase’’ is character-ised by:
- 1.HBeAg positivity
- 2.Relatively low level of viral replication (as reflected by low serum HBV DNA levels)
- 3.Increased or fluctuating levels of aminotransferases.
- 4. Moderate or severe liver necroinflammation.
- 5. Rapid progression of fibrosis.
When is the immune-reactive HBeAg-positive phase commonly seen?
- 1. In subjects infected duringadulthood.
- 2. After several years of immune tolerance (partial breakdown of tolerance).
What is meant by 'partial breakdown of tolerance' in chronic hepatitis B viral infection?
The passage from the immunetolerant phase to the HBeAg-positive phase of chronic hepatitis B infection
How long does the immune-reactive HBeAg-positive infection last?
It may last for several weeks to several years.
Describe the rate of spontaneous HBeAg loss in the immune-reactive HBeAg-positive phase
The rate of spontaneous HBeAg loss is high
How does the immune-reactive HBeAg-positive phase end?
- It ends with seroconversion to anti-HBe
- It may lead to:
- -Inactive HBV carrier state
- -HbeAg-negative CHB
Describe inactive HBV carrier
- It is characterised by:
- 1.Very low or undetectable serum HBV DNA levels.
- 2. Normal serum aminotransferases.
When is the inactive HBV carrier state seen?
Following seroconversion from HBeAg to anti-HBe antibody.
When can we safely classify a patient as an 'inactive HBV carrier'
- Usually when thery show:
- 1. ALT levels persistently within the normal range according
- to traditional cut-off values.
- 2. HBV DNA below 2000 IU/ml throughout at least 1 year of follow-up of 1 year with alanine aminotransferase (ALT) levels at least every 3–4 months and serum HBV DNA levels.
Some inactive carriers, however, may have HBV DNA levels greater than 2000 IU/ml (usually below 20,000 IU/ml) accompanied by persistently normal ALT levels
IT MAY BE MISTAKEN WITH active HBeAg negative CHB.
What is the recommended work up for patients with HBV DNA <2000 IU/ml and elevated ALT valutes?
Liver biopsy for the evaluation of the cause of liver injury.
What is the prognosis of the inactive HBV carrier state? Why?
- It is very favourable with a very low risk low risk of cirrhosis orHCC in the majority of patients
- because of the immunological control of the infection.
How does the inactive HBV carrier state evolve?
- 1. HBsAg loss and seroconversion to anti-HBs antibody may occur spontaneously in 1–3% of cases per year (usually after several years with persistently undetectable HBV DNA)
- 2. Progression to CHB, usually HBeAg-negative, may also occur.
What is the recommended follow up for inactive HBV carriers?
- Inactive HBV carriers shouldbe followed up for life with:
- 1. ALT determinations at least every 6 months after the first year.
- 2. periodical measure-ment of HBV DNA levels.
- 3.The follow-up should be closer in cases with baseline serum HBV DNA levels above 2000 IU/ml, in whom non-invasive evaluation of liver fibrosis may be useful and even liver biopsy might be considered.
This usually allows detection of fluctuations of activity in patients with active HBeAg-negative
How are HBsAg levels in inactive HBV carriers?
- Usually high
- However, inactive carriers have been reported to have serum HBsAg levels <1000 IU/ml
What are the characteristics of HBeAg negative Chronic hepatitis B?
- Periodic reactivation with a pattern of:
- 1.Fluctuating levels of HBV DNA.
- 2.Fluctuating levels of aminotransferases
- 3.Active hepatitis
- 4.These patients are HBeAg-negative.
- 5.They harbour a predominance of HBV virions with nucleotide substitutions in the precore and/or the basal core promoter regions.
When is HBeAg-negative CHB seen?
- 1. It may follow seroconversion from HBeAg to anti-HBe antibodies during the immune reactive phase.
- 2. It may develop after years or decades of the inactive carrier state. .
It represents a later immune reactive phase in the natural history of chronic HBV infection.
What is the prognosis of HBeAg-negative CHB?
It shows low rates of prolonged spontaneous disease remission.
- These patients have active liver disease with a high risk of progression to:
- 1.Advanced hepatic fibrosis, cirrhosis and subsequent compli-cations such as decompensated cirrhosis
Describe the HBsAg-negative Chronic hepatitis B
- Patients show:
- 1. Undetectable HBV DNA in SERUM (low-level HBV replication may persist with detectable HBV DNA inthe liver)
- 2. Positive anti-HBc antibodies.
- 3. anti-HBs may or may not be detectable.
What is the prognosis of HBsAg-negative chronic hepatitis B?
It depends on whether the HBsAg loss has occured before the onset of cirrhosis.
In that case it is associated with improvement of the outcomewith reduced risk of cirrhosis, decompensation and HCC.
If cirrhosis has developed before spontaneous or treatment-induced HBsAg loss, patients remain at risk of HCC.
What constitutes occult HBV infection?
- 1. HBsAg-negative CHB
- 2. Detectable HBV DNA in the liver
- 3. With low level (<200 IU/ml) or unde-tectable HBV DNA in blood.
What are the main parts of the initial evalution of Chronic hepatitis B infection?
- 1. Establish the causal relationship between chronic HBV infection and liver disease.
- 2. Assess of the severity of liver disease.
- 3. Screening of contacts
- 4. Look for other causes of chronic liver disease
How should contacts of chronic HBV patients be managed?
- 1.ALL first degree relatives and sexual partners of patients with chronic HBV infection should be advised to be tested for HBV serological markers (HBsAg, anti-HBc, anti-HBs)
- 2. If negative, they should be advised to be vaccinated
Do patients with chronic HBV infection have elevated aminotransferases?
- Not all of them. Patients may have normal ALT levels:
- -Persistently: Immune tolerant and inactive carriers
- -Intermittedly: HBeAg-negative patients
How to assess the severity of the liver disease?
- 1.Biochemical markers, including aspartate aminotransferase (AST) and ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, bilirubin, and serum albumin and globulins
- 2.Blood counts
- 3.Prothrombin time
- 4. hepatic ultrasound
Describe aminotransferase behavior in chronic HBV infection?
- 1. May or may not be elevated according to phase (persistently normal in immuno tollerant and inactive carriers, intermittently normal in HBeAg-negative)
- 2. Usually ALT levels are higher than those of AST.
- 3. THe ratio may be reversed when the disease progresses to cirrhosis.
What are the characteristic biochemical changes that are observed in cirrhosis?
- 1.A progressive decline in serum albumin concentrations and/or increase of (gamma-)globulins
- 2. Prolongation of the prothrombin time
- 3. Declining platelet counts
- 4. A reversal of the ALT/AST ratio
What is the role of HBV DNA detection in management of patients with chronic hepatitis B infection?
HBV DNA level measurement are essential for the diagnosis, decision to treat and subsequent monitoring of patients
What are the recommendations for HBV DNA detection
- 1.Using realtime PCR quantification for follow-up
- 2.Expression of HBV DNA concentrations in IU/ml to ensure comparability
- 3.Using the same assay in the same patient to evaluate antiviral efficacy.
How to convert HBV DNA values given as copies/ml into IU/ml?
Roughly by dividing by a factor of 5
What other causes of liver disease should be assessed in the initial evaluation of a patient with chronic hepatitis B infection?
- 1. Co-infections with:
- 2. anti-HAV (vaccinate if negative)
- 3. Alcoholic liver disease
- 4. Autoimmune liver disease
- 5. Metabolic liver disease with steatosis or steatohepatitis
What is the role of liver biopsy?
- 1. Determining the degree of necroinflammation and fibrosis to assist the decision to start treatment.
- 2. Evaluating other possible causes of liver disease such as fatty liver disease.
How high is the risk of severe complications following liver biopsies?
Very low (1/4000–10,000).
What technical recommendation should be bourn in mind when performing a liver biopsy?
The size of the needle biopsy specimen should be large enough to accurately assess the degree of liver injury, in particular fibrosis.
When is a liver biopsy NOT required in the evaluation of a patient with chronic hepatitis B infection?
- 1. Patients with clinical evidence of cirrhosis.
- 2. Patientsin in whom treatment is indicated irrespective of the grade of activity or the stage of fibrosis.
What is the role of transient elastography?
- 1. May be used to complement or avoid a liver biopsy.
- 2. It is highly accurate for diagnosis of cirrhosis
- 3. Results may be confounded by severe inflammation associated with high ALT levels
What is the The goal of therapy for CHB?
- The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to:
- - Cirrhosis
- - Decompensated cirrhosis
- - End-stage liver disease
- - HCC
- - Death.
How can prevention of progression of diseases in CHB patients be achieved?
- By suppressiopn of HBV replication in a sustained manner.
- This in turn, is accompanied by a reduction in histological activity of CHB with a lessened risk of cirrhosis and decreased risk of HCC
In which patients is suppression of HBV replication accompanied by a decreased risk of HCC?
Can chronic HBV infection cannot be completely eradicated ? why?
- No it can't.
- 1. the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes
- 2. The HBV genome integrates into the host genome
How do you account for HBV reactivation?
Because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus
What favours oncogenesis in chronic HBV infection?
The HBV genome integrates into the host genome
What are the end points of HBV therapy?
- 1. Ideally, HBsAg loss (infrequently achievable with currently available anti-HBV agents)
- 2. The induction of sustained or maintained virological remission preferably off therapy, other wise on long-term antiviral therapy.
How do end points of CHB therapy correlate with outcome?
- 1. HBsAg loss (with or without seroconversion to anti-HBs) in both HBeAg-positive and HBe-Ag negative patients, is associated with a complete and definitive remission of the activity of CHB and an improved long-term outcome.
- 2. Induction of sustained off-therapy virological and biochemical response in HBeAg-negative patients is associated with improved prognosis.
- 3. the least favoravle is maintained virological remission under long-term antiviral therapy in HBe-Ag positive patients.
What are the types of responses to antiviral therapy in CHB?
- Response may be:
- - Biochemical.
- - Serological.
- - Virological.
- - Histological.
What are the types of drugs that can be used in treatment of CHB?
- Two different types of drugs can be used in the treatment of CHB:
- 1. Conventional or pegylated interferon alpha (IFN or PEG-IFN).
- 2. Nucleoside/nucleotide analogues.
What is biochemical response to antiviral therapy in CHB?
It is defined as the normalisation of ALT levels.
At what points of antivral therapy is the biochemical response evaluated?
- 1. At several time points on-therapy.
- 2. At the end of therapy.
- 3.After the end of therapy.
How is sustained off-treatment biochemical response defined? why?
It is defined as persistently normal ALT levels over a follow-up period of at least 1 year post-treatment with ALT determinations at least every 3 months.
This is because ALT activity often fluctuates over time-
Are ALT elevations after treatment discontinuation equivalent to biochemical failure of treatment?
- No. Transient (usually no more than 3 months duration) ALT elevations before
- long-term biochemical remission may occur in some CHB
- patients within the first year after treatment discontinuation
What to do in case of ALT elevation after antiviral treatment discontinuation in CHB? DOUBLE CHECK
- Close monitoring.
- - If for no more than 3 months AND within first year after treatment, it may be considered as a transient elevation
- -->in which case, additional close ALT follow-up of at least 2 years is suggested.
-If ALT elevation for more than 3 months --> biochemical failure
What constitutes a serological response in CHB patients?
- It depends on their serostatus:
- - In HbeAg-positive CHB: HBeAg-loss and development of anti-HBe.
- - In all CHB patients: HBsAg loss and development of anti-HBs.
How is virological response to IFN/PEG-IFN defined?
Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml.
When is virological response to IFN/PEG-IFN evaluated?
- It is usually evaluated at:
- - 6 months of therapy.
- - At the end of therapy.
- - At 6 months after the end of therapy.
- - At 12 months after the end of therapy.
How is sustained off-treatment virological response in CHB defined as?
HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy.
What is primary nonresponse?
Primary nonresponse is generally defined as the lack of improvement of clinical signs and symptoms during induction therapy.
What is the definition of primary non-response to IFN/PEG-IFN in CHB treatment?
How is primary non-response to antiviral therapy of CHB using nucleoside/nucleotide analogues?defined?
It is defined as less than 1 log 10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.
Define partial virological response to antiviral therapy of CHB using nucleoside/nucleotide analogues
Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients
How do you define virological response to antiviral therapy of CHB using nucleoside/nucleotide analogues?
Virological response is defined as undetectable HBV DNA by a sensitive PCR assay.
When is virological response in course of antiviral therapy for CHB using nucleoside/nucleotide analogues evaluated?
Every 3-6 months depending on the severity of liver disease and type of nucleoside/nucleotide analogue.
What is virological brakthrough during antiviral therapy of CHB using nucleoside/nucleotide analogues?
- Virological breakthrough is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy.
- It may precede a biochemical breakthrough.
What is a biochemical breakthroug during antiviral therapy with a nucleoside/nucleotide analogue?
- It is defined as Increase in ALT above upper limit of normal after
- achieving normalization, during continued
What is viral rebound during antiviral treatment with nucleoside/nucleotide analogues?
Increase in serum HBV DNA to 20,000 IU/ml or above pretreatment level after achieving virologic response, during continued treatment
What are the main causes of virological breakthrough on antiviral therapy with nucleoside/nucleotide analogues?
- 1.Poor adherence to therapy
- 2. and/or selection of drug-resistant HBV variants (resistance)
How does HBV resistance to nucleoside/nucleotide analogues develop?
Through the selection of HBV variants with aminoacid substitutions that confer reduced susceptibility to the administered nucleoside/nucleotide analogue
What is the effect of HBV resistance to nucleoside/nucleotide analogues?
Resistance may result in primary non-response or virological breakthrough on therapy
Is there an 'off-therapy' when it comes to nucleoside/nucleotide analogues?
- DIscontinuation on nucleoside/nucleotide analogues is not common practice.
- However they may be discontinued in some patients.
Define histological response to antiviral therapy
- decrease in necroinflammatory
- activity (by less than points in HAI or Ishak’s system) without
- worsening in fibrosis compared to pre-treatment histological
Define complete response to antiviral treatment
- It is defined as sustained off-treatment virological response
- TOGETHER WITH
- loss og HBsAg.
What parameters should be kept in mind when deciding whether or not to treat CHB?
- Decision is based on three criteria:
- 1.Serum HBV DNA levels.
- 2.Serum ALT levels.
- 3.Severity of liver disease.
What are the indications of antiviral treatment for CHB?
- Patients should be considered for treatment, regardless of their HBeAg serostatus, when they have:
- 1. HBV DNA levels above 2000 IU/ml.
- 2.Severity of liver disease assessed by liver biopsy (or non-invasive markers) showing moderate to severe active necroinflammation and/or at least moderate fibrosis using a standardised scoring system.
- 3. +/- Serum ALT levels above the upper limit of normal (ULN).
What are the indications for performing a liver biopsy in patients with CHB?
- It depeds on the subgroup of patients:
- 1. Immunotolerant patients >30 years and/or with a a family history of HCC or cirrhosis
How to manage young immunotolerant patients with no evidence of liver diseases or family history of HCC or cirrhosis?
- Follow up every 3-6 months is mandatory for all HBeAg-positive patients under30 years of age with persistently normal ALT levels and ahigh HBV DNA level, without any evidence of liver disease and without a family history of HCC or cirrhosis.
- These patients DO NOT require immediate liver biopsy or therapy.
How to manage immunotolerant HBeAg-positive patients who are over 30 years old?
Consider liver biopsy or even therapy ESPECIALLY if they have a family history of HCC or cirrhosis
How to manage immunotolerant HBeAg-positive patients who have a family history of cirrhosis or HCC?
Consider liver biopsy or even therapy
How to manage HBeAg-negative with persistently normal ALT levels and HBV-DNA levels between 2000 and 20,000 with no evidence of liver disease?
- Close follow-up for 3 years with:
- -ALT determinations every 3 months.
- -HBV DNA every 6-12 months
- Afterwards, follow-up for life like inactive chronic HBV carriers:
- - ALT determinations at least
- every 6 months
- - Periodical measurement of HBV DNA levels.
- - +/- Non-invasive evaluation of liver fibrosis in cases with baseline serum HBV DNA levels above 2000 IU/ml or even biopsy.
How should patients with active chronic hepatitis B