Gastroenterology training and education

Discuss HBV?

Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae (cirrhosis/HCC) during their lifetime.

Discuss the modes of transmission of HBV?

HBV is transmitted by perinatal, percutaneous, and sexual exposure, as well as by close person-to-person contact presumably by open cuts and sores, especially among children in hyper endemic areas.
HBV can survive outside the body for prolonged periods, and carriers who are HBeAg positive can shed large quantities of viral particles on environmental surfaces through open cuts or sores. The risk of developing chronic HBV infection after acute exposure ranges from 90% in newborns of HBeAg-positive mothers to 25% to 30% in infants and children under 5 and less than 10% in adults.

Who should be tested for HBV?

Persons born in hyper endemic areas, men who have sex with men, injecting drug users, dialysis patients, HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons. Testing for HBsAg and antibody to HBsAg (anti-HBs) should be performed, seronegative persons should be vaccinated.

Discuss the diagnostic criterion for chronic hepatitis B?

Chronic hepatitis B

• HBsAg + > 6 months
• Serum HBV DNA >20,000 IU/ml (>105 copies/ml)
• Persistent or intermittent elevation in ALT/AST levels
• Liver biopsy showing chronic hepatitis (necroinflammatory score more than equal to 4)

Inactive HBsAg carrier state

• HBsAg+ > 6 months
• HBeAg-, anti-HBe+
• Serum HBV DNA <2000 IU/ml
• Persistently normal ALT/AST levels
• Liver biopsy confirms absence of significant hepatitis (necroinflammatory score <4)

Discuss the serologic patterns of chronic HBV infection?

• Perinatal transmission- occurs mostly in Asia and the South Pacific Islands. Persistence of HBeAg is longer and seroconversion does not occur in most persons until later in adulthood. Among individuals with perinatally acquired HBV infection, a large percent of HBeAg-positive patients have high serum HBV DNA but normal ALT levels. These patients are considered to be in the “immune tolerant” phase. Many of these patients develop HBeAg-positive chronic hepatitis B with elevated ALT levels described as pattern 2 in later life.
• In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs from person to person in childhood, whereas perinatal transmission is less common. In these populations most children who are HBeAg positive have elevated ALT levels and seroconversion to anti-HBe is common near or shortly after the onset of puberty.
• The third pattern is usually observed in individuals who acquired HBV infection during adulthood. This is most common in developed countries where sexual transmission is the predominant mode of spread. Very little longitudinal data is available on the latter patients but liver disease is generally present in patients with high HBV DNA levels.

Discuss the natural history of HBV?

• The rate of clearance of HBeAg averages between 8% and 12% per year. HBeAg clearance may follow an exacerbation of hepatitis, manifested by an elevation of ALT levels.
• After spontaneous HBeAg seroconversion, 67% to 80% of carriers remain HBeAg negative and anti-HBe positive with normal ALT levels and minimal or no necroinflammation on liver biopsy. This has been referred to as the “inactive carrier state.”
• The course and outcome of the inactive HBsAg carrier state is generally but not invariably benign. Up to 20% of carriers in the inactive state can have exacerbations of hepatitis, as evidenced by elevations of ALT levels to 5 to 10 times the upper limit of normal, with or without seroreversion to HBeAg. Repeated exacerbations or reactivations can lead to progressive fibrosis.
• Approx 0.5% of HBsAg carriers will clear HBsAg yearly; most will develop anti-HBs.

Discuss HBeAg negative chronic hepatitis?

Most patients with HBeAg negative chronic hepatitis B harbour HBV variants in the precore or core promoter region. The most common precore mutation, G1896A, creates a premature stop codon in the precore region thus abolishing production of HBeAg.
Patients with HBeAg-negative chronic hepatitis B tend to have lower serum HBV DNA levels than those with HBeAg-positive chronic hepatitis B and are more likely to run a ?uctuating course. These patients are also older and have more advanced liver disease since HBeAg-negative chronic hepatitis B represents a later stage in the course of chronic HBV infection.

Patients with compensated cirrhosis who were HBeAg-negative had significantly better 5-year survival (97%) than those who were HBeAg-positive (72%).

Discuss the evaluation of patients with chronic HBV infection?

• History and physical examination
• Family History of liver disease, HCC
• Laboratory tests to assess liver disease—complete blood counts with platelets, liver screen, and prothrombin time
• Tests for HBV replication—HBeAg/anti-HBe, HBV DNA
• Tests to rule out viral coinfections—anti-HCV, anti-HDV and anti-HIV in those at risk
• Tests to screen for HCC–AFP at baseline and, in high risk patients, ultrasound
• Consider liver biopsy to grade and stage liver disease – for patients who meet criteria for chronic hepatitis.
• All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart. Prevaccination screening for antibody to hepatitis A should be considered if the prevalence of infection in the population is likely to be greater than 33%.

Who would you consider for treatment?

The following patients should be considered for treatment:

• HBsAg+, HBeAg+ and ALT > 2 times the upper limit of normal
• HBsAg+, HBeAg- , HBV DNA > 20,000 IU/ml and ALT > 2 times the upper limit of normal.

Liver biopsy is optional in the above two groups. Also, HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3 to 6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment.

A liver biopsy should be considered if the ALT in either of the above two groups is persistently more than 1-2 times the upper limit of normal (especially in age above 40). Consider treatment if biopsy shows moderate/severe in?ammation or signi?cant ?brosis.

Discuss follow up of patients not considered for treatment?

• HBeAg-Positive Patients with High Serum HBV DNA but Normal ALT Levels. These patients should be monitored at 3 to 6 month intervals.
• HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL (inactive carriers) should be tested for ALT every 3 months during the ?rst year to verify that they are truly in the “inactive carrier state” and then every 6-12 months.

What is the goal of HBV treatment?

The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC. Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology.

Discuss the drugs available for HBV?

Current therapy of chronic hepatitis B has limited long-term efficacy. Thus, careful balance of patient age, severity of liver disease, likelihood of response, and potential adverse events and complications is needed before treatment is initiated.
The ?rst-line drugs recommended for treatment of hepatitis B are pegIFN, entecavir or tenofovir. In view of the high rate of drug resistance during long-term treatment, lamivudine and telbivudine are not preferred. Since adefovir is less potent than other NA and is associated with increasing rate of antiviral resistance after the ?rst year of therapy, it is best utilized as a second line drug in treatment-naive patients.
The advantages of IFN- include a finite duration of treatment, more durable response, and the lack of resistant mutants. The disadvantages of IFN- are the costs and side effects.

Discuss the treatment of HBV?

• HBeAg+ chronic hepatitis- IFN?/PEG IFN? or one of the nucleoside analogues (NA) may be used as initial therapy. Entecavir or tenofovir is preferred.
  • Duration of therapy:
    • IFN? 16 weeks
    • PegIFN?- 48 weeks
    • NA’s- Treatment should be continued until the patient has achieved HBeAg seroconversion (at least 12 months)and undetectable serum HBV DNA and completed at least 6 months of additional treatment after appearance of anti-HBe.
  • Efficacy of treatment
    • IFN- Loss of HBeAg and HBV DNA in approx 1/3 rd of the cases. Response is durable in 80-90% of cases.
    • NA treatment for 48-52 weeks- loss of e antigen-around 30%. Loss of HBV DNA- 60-70% with entecavir and tenofovir. Response is durable in 50-80% of patients.
  • IFN non responders or contraindications to IFN- use NA’s
• HBeAg negative chronic hepatitis- treatment options are as above, however endpoint of treatment is not defined.
  • Duration of treatment
    • IFN- ?/pegIFN-?: 1 year
    • NA’s: more than 1 year. Treatment should be continued until the patient has achieved HBsAg clearance.
  • Efficacy of treatment
    • IFN- loss of HBV DNA 60-70%
    • NA for 48-52 weeks treatment- 90% or more with entecavir or tenofovir. However durability of response is only 10-20% with both IFN and NA
  • IFN non responders or contraindications to IFN- use NA’s
• Compensated cirrhotic patient with HBV DNA > 2000IU/ml with or without e antigen positivity- consider treatment with NA’s. These patients should receive long-term treatment. However, treatment may be stopped in HBeAg-positive patients if they have con?rmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg-negative patients if they have con?rmed HBsAg clearance. IFN should not be used because of the risk of hepatic decompensation associated with IFN- related flares of hepatitis.
• Decompensated cirrhosis- Treatment should be promptly initiated with a NA (coordinate care with the transplant centre). Life-long treatment is recommended.
  NB
• Patients who failed to achieve primary response as evidenced by <2 log decrease in serum HBV DNA level after at least 6 months of NA therapy should be switched to an alternative treatment or receive additional treatment.

Discuss the dose regimens?

• IFN- 5 MU SC daily or 10 MU thrice weekly. PEG IFN- 180mcg SC weekly.
• All NA’s are administered orally.

Discuss HCC surveillance in HBV infection?

HBV carriers at high risk for HCC such as Asian men over 40 years and Asian women over 50 years of age, persons with cirrhosis, persons with a family history of HCC, Africans over 20 years of age, and any carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000 IU/mL should be screened with US examination every 6-12 months.

Discuss antiviral prophylaxis of HBV who receive immunosuppressive or cytotoxic therapy?

• Reactivation of HBV replication with increase in serum HBV DNA and ALT level has been reported in 20% to 50% of hepatitis B carriers undergoing immunosuppressive or cancer chemo therapies. In most instances, the hepatitis flares are asymptomatic, but icteric flares, and even hepatic decompensation and death have been observed.
• HBsAg and anti-HBc testing should be performed in patients who are at high risk of HBV infection, prior to initiation of chemotherapy or immunosuppressive therapy.
• Prophylactic antiviral therapy is recommended for HBV carriers at the onset of cancer chemotherapy or of a ?nite course of immunosuppressive therapy.
• Patients with baseline HBVDNA<2,000IU/mL level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy.
• Patients with high baseline HBV DNA (>2,000 IU/mL) level should continue treatment until they reach treatment endpoints as in immunocompetent patients.
• Lamivudine or telbivudine can be used if the anticipated duration of treatment is short (<12 months) and baseline serum HBV DNA is not detectable.
• Tenofovir or entecavir is preferred if longer duration of treatment is anticipated.
• IFN should be avoided in view of the bone marrow suppressive effect.

Discuss management of pregnant women with HBV?

Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. (With this strategy- a recent study showed no increased risk with breast feeding).

Discuss precautions for infected persons regarding prevention of transmission of HBV to others?

Persons who are HBsAg-positive should:

• Have sexual contacts vaccinated
• Use barrier protection  if partner not vaccinated or naturally immune.

• Not share toothbrushes or razors
• Cover open cuts and scratches
• Clean blood spills with detergent or bleach
• Not donate blood, organs or sperms

Children and adults who are HBsAg-positive:

• Can participate in all activities including contact sports
• Should not be excluded from day care or school participation and should not be isolated from other children
• Can share food, utensils, or kiss others

Discuss treatment of acute hepatitis B?

• Antiviral therapy is generally not necessary in patients with symptomatic acute hepatitis B because 95% of immunocompetent adults with acute hepatitis B recover spontaneously.
• Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B (increase in INR and deep jaundice persisting for more than 4 weeks).
• Lamivudine or telbivudine may be used when the anticipated duration of treatment is short; otherwise, entecavir is preferred.
• Treatment should be continued until HBsAg clearance is con?rmed or inde?nitely in those who undergo liver transplantation.
• IFN is contraindicated.

Ref

1. AASLD Practice Guidelines. Chronic Hepatitis B: Update 2009