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Should all chronic Hepatitis B patients be treated; what are the endpoints?: Dr. Anand V Kulkarni

M3 India Newsdesk Aug 08, 2019

Dr. Anand V Kulkarni answers,

  • Should all cases of chronic Hepatitis B be treated?
  • How long should patients be treated; what are the optimal endpoints?

What is the natural course and symptoms of Hepatitis B?

After an incubation period of 30-120 days, infected individuals develop prodromal symptoms akin to serum sickness. This is followed by the onset of con­stitutional symptoms, including malaise, anorexia, nausea, vomit­ing, low-grade fever, myalgia, and fatigue. Thirty percent have icteric hepatitis, and <1% of patients with acute hepatitis B develop acute liver failure. Chronicity develops in 90% of individuals infected in the neonatal period (vertically transmitted).

Most patients with chronic HBV infection are asymptomatic until they have advanced cirrhosis or may have vague symptoms like fatigue or right upper quadrant pain. Extrahepatic manifestations are seen in up to 10% of chronic Hepatitis B without any evidence of liver disease. Conversely, 10 to 50% of patients with polyarteritis nodosa (PAN) are found to be HBsAg positive. Hepatitis B is the leading cause of non-cirrhotic hepatocellular carcinoma with even an inactive carrier developing HCC, although, the annual estimate is <0.2%.

What are the medicines available for treatment, and how long to treat?

With the availability of potent oral nucleos(t)ide analogues (NA), the therapy has become easy. Generally, it is said to be a lifelong therapy. However, it can be stopped after 3 to 5 years if the DNA is persistently suppressed in non-cirrhotic patients.

For apparent reasons, loss of HBsAg with the appearance of anti-HBs (called as complete remission) is the desired optimal endpoint, which is when the therapy can be withheld. However, in practice, the main endpoints are virologic response (long-term suppression of HBV DNA), biochemical response (normalisation of ALT), and seroconversion (loss of HBeAg with or without anti-HBe appearance).

The available drugs are Entecavir (ETV) 0.5mg, tenofovir disoproxil fumarate (TDF) 300mg, and tenofovir alafenamide (TAF) 25mg. Tenofovir Alafenamide is the preferred drug now- one tablet a day till there is loss of HBeAg (if previously positive) with the sustained virologic response. In case of HBeAg negative chronic hepatitis, sustained suppression of HBV DNA (virologic response) for three consecutive times (6 months apart) is also considered an endpoint, and the therapy can be stopped. The advantage of Peg-Interferon is the limited duration of therapy, which is preferred in HBeAg positivity, where the efficacy is comparable to nucleoside analogues. All the patients should be under strict surveillance after the therapy is withheld.

Should we treat all cases of chronic Hepatitis B?

As any person would expect, that all infected individuals should be treated (as HBV is also a leading cause of Hepatocellular carcinoma), the guidelines, however, say no. Treatment is based on three criteria - e antigen status, ALT levels, and HBV DNA levels.

  1. e antigen-negative with DNA >2000 IU/mL with elevated ALT, and e antigen-positive with DNA>20,000 IU/mL with elevated ALT (>2 upper limit) is an indication for treatment.
  2. If any grey zone (not fitting all the three criteria) exists, then the patient should be rendered for liver biopsy (≥F2 is an indication).

Treatment in unique populations:

  • Cirrhotic patient with detectable HBV DNA level irrespective of e antigen and ALT levels should be treated with TDF or Entecavir indefinitely; no nucleoside therapy is recommended for acute hepatitis B
  • Healthcare workers who perform exposure-prone procedures should be treated even if the DNA >200 IU/ml according to EASL (AASLD recommends >1000 IU/ml) to reduce the transmission
  • Pregnant women with HBV DNA >200,000 IU/ml should be started on antiviral prophylaxis with TDF (Tenofovir Disoproxil Fumarate) at week 24–28 of gestation and be continued for up to 12 weeks after delivery
  • A newborn should be given Hepatitis B immunoglobulin (HBIG) 200 IU along with Hepatitis B vaccination (10 mcg/0.5 ml) within 12 hours of birth and at four weeks (1month) and only HBV vaccination should be repeated at 2 and 6 months (baby receives a total of 4 doses of HBV vaccination); breastfeeding is not contraindicated
  • In kidney disease patients, TAF at 25 mg dose can be continued until eGFR is <15 ml/min, but ETV and TDF require dosage adjustment for patients with eGFR <50 ml/min.

How to follow up with an infected individual?

All treated patients should be followed up with periodic assessments, including kidney function tests, ALT levels, and serum HBV DNA. Irrespective of treatment, all patients should be on regular surveillance with ultrasonography every six months to look for evidence of hepatocellular carcinoma.

What is the role of Genotyping in HBV?

Genotyping is done if the patient is HBeAg positive to predict who might benefit from Interferon therapy (as Genotype A has the best response to Interferon therapy). Response to newly available oral drugs is not related to the genotype of Hepatitis B. There are 10 Genotypes (A-J) and around 40 subtypes of HBV. Genotype D subtype 5 is the most common Hepatitis B genotype in India. Genotypes can also aid in prognostication. HBV genotype B is associated with a slower rate of progression to cirrhosis and HCC while C is associated with increased risk of HCC.

What should be your advice for an HBsAg positive individual?

  1. The first thing is to have all household individuals screened with HBsAg, Anti HBS, and Anti HBcore testing and vaccinate them if HBsAg and anti-HB core are negative with anti-HBs <10 mIU/ml.
  2. The individual cannot share toothbrushes, nail cutters, or razors.
  3. They have to be educated to cover open cuts adequately, and scratches and clean blood spills with bleach solution.
  4. They should not donate blood, organs (exception exists), or sperm.
  5. They can take part in all household and outdoor activities, can share utensils, cook, and share food.

World Hepatitis Day was celebrated on 28th July in recognition of Nobel Laureate Baruch Samuel Blumberg’s birth anniversary, the discoverer of the hepatitis B virus surface antigen. The World Health Organization (WHO) estimates that 325 million people are living with Hepatitis B and C, and of them, 290 million are unaware of it. In recent years, advances in Hepatology research have reached a peak. Hepatitis C has become curable with simple oral tablets, and the prevalence of Hepatitis B is declining due to the improved vaccination program.


Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anand V Kulkarni is a Hepatologist at a reputed hospital in Hyderabad.

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