Lebanese Guidelines for the Treatment of HBV Infection

Joint Taskforce from the Lebanese Society of Gastroenterology and the Lebanese Society of Infectious Diseases.

Abou Rached Antoine, Roula Housni, Paul Rassam

I- Introduction

Hepatitis B infection is a global problem affecting about 350 million people in the world. It remains a leading cause of end-stage liver disease and hepatocellular carcinoma.  It also causes mortality in those patients with cirrhosis and carcinoma. New therapeutic agents for HBV treatment are available now, but because the current agents often require lifelong administration, optimizing initial therapy is important.

The present guidelines summarize the natural history of this infection, whom should be screened for hepatitis B, required laboratory tests upon presentation, therapeutic strategies for all patients including special groups, and follow up of these patients.

II- Natural history

It is well known that most immunocompetent patients will overcome the acute infection and less than 5 % will progress to chronic disease. The natural history of chronically infected patients is summarized below.

II-1. Patients’ immunologic reaction to the hepatitis B varies and it can be stratified into five categories summarized in the following  table.

Definitions of different phases of chronic hepatitis

I. Who should be screened for hepatitis B?

Specific groups of the population are at risk of acquiring this infection. It is transmitted sexually or by receiving infected blood products. The following are the individuals who need screening.

- Donors of blood, plasma, tissues, organs or semen

- Persons who are at risk of blood or body fluid exposures that might warrant post exposure prophylaxis

- Household and sexual contacts of persons with CHB

- HIV or HCV infected persons

- Persons who inject drugs (PWID)

- Men who have sex with men

- Multiple sexual partners (>2/year or more than 20/life)

- History of sexually transmitted disease

- Sex workers

- Persons who are incarcerated

- Persons of transgender.

- Pregnant women

- Patients on hemodialysis

- Infants born to positive HBs Ag mother.    

- Persons born in geographic regions with HBsAg prevalence > 2%

- Persons with elevated ALT/AST of unknown etiology

- Persons with selected conditions who require immunosuppressive therapy:         

- Chemotherapy

- Immunosuppression for rheumatologic or gastroenterologic disorders

- Immunosuppression related to organ transplantation

II. Diagnosis and staging

When patients are diagnosed with Hepatitis B infection, a complete workup should be done. This includes blood tests to determine the type of immunologic response, non-invasive test to assess the liver status, and invasive testing to stage the liver fibrosis before therapy is started.

IV-1. Serologic and other laboratory tests for viral Hepatitis B (HBV) are:

• • Hepatitis B surface antigen (HBsAg)
  • Antibody to HBsAg (Anti – HBs)
  • Hepatitis Be Antigen (HBeAg)
  • Antibody to HBe Antigen (Anti – HBe )
  • Antibody to Hepatitis B Core – Total  (Anti – HBc Total)
  • Anti – HBcIgM
  • Quantitative HBsAg: qHBsAg
  • PCR HBV DNA
  • Other Laboratory Tests
    • CBCD, BUN, creatinine
    • SGPT (ALT), SGOT (AST), gamma GT, Alkaline phosphatase, bilirubin, Albumin, globulin.(normal ALT<30 IU/ml, AST<30 IU/ml)
    • Prothrombin time (PT)

IV-2. Noninvasive assessment of liver damage:

Special scores are used to stage liver involvement and are listed below.

APRI= (AST/ULN) X 100/platelet count (10⁹/L)

FIB-4= (age (yr) X AST (IU/L)) / (platelet count (10⁹/L X {ALT (ALT (IU/L)⅟₂})

IV-3.  Invasive assessment:

Liver biopsy is considered the gold standard method to stage liver disease and assess the degree of fibrosis. The scoring system recommended is METAVIR.

I. Evaluation of Patients with Chronic HBV Infection

Any patient diagnosed with hepatitis B infection should be evaluated clinically and with laboratory tests that are listed below.

Initial evaluation should include

• History and physical examination
• Family History of liver disease, HCC
• Laboratory tests to assess liver disease—complete blood counts with platelets, hepatic panel and prothrombin time
• Tests for HBV replication—HBeAg/anti-HBe, HBV DNA
• Tests to rule out viral coinfections—anti-HCV, anti-HDV (in persons from countries where HDV infection is common and in those with history of injection drug use), and anti-HIV in those at risk
• Tests to screen for HCC–Alpha Foeto Protein at baseline and, in high risk patients, ultrasound
• Consider liver biopsy and /or fibroscan to grade and stage liver disease for patients who meet criteria for chronic hepatitis

II. Treatment

Indication to treat patients with hepatitis B infection depends on their immunologic reaction.

VI-1. Indications for treatment and/or monitoring

VI-1.1. Who should be treated:

The group that has priority for treatment includes:

- All adults, adolescents and children with chronic hepatitis B and clinical evidence of compensated or decompensated cirrhosis

- Adults who do not have clinical evidence of cirrhosis but are more than 30 years old and have persistently abnormal ALT{ >2ULN} levels and evidence of high level HBV replication regardless of HBeAg status

VI-1.2. Who should not to be treated but monitored

            - Antiviral therapy is not recommended and can be deferred in persons without clinical evidence of cirrhosis, with persistently normal ALT levels and low level of HBV replication regardless of HBeAg status or age

            - Continued monitoring is necessary in all persons with chronic hepatitis B, but in particular those who do not currently meet the above-recommended criteria to treat as antiviral therapy may be indicated in the future to prevent progressive liver disease. These include:

- Persons without cirrhosis aged 30 years or less with HBVDNA levels>20000IU/ml but persistently normal ALT

- HBeAg-negative persons without cirrhosis and are 30 years old or less, with HBV DNA levels that fluctuate between 2000 and 20000 IU/ml, or who have intermittently abnormal ALT levels

VI-1.3. - Monitoring for disease in persons who do not meet the criteria for antiviral therapy

- Persons with normal ALT: annual monitoring

- Persons who have intermittently abnormal ALT levels or HBV DNA levels that fluctuate between 2000 IU/ml and 20000 IU/ml: more frequent monitoring every 3-6 months

- Monitoring tests

- ALT levels, HBsAg, HBeAg and HBVDNA levels

- Non-invasive tests (APRI score or fibrotest or fibroscan annually) to assess for the presence of cirrhosis, in those without cirrhosis at baseline.

VI-2. Drugs used for the treatment of chronic hepatitis B

VI-2.1. Recommended drugs for the treatment of CHB and their doses

VI-2.2. recommended dosage in adults with renal impairment: CrCl (mL/min)

VI-3. Treatment algorithms

VI-3.1. Treatment of patients with HBeAg-positive

Note: Assess for fibrosis in all HBsAg positive patients ≥ 50 years. Treat as recommended according to fibrosis score.

VI-3.3. Treatment of patients with HBeAg-negative

VI-3.4. Treatment of patients with cirrhosis

VI-4. Management of Specific situations:

VI-4.1. Acute hepatitis

Oral antiviral (Lamivudine, Tenofovir or Entecavir) therapy may be given at the discretion of the treating physician for patients with severe acute hepatitis B, before the prothrombin time drops below 40%.

The drugs should be stopped when HBsAg testing becomes negative with positive anti-HBs antibodies detection. HIV status should be determined before starting lamivudine or Tenofovir therapy.

VI-4.2. Fulminant hepatitis

Antiviral therapy for fulminant hepatitis B should be given as soon as possible using NAs, whether it is a rapidly progressive acute infection or acute exacerbation of the carrier state.

NAs should be administered immediately to patients with severe acute hepatitis B, aiming to start therapy before the prothrombin time goes below 40% in patients with severe acute hepatitis B, and before the prothrombin time goes below 60% in patients with acute exacerbation of the carrier state.

IFN may be administered in combination with NAs. However, careful attention should be paid to possible exacerbation of hepatic dysfunction or the development of decline of blood cell count during treatment.

VI-4.3. Health care workers

Health care workers who are HBsAg-positive with HBV DNA ˃2000 IU/ml should be treated with a potent antiviral agent with a high barrier to resistance (i.e. entecavir or tenofovir), to reduce levels of HBV DNA ideally to undetectable or at least to <2000 IU/ml before resuming exposure-prone procedures.

VI-4.4. Pregnant women

In pregnant women who do not fulfill criteria for treatment of chronic hepatitis B, start oral antiviral therapy treatment during second trimester to prevent HBV perinatal transmission, and continue treatment for three months following delivery. Monitor HBV and ALT bi-monthly for at least 6 months following discontinuation of the treatment.

Pregnant women with chronic hepatitis B should be treated like none-pregnant patients.

Recommended regimen for pregnant women includes Tenofovir (Category B) or Lamivudine (Category C).

VI-4.5. Treatment of patients on Chemo/Immunosuppressive therapy

VII- Monitoring During and After Treatment and Deciding When to Stop Treatment

VII-1. Patients receiving PEG-IFN

VII-1.1. The following follow-up blood tests should be performed:

• Blood count and liver panel at 4 weeks and then every 4 to 12 weeks as required according to previous CBC.
• TSH every 12 weeks
• HBV-DNA at week 24 and 48 (optional at week 12)
• Quantitative HBsAg at week 24 (optional at week 12)
• HBeAg and Ab every 24 week in initially HBeAg positive patients

VII-1.2. On treatment stopping rules

Treatment should be stopped if there is no response.

- In HBeAg positive patients: stop treatment if

- At Week 12: there is no decline in HBsAg from baseline (any decline?) and/or HBsAg> 20000IU/ml

- At Week 24:  HBsAg>20000 IU/ml

- In HBeAg negative patients: stop treatment if

- At week 12: there is no decline in HBsAg and there is <2 log decline in HBV DNA

- At week 24: the HBsAg is >7500 IU/mL and/or there is ≤10% decline in HBsAg

VII-1.3. Monitoring after treatment discontinuation

After completion of treatment, the following blood tests should be performed:

• Complete blood count, liver panel, HBe-Ag and anti-HBe (if initially HBe-Ag positive) at weeks 12 and 24 post-treatment
• If HBe-Ag seroconversion occurs, test for HBsAb every 12 months
• HBV-DNA every 3 months for the first year

VII-2. Patients receiving NUC

VII-2.1. the following follow-up blood tests should be performed:

• Measurement of baseline renal function and assessment of baseline risk for renal dysfunction should be considered in all persons prior to initiation of antiviral therapy.
• Renal function should be monitored annually in persons on long-term Tenofovir or Entecavir therapy,
• Growth should be monitored carefully in children.
• HBV DNA every 6 months until it becomes undetectable, then every 12 months thereafter
• HBe-Ag and Ab (patient who are initially HBe Ag positive) every 12 months
• HBs-Ag every 12 months in patients HBeAg negative or patient who seroconvert from HBe-Ag positive to Anti HBeIn non-cirrhotic HBeAg positive who seroconvert to HBe-Ab, discontinue treatment  after at least 12 months of consolidation
• In non-cirrhotic HBeAg negative patients discontinue treatment after HBsAg loss (12 months of consolidation)
• In cirrhotic HBeAg positive or HBeAg negative patients or older than 60 year continue treatment until loss of HBsAg

VII-2.2. On treatment stopping rules

• Persons with cirrhosis should never discontinue NUC therapy
• HBV/HIV-coinfected persons initiated on therapy should also remain on long-term HBV suppressive therapy
• Discontinuation of therapy can be considered in:
  •  Sustained HBsAg loss.
  • HBeAg-positive persons who seroconvert to anti- HBe after at least 1 year of treatment consolidation, and have undetectable HBV DNA levels and normal ALT levels. These persons should be closely monitored with serum ALT and preferably HBV DNA levels immediately after and for 1 year after stopping therapy because of the high early risk of relapse.

VII-2.3. Monitoring after treatment discontinuation:

• Annual monitoring of ALT, HBeAg (for seroconversion to anti-HBe) and HBV DNA levels
• In compensated or decompensated cirrhosis, monitoring is recommended every 6 months.
• After stopping treatment, long-term monitoring is required. ALT and HBV DNA can be measured monthly for the first 3 months, then every 3 months during the first year to detect severe exacerbations.
• Retreatment is recommended if there are consistent signs of reactivation (HBsAg or HBeAg becomes positive, ALT levels increase, or HBV DNA becomes detectable again).

VII-3. Monitoring for hepatocellular carcinoma (HCC)

The risk of HCC is reduced but not eliminated with treatment. Routine surveillance for HCC with abdominal ultrasound and alpha-fetoprotein testing is recommended

- Every year for HBs Ag positive without cirrhosis

- Every six month for:

- Persons with cirrhosis, regardless of age or other risk factors

- Persons with a family history of HCC

- Persons aged over 40 years, without clinical evidence of cirrhosis, and with HBV DNA level >2000 IU/mL

VIII- Prevention of viral hepatitis, vaccination indications and vaccination protocols

VIII-1. Prevention of viral hepatitis: 

• General measures to reduce HBV transmission include
• HBV vaccination of household and sexual contacts
• Alcohol reduction to reduce disease progression
•  Individuals who are HBsAg positive should also
  • Adopt correct and consistent condom use during sexual intercourse
  • Not share razors, toothbrushes, or other personal care items
  • Not donate blood, organs or sperm
  • Follow standard universal precautions with open cuts or bleeding.

VIII-2. Who should be vaccinated?

            - All neonates

- Healthcare workers

- Sexually active individuals with multiple sexual partners and homosexual or bisexual males

- Household contacts of patients with hepatitis B

- Intravenous drug users

- Patients on chronic hemodialysis and patients requiring repeated blood or blood products transfusion

- Patients with chronic liver disease

- Immunocompromised patients

- HIV infected patients

- Prisoners

VIII-3. Vaccination protocols

VIII-3.1. At birth:

- Administer monovalent Hepatitis B vaccine to all newborns before hospital discharge.

- If mother is HBsAg-positive, administer Hepatitis B vaccine and 0.5 mL of hepatitis B immune globulin (HBIG) within 12 hours of birth.

 - If mother's HBsAg status is unknown, administer Hepatitis B vaccine within 12 hours of birth. Determine mother's HBsAg status as soon as possible and, if HBsAg-positive, administer HBIG (not later than age 1 week).

- After the birth dose, the second dose should be administered at age 1 or 2 months and the final dose should be administered no earlier than age 24 weeks.

- Administration of 4 doses of Hep B vaccine to infants is permissible when combination vaccines containing Hep B vaccine are administered after the birth dose.

VIII-3.2. In adults

- Regimen consists of 3 doses: at times 0, 1 month and 6months

-Booster in 10 years (in high risk groups)

VIII-4. Post vaccination testing for Serologic Response

- Serologic testing for immunity (anti-HBs) is not necessary after routine vaccination of adults.

- Testing after vaccination is recommended only for the following persons whose subsequent clinical management depends on knowledge of their immune status:

- Health-care workers and public safety workers at high risk for continued percutaneous or mucosal exposure to blood or body fluids

- Chronic hemodialysis patients, HIV-infected patients, and other immunocompromised patients

- Sexual partners of HBsAg-positive persons

- Infants born to HBsAg-positive mothers should be tested for HBsAg and antibody to HBsAg (anti-HBs) after completion of 3 doses of the HepB vaccine, at age 9 through 18 months.

- Testing should be performed 1-2 months after administration of the last dose of the vaccine (concentration of anti-HBs >10 mIU/mL).

IBD Guidelines

Definitions

Clinical remission:

Resolution of symptoms (stool frequency ≤ 3/day, no bleeding and no urgency)

Endoscopic remission:

Absent or minimal endoscopic lesions

No response:

No clinical improvement within 2-3 weeks of corticosteroid therapy, or up to 12 weeks of anti-TNF therapy

Relapse:

Flare of symptoms associated with evidence of inflammation as determined by CRP, fecal calprotectin, MR or CT enterography, endoscopy or ultrasound and absence of viral/bacterial infection

Recurrence:

The reappearance of lesions after surgical resection

Steroid-resistant:

Patients who have active disease despite prednisolone of up to 0.75 mg/kg/day over a period of 4 weeks

Steroid-dependent:

Patients who are either

-Unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids without recurrent active disease, or

-Who have a relapse within 3 months of stopping steroids

Treatment Algorithm for Crohn’s Disease

ULCERATIVE COLITIS

Definitions

Clinical remission:

Resolution of symptoms (stool frequency ≤ 3/day, no bleeding and no urgency)

Endoscopic remission:

Absent or minimal endoscopic lesions

Relapse:

Flare of symptoms (blood in stool, tenesmus, diarrhea) with or without evidence of mucosal inflammation and in the absence of concomitant infection

Steroid-resistant:

Patients who have active disease despite prednisolone of up to 0.75 mg/kg/day over a period of 4 weeks

Steroid-dependent: Patients who are either:

-Unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease, or

-Who have a relapse within 3 months of stopping steroids

Treatment Algorithm for Ulcerative Colitis

Mild to Moderate Distal Colitis

Mild to Moderate Extensive Colitis

Moderate to Severe Extensive Colitis

Severe to Fulminant Ulcerative Colitis

Algorithm A: Loss of Response to 1st Anti-TNF Agent

National Guidelines for Colorectal Cancer Early Detection

http://www.digitalscope.me/lsge/6a-3.pdf