NCCVH Guidelines for the Management
of Patients with HBV Infection
June 2022
1. Initial Assessment of Patients with Chronic HBV Infection
- Clinical assessment (history/physical examination)
- Laboratory investigations:
- ALT
- AST
- CBC
- Random blood sugar
- Serum total bilirubin
- Serum albumin
- PT and INR
- Serum phosphorus
- Serum creatinine, and estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI equation
- Anti-HCV
- Anti-HIV
- HBeAg
- Quantitative HBV DNA serum level
- AFP
- Abdominal ultrasound
- Transient elastography (TE):
- It is only recommended if:
- HBV DNA ≥ 2,000 IU/ml + normal transaminases,
- HBV DNA < 2,000 IU/ml + elevated transaminases, or
- HBV DNA < 2,000 IU/ml + normal transaminases + imaging suggestive of liver cirrhosis.
- If it is not available in the treatment center, FIB-4 can be used.
2. Patients who should be treated:
HBV DNA (IU/ml) |
ALT |
Other Factors |
≥ 2000 |
> ULN |
Negative HBeAg |
≥ 20000 |
> ULN |
Positive HBeAg |
≥ 2000 |
Persistently normal |
Positive HBeAg and age > 30 years |
< 2000 |
> ULN |
TE > 7 kPa, or FIB4 > 1.45 |
≥ 2000 |
Normal |
TE > 7 kPa, or FIB4 > 1.45 |
Any |
Any |
- Family history of HCC,
- cirrhosis (FIB4 > 3.25, or TE > 12 KPa),or
- severe extra-hepatic manifestations(documented by specialty consultation)
|
ULN, upper limit of normal.
3. Treatment Strategies
a. Treatment-naïve patients:
- Tenofovir disoproxil fumarate (TDF) 300 mg once daily, tenofovir alafenamide (TAF) 25 mg once daily, or entecavir (ETV) 0.5 mg once daily.
- ETV or TAF is preferred in patients over 60 years or with bone disease (chronic steroid use or use of other medications that worsen bone density, osteoporosis).
b. Treatment-experienced patients:
- Patients on lamivudine (LAM): shift to TDF 300 mg once daily or TAF 25 mg once daily.
- Patients on combined LAM and adefovir: shift to TDF 300 mg once daily or TAF 25 mg once daily.
c. Treatment failure:
- Primary non-response: < 1 log10 decrease in HBV DNA after 3 months of therapy.
- Partial virological response: HBV DNA decreased by > 1 log10, but still detectable after ≥ 12 months of therapy.
- Virological breakthrough: HBV DNA increase of > 1 log10 above on-therapy lowest level.
- Compliance should be confirmed.
- ETV should not be used in LAM experienced patients.
Resistance/failure |
Recommended strategies |
LAM |
Switch to TDF or TAF |
ETV (very rare except in patients withprevious LAM failure) |
Switch to TDF or TAF |
ADV |
• If LAM-naive: switch to ETV or TDF or TAF • If LAM-failure: switch to TDF or TAF |
TDF or TAF (very rare if any) |
• If LAM-naive: switch to ETV • If LAM-failure: add ETV |
Multidrug |
Switch to ETV + TDF or TAF |
ADV, adefovir; ETV, entecavir; LAM, lamivudine; TDF, tenofovir disoproxil
fumarate TAF tenofovir alafenamide.
Follow-up of patients with chronic HBV
a. Currently on treatment
- Every month: to receive medication and monitor for compliance and side effects.
- Every 3 months during the first year, and every 6-12 months thereafter:
- ALT
- AST
- Serum total bilirubin
- Serum albumin
- PT and INR
- Quantitative serum HBV DNA level
- AFP
- Abdominal ultrasound
- Serum phosphorus
- Serum creatinine and eGFR
- Closer renal monitoring is required in patients who develop eGFR < 60 ml/min or serum phosphorus levels < 2 mg/dl
- Long-term follow-up: HCC surveillance for all patients under effective long-term nucleos(t)ide analogue (NA) therapy (AFP, U/S every 4 months).
b. Currently not on treatment
- Every 6 months:
- ALT
- Quantitative serum HBV DNA
- AFP
- Abdominal ultrasound
- Every 2 years: TE or FIB-4 to assess liver fibrosis.
5. NAs discontinuation rules
|
Discontinuation strategy |
No cirrhosis |
|
Positive HBeAg |
HBeAg seroconversion and undetectable HBV DNA after: • 12 months of consolidation therapy, • 3 years of continuous treatment, and • age > 40 years |
Negative HBeAg |
Indefinitely, or until HBsAg seroconversion and after 12 months of consolidation treatment |
Cirrhosis |
Do not stop anti-viral therapy |
Special groups:
a. Acute Infection
- Antiviral treatment is indicated in patients with acute liver failure or who have a severe course indicated by the presence of 2 out of the following 3 criteria:
- serum total bilirubin > 10 mg/dl
- INR > 1.6
- encephalopathy
- Entecavir 0.5 mg daily for:
- at least 6 months after seroconversion to anti-HBs, or
- at least 12 months after seroconversion to anti-HBe without HBsAg loss.
b. Liver Cirrhosis
All patients with cirrhosis should receive oral antiviral therapy if HBV DNA is detectable.
- Compensated cirrhosis: ETV 0.5 mg or TDF 300 mg or TAF 25 mg once daily.
- Decompensated cirrhosis: ETV 1 mg once daily.
- The dose of antiviral therapy needs to be adjusted in patients with low creatinine clearance (< 50 ml/min).
c. Co-infection with other viruses
HBV/HCV co-infection
- Treatment of HCV with DAAs may cause reactivation of HBV.
- Patients fulfilling the standard criteria for HBV treatment should receive NA:
- Patients with positive HBsAg undergoing DAA therapy should be considered for concomitant NA prophylaxis and continue until 12 weeks after completion of DAA, then re-evaluated.
- Patients with negative HBsAg and positive anti-HBc undergoing DAA therapy should be monitored (and tested for HBV reactivation in case of ALT elevation) every 4 weeks during treatment.
HBV/HIV co-infection
- All HIV-positive patients with HBV co-infection should start antiretroviral therapy (ART):
- irrespective of CD4 cell count.
- with a TDF or TAF-based ART regimen.
HBV/HDV co-infection
- Should be suspected if there is:
- re-rise of serum transaminases (double peak pattern) in acute viral hepatitis B.
- on-treatment with unexplained increase of transaminases.
- failure to achieve virologic response with potent NAs.
- Active HDV infection should be confirmed by HDV RNA assays.
- Peg-INFα is the only effective drug against HDV.
- Optimal duration of therapy is at least 48 wks.
- Oral antiviral therapy for HBV should be considered in patients with:
- HBV DNA levels persistently > 2,000 IU/ml.
- evidence of advanced liver disease.
d. Pregnancy
- All pregnant females should be screened for HBsAg in the first trimester and if negative, they should be vaccinated (test anti-HBc IgG and anti-HBs).
- Criteria for NA use during pregnancy:
- HBV DNA level ≥ 200,000 IU/ml at the end of the second trimester:
- TDF (class B drug) 300 mg once daily should start at gestational week 24-28, and
- continue to 12 weeks after delivery, then re-evaluate.
- Females who become pregnant while on treatment: continue or shift to TDF.
- FIB-4 > 1.45 (if not already on treatment): start TDF 300 mg once daily.
- Pregnant women not fulfilling the criteria for NA use should be followed during pregnancy and after delivery for HBV reactivation.
- Cesarean section does not decrease chances of MTC transmission compared to normal delivery and is not indicated to reduce this chance.
- Newborns for chronic HBV mothers should receive hepatitis B immunoglobulin (HBIG) and the first dose of HBV vaccine at birth (6-12 hours after delivery).
- Breastfeeding is not contraindicated in mothers who are HBsAg-positive and untreated or on TDF.
e. Renal impairment, dialysis and renal transplantation
All dialysis and renal transplant recipients should be screened for HBsAg.
- Seronegative patients should be vaccinated.
- TAF is preferred in naïve patients.
- Patients who were already on TDF or ETV, should shift to TAF.
- No TAF dose adjustment is needed in patients with eGFR ≥ 15 ml/min or in those who are on hemodialysis.
- In patients with LAM failure or decompensated cirrhosis, ETV is used with dose adjustment according to eGFR as follows:
- eGFR (ml/min) Entecavir dose
- ≥ 50 1 mg / day
- 30 - 49 1 mg / 2 days
- 10 - 29 1 mg / 3 days
- < 10 or on hemodialysis 1 mg / week
eGFR (ml/min) |
Entecavir dose |
≥ 50 |
1 mg / day |
30 - 49 |
1 mg / 2 days |
10 - 29 |
1 mg / 3 days |
< 10 or on hemodialysis |
1 mg / week |
• In patients undergoing dialysis, ETV (once weekly) and TAF should be given
after the dialysis session.
f. Immunosuppressed patients
- All candidates for chemotherapy and immunosuppressive therapy should be screened for HBsAg, anti-HBs, and anti-HBc prior to initiation of treatment.
- Vaccination is mandatory for seronegative patients. Higher vaccine doses may be needed.
HBsAg |
Other conditions |
Strategy |
Positive |
Irrespective of the viral load |
NA at the onset of chemotherapy and for 12 months after cessation of treatment |
Negative |
Anti-HBc positive, and HBV DNA positive |
Anti-HBc positive, and HBV DNA negative |
• Follow-up every 3 months. • Start NA if DNA becomes positive. |
NA, nucleos(t)ide analogue.
g. Liver Transplantation
- Pre-transplant: All patients with HBV who are candidates for liver transplantation should receive an NA to achieve undetectable HBV DNA and reduce the risk of graft infection.
- Post-transplant: Combination of hepatitis B immunoglobulin (HBIG) and a potent NA is recommended to prevent HBV recurrence.
- Patients with a low risk of recurrence can discontinue HBIG but need continued monoprophylaxis with a potent NA.
- HBsAg-negative patients receiving livers from donors with evidence of past HBV infection (anti-HBc positive) are at risk of HBV activation and should receive antiviral prophylaxis with NA.