Work-up and management of chronic hepatitis B in non-pregnant adults, especially in a setting with limited resources such as Pakistan's healthcare system.

1. Chronic Hepatitis B
Management in Non-
Pregnant Adults.
(THIS VIDEO/PRESENTATION DOES NOT INCLUDE HISTORY-TAKING AND
PHYSICAL EXAMINATION OF HEPATITIS PATIENTS.)
By Wajahat Sher Dil Khan

2. Work-up in a newly diagnosed patient.
Routine labs Virologic Imaging/Staging
CBC HBeAg, anti-HBe, anti-HBc Abdominal USG
LFTs HBV DNA Vibration-controlled
transient elastography
OR
RPMs, PT INR Anti-HAV (to determine
need for vaccination)
Serum fibrosis marker
panel1
Serum Albumin
• 1 APRI (AST-to-Platelet ratio index), FIB-4 and Fibrotest are blood tests that can be used as
markers of liver fibrosis. Mdcalc can be used to score and interpret the results. In clinical practice,
Fibroscan® remains the preferred choice.
• In select patients, HBV genotyping and testing for coinfection with HCV, HDV and HIV may be done.

3. NICE Guidelines
 For chronic hepatitis B, NICE recommends peginterferon alfa-2a as first-line
therapy in non-pregnant adults with compensated liver disease for both HBeAg-
positive and HBeAg-negative patients. The recommended dosage and duration is
180 micrograms once weekly as a subcutaneous injection for a total of 48 weeks.
For decompensated liver disease, NICE recommends entecavir as first-line
treatment, if there is no history of lamivudine resistance.
 See NICE guidelines for further details: https://www.nice.org.uk/guidance/cg165
 Useful links to read more on Pegasys®
https://www.medicines.org.uk/emc/product/13250/pil - gref
 https://www.ema.europa.eu/en/documents/product-information/pegasys-epar-
product-information_en.pdf

4. Peginterferon alfa-2a for Pakistan.
 An injection of Pegasys® costs around 7000 PKR, which makes it financially
inaccessible for a vast majority of the population in Pakistan. Therefore, we are
left with Tenofovir, listed as second-line therapy by NICE, as the subsequent
optimal choice.

5. AASLD Guidelines.
 Unlike NICE, which designates PEG-IFN alfa-2a as first-line and tenofovir or
entecavir as second-line, AASLD guidelines list PEG-IFN alfa-2a, tenofovir
depovoxil fumarate, tenofovir alafenamide and entecavir as “preferred
drugs.” AASLD guidelines list Adefovir, Lamivudine and Telbivudine as “non-
preferred drugs.”
 The discussion in succeeding slides, unless stated otherwise, will adhere to
principles outlined by AASLD guidelines.

6. Treatment recommendations.
 Adults with immune-active chronic hepatitis B, i.e.
 ALT > 2 times upper limit of normal or significant histologic disease.
 HBeAg negative and HBV DNA > 2000 IU/mL - OR - HBeAg positive and HBV DNA >
20,000 IU/mL.
Administer antiviral treatment
 All adults with evidence of cirrhosis, irrespective of ALT level, HBV DNA or HBeAg
status are offered treatment.

7. Treatment recommendations cont.
 Adults with immune-tolerant chronic hepatitis B (HBeAg-positive, noncirrhotic
patient), i.e.
1. ALT level <30 IU/L for men and <19 IU/L for women + active viral replication
Antiviral treatment is not recommended.1
1The AASLD recommends obtaining ALT levels at least every 6 months to monitor
potential transition to immune-reactive or –inactive chronic hepatitis B. Monitor ALT
every 3 months if there is an increase in ALT levels.

8. Treatment recommendations cont.
 Noncirrhotic patients with HBeAg-positive immune-active chronic hepatitis B who
seroconvert to anti-HBe on nucleos(t)ide analog (NA) therapy:
 After a period of treatment consolidation (treatment for ≥12 months in the setting of
persistently normal ALT and undetectable serum HBV DNA), consider discontinuing NA
therapy (conditional recommendation: Noncirrhotic patient/compensated liver disease.)
Monitor every 3 months for a minimum of 1 year for recurrent viremia, ALT flares,
seroeversion and clinical decompensation. Do not stop treatment in patients with
cirrhosis, even after seroconversion.
 For cirrhotic HBeAg-positive patients who seroconvert to anti-HBe on NA therapy,
AASLD recommends indefinite treatment.

9. Treatment recommendations cont.
 For select patients older than 40 years, the AASLD suggests antiviral therapy in
the setting of normal ALT levels, elevated HBV DNA (≥1,000,000 IU/mL) and
significant necroinflammation or fibrosis on liver biospy specimens.
 In adults with compensated cirrhosis and low levels of viremia ( < 2000 IU/mL),
regardless of the ALT level, the AASLD recommends commencing antiviral
therapy.

10. Treatment recommendations cont.
(HBeAg negative patient)
 Adults with HBeAg-negative immune-active (ALT > 2 ULN and HBV DNA > 2000
IU/mL) chronic hepatitis B:
 AASLD suggests indefinite treatment. If treatment is stopped for some reason, monitor
every 3 months for a minimum of 1 year for recurrent viremia, ALT flares and clinical
decompensation.
 Adults with HBeAg-negative immune-control phase defined as ALT < 30 IU/L in
males or < 19 IU/L in females, and HBV DNA < 2000 IU/mL: Monitor ALT and
HBV DNA every 48 weeks. (NICE)
Antiviral therapy is not recommended

11. Treatment recommendations cont.
(Decompensated cirrhosis)
 For decompensated cirrhosis, the AASLD suggests indefinite antiviral therapy
(preferred: tenofovir or entecavir, regardless of HBV DNA, HBeAg status or ALT
level.

12. Some key points
 To detect persistent viremia and virologic breakthrough, the AASLD suggests
monitoring HBV DNA level every 3 months until they are undetectable, followed
by every 3-6 months thereafter. Continue treatment for ≥ 12 months after undetectable
levels are achieved – ‘treatment consolidation.’
 If NA therapy with a drug other than tenofovir or entecavir is used and virologic
breakthrough occurs, switch to another antiviral monotherapy with a high genetic
barrier to resistance or add a second antiviral with a complementary resistance profile.
 Patients with transiet elastography score of ≥ 11kPa are very likely to have cirrhosis.
Between 6-10, the degree of fibrosis cannot be predicted accurately. Those with score
of less than 6 are unlikely to have significant fibrosis.
 Elastography, FIB-4, FibroTest and APRI are some of the noninvasive tests for
measuring detecting cirrhosis. Liver biospy is an invasive procedure.

13. Some key points (cont.)
 Video on how FibroScan® works:
https://www.youtube.com/watch?v=J97lWzEeO2Q

14. Treatment failure
 For patients with persistent low-level viremia (< 2000 IU/mL) (plateau in the
decline of HBV DNA and/or failure to achieve undetetacble level after 96 weeks
of therapy) on entecavir or tenofovir monotherapy, the AASLD suggests
continuing monotherapy, regardless of the ALT level.
 For patients with virologic breakthrough (an increase in HBV DNA by >1 log
compared to nadir or HBV DNA ≥ 100 IU/mL in those on NA therapy with
previously undetectable levels (<10 IU/mL), either (1) switch to another antiviral
therapy with a higher barrier to resistance or (2) add a second antiviral drug that
lacks cross-resistance.

15. Tenofovir disoproxil fumarate
 Dosage for chronic hepatitis B: 300 mg orally once daily.1 (BNF states the dosage as 245 mg once
daily.)
 Monitoring requirements2: Test renal function and serum phosphate (especially in CKD pateints)
before starting treatment, then every 4 weeks (more frequently if at increased risk of renal
impairment) for 1 year and then every 3 months. Interrupt treatment if renal function deteriorates3
or serum phosphate decreases.
 Consider baseline and during-treatment bone density scans for those with a fracture history or at
risk for osteopenia.
1For tablet form. Dosage for granules is different. Adjust dose if renal impairment - see medscape.
https://reference.medscape.com/drug/viread-tenofovir-df-342633
2As stated in the BNF.
3Monitored with creatinine clearance. Urine glucose and urine protein may also be checked.

16. Tenofovir disoproxil fumarate (cont.)
 Treatment duration: There is no specific durartion of treatment for nucleos(t)ide
analog therapy. The primary treatment goals are to prevent disease progression,
paricularly to cirrhosis, liver failure and HCC. This is accomplished by achieving
undetectable HBV DNA levels. Treatment is usually continued for ≥ 12 months
after undetectable levels are achieved – see slide “some key points.”
 Failure to achieve undetectable HBV DNA level by 96 weeks of therapy is an
indication for reconsidering treatment strategy – see slide “treatment failure.”