Hepatitis B: Update 2022 and

beyond
Robert Gish MD, FAASLD, AGAF, FAST
Robert G Gish Consultants LLC – Principal
Hepatitis B Foundation - Medical Director
Adjunct Professor of Medicine:
University of Nevada Las Vegas
University of Nevada Reno
UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences
Disclosures

• See robertgish.com

• Resources are also at robertgish.com for HBV and all forms of liver
disease

• Please subscribe to my newsletter via my website

 Objectives
• Describe the epidemiology and virology of
hepatitis B and how this links to testing

• Summarize the natural history of hepatitis B

• Recommend screening for HBV: Test all adults

with triple panel

• Facts and Fictions of HBV

• Treatment options for HBV: Consider to treat

all HBV DNA+

• Vaccination: Current discussions

 Hepatitis B Virus (“Hepadnavirus”)

•DNA virus
• Other hosts for
hepadnaviruses include
woodchucks, Peking ducks,
ground squirrels, herons,
and more
• HBV replicates through an
RNA intermediate and can
integrate into the host
genome
•Eight HBV genotypes, A- H

Courtesy of: Oligonucleotide Therapeutics Society

 Tremendous Medical Need

270 million in 2021

HBV Disease Progression
 HBV Tests Part I:
All patients need this “triple panel”
when evaluating for HBV

• +HBsAg = infection (Test all patients for HDV)

• +Anti-HBc = exposure = cccDNA = persistence

– Evaluate for Occult HBV (OBI) if HBsAg (-)
– Educate about reactivation risk
– No HBV vaccine boosting recommended

• +Anti-HBs = vaccine immunity, if anti-HBc is negative

(if anti-HBc+ “immune control”)

• Note:
– HBV is incurable

– There is no “natural immunity”

 HBV Tests Part II:
for patients who are HBsAg+
All HBsAg + patients need • CMP, Liver panel with liver
these tests: enzymes and liver function,
• HBeAg CBC including platelets
• Anti-HBe • AFP/DCP AFP-L3% and
calc GALAD score
• HBV DNA quant
• NASH assessment by
• Quant/HBsAg
imaging
• HCV antibody
• US doppler with spleen and
• HAV antibody total PV size
• HIV antibody • Elastography with CAP
• HDV antibodyIgG (not IgM)
• APRI/FIB4
(IF IgG +)>> qHDV RNA
reflex
Evaluating the HBsAg + Patient Part III
• ALT/AST : calc ratio
• Liver biopsy only if mixed
• Family History of HCC
picture of other diseases such
and/or cirrhosis
as NASH or AIH
• Alcohol history and current
– Consider if other noninvasive
use, PETH testing tests are inconclusive
• Renal function • Advanced Serum maker panels
• Bone DEXA of fibrosis and inflammation

• Pregnancy testing if
appropriate
• Family testing for HBsAg,
anti-HBs, and anti-HBc
A focus here on the OLD NAMES
 Determination of
Hepatitis B
Phenotype Using
Biochemical and
Serological Markers

J Viral Hepat. 2017 Apr; 24(4): 320–329. doi: 10.1111/jvh.12643

Adrian M. Di Bisceglie,1 Manuel Lombardero,2 Jeffrey Teckman,1 Lewis
Roberts,3 Harry L. A. Janssen,4 Steven H. Belle,2 Jay H. Hoofnagle,5 and for
the Hepatitis B Research Network (HBRN)6
 REVEAL-HBV: HBV DNA Levels and
Long-term Outcomes
HBV DNA at Study Entry, copies/mL
< 300
300-9999
10,000-99,999
100,000-999,999
≥ 1 million

HCC After 13 Yrs 40 Cirrhosis After Mean 11 Yrs

20 (N = 3653)[1] (n = 3582)[2] 36.2
30

Cumulative Incidence (%)

Cumulative Incidence (%)

15 14.89 30
12.17 25 23.5

10 20

15
10 9.8
5
3.57 5.9
5 4.5
1.30 1.37
0 0

1. Chen. JAMA. 2006;295:65.

2. 2. Iloeje. Gastroenterology. 2006;130:678. Slide credit: clinicaloptions.com
 Quantitative HBsAg Levels and Risk
for HCC
HBsAg Level, IU/mL Relative Risk 95% CI
Tseng et al[1]
< 10 1.0
10-99 1.1 0.3-4.2
100-999 2.3 0.7-7.3
1000-9999 3.2 1.0-10.0
≥ 10,000 2.9 0.9-9.5
Lee et al[2]
< 100 1.0
100-999 3.2 1.7-6.1
≥ 1000 5.4 3.0-9.9

qHBsAg can also be used for establishing phase of HBV disease, infectivity, risk of cirrhosis,
Natural history of disease, risk of liver cancer, treatment response

1. Tseng. Gastroenterology. 2012;142:1140.

2. 2. Lee. Hepatology. 2013;58:546. Slide credit: clinicaloptions.com
 Progression of Fibrosis in Viral Hepatitis on
Biopsy (Metavir)

No Fibrosis Stage 1 Stage 2

Fibrous expansion of Fibrous expansion of most

some portal areas portal areas with occasional
portal to portal bridging

Stage 3 Stage 4

Fibrous expansion of portal areas

with marked bridging (portal-to-portal
Cirrhosis Cirrhotic
and portal-to-central) Liver

Faria SC, et al. Radiographics. 2009;29:1615-1635. Adapted from Everson GT.

 Rationale for Prompt Identification of
HBV-Infected Persons: Test all adults
Implement important interventions to reduce morbidity and mortality
– Clinical evaluations to detect onset and progression of HBV-related liver disease
• HBV DNA, HBeAg, ALT, HCC biomarker panel, imaging, APRI, FIB-4, transient
elastography

– Antiviral therapy can delay or reverse progression of liver disease

– Detect HCC at a potentially treatable stage with baseline AFP and periodic
ultrasound/biomarker surveillance
– Stop transmission

– Implement interventions to reduce progression of liver injury

• Hepatitis A vaccination

• Counseling to avoid excessive alcohol use

• Manage MAFLD

Adapted from Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Chaiteerakij R, et al. Clin Gastroenterol Hepatol. 2015;13:237-245.
 WHO Hepatitis Elimination Targets

WHO. Combating Hepatitis B and C to Reach Elimination by 2030. Geneva, Switzerland: WHO, 2016.
 Occult HBV Infection/Viremia and
Occult HBV
• Occult HBV infection/viremia
– Presence of HBV DNA in the liver (+ detectable serum HBV DNA) of individuals testing
HBsAg negative by currently available assays, most patients are anti-HBc positive

• Occult HBV is the preferred term when the level of infectivity can not be
established
– Detection of HBV DNA does not always correspond to infectivity or to the number of
progeny viruses released from hepatocytes
– Prevalence varies significantly between geographic regions, various patient populations
tested, and type of routine screening assay used

– Detection requires assays with a lower limit of detection of <10 IU/L for HBV DNA and
<0.1 ng/mL for HBsAg
– Relatively common among HCV-infected patients

– Transmission via solid organ transplantation or transfusion has been reported

– Reactivation can occur with immunosuppression or intensive cytotoxic chemotherapy

Torbenson M, et al. Lancet Infect. 2002;2:479-486.

Hollinger FB, et al. J Viral Hepat. 2010;17:1-15.
 Natural History of HBV and
Treatment Indications
HBeAg Positive HBeAg Negative Resolved HBV
Parameter
Chronic Infection Chronic Hepatitis Chronic Infection Chronic Hepatitis infection
Old Immune Immune reactive Inactive HBeAg negative HBsAg negative,
terminology tolerant HBeAg positive carrier chronic hepatitis anti-HBc positive
HBsAg High High/intermediate Low Intermediate Negative
HBeAg Positive Positive Negative Negative Negative
HBV DNA > 107 IU/mL 104 to 107 IU/mL < 2000 IU/mL* > 2000 IU/mL Undetectable
ALT Normal Elevated Normal Elevated† Normal
Liver disease None/minimal Moderate/severe None Moderate/severe None
Disease
Low Moderate to high Low Moderate to high None (HCC)
progression
Treatment Not indicated‡ Indicated Not indicated Indicated Not indicated§
*HBV DNA levels up to 20,000 IU/mL can occur without signs of chronic hepatitis. †Persistently or intermittently. ‡Treatment is indicated in some
patients. §Prophylaxis for select cases.

EASL. J Hepatol. 2017;67:370. Slide credit: clinicaloptions.com

 Timeline for drug HBV development

First line agents

Peginterferon alfa-2a

Entecavir Tenofovir
Lamivudine (ETV) DF (TDF)

1991 1998 2002 2005 2006 2008 2016

Interferon alfa-2b Adefovir Telbivudine

Tenofovir
Alefenamide (TAF)
 TDF versus TAF: What is the Difference?
TDF TAF
• Tenofovir disoproxil fumarate • Tenofovir alafenamide
• 300 mg tenofovir • 25 mg tenofovir
• Less efficient delivery to liver • More efficient delivery to liver
• Greater systemic exposure • Less systemic exposure
• Equivalent antiviral efficacy • Equivalent antiviral efficacy
Indications for Selecting ETV or TAF Over TDF*

• In some circumstances ETV or TAF may be a more appropriate treatment choice

than TDF

Age • >60 years

• Chronic steroid use or use of other medications
that worsen bone density
Bone disease
• History of fragility fracture
• Osteoporosis
• eGFR <60 ml/min/1.73 m2
• Albuminuria >30 mg/24 h or moderate dipstick
Renal alteration† proteinuria
• Low phosphate (<2.5 mg/dl)
• Haemodialysis
*TAF should be preferred to ETV in patients with previous exposure to NAs; †ETV dose needs to be adjusted if eGFR <50 ml/min; no dose adjustment of TAF is required in adults or
adolescents (aged ≥12 years and ≥35 kg body weight) with estimated CrCl ≥15 ml/min or in patients with CrCl <15 ml/min who are receiving haemodialysis.
EASL CPG HBV. J Hepatol. 2017;67:370–98.
Treatment Endpoints

HBeAg+ HBeAg-

HBeAg loss or
No HBeAg loss
seroconversion

Stop >12 Treat

Continue Indefinitely - Until
months later
HBsAg loss
Many experts Viremia will recur Some consider
prefer if therapy stopping >5 years
≥3 years later stopped for certain
patients
• Can stop therapy if HBsAg clearance documented for ≥6 months
• Late reappearance of HBsAg very uncommon even without anti-HBs
 Definitions Of HBV Cure:
How Much of a Difference in Functional Cure?
Integrated
HBsAg Anti-HBs Viremia cccDNA HBV DNA

Inactive + - - + +
carrier
Functional - + - + +
cure
Complete - + - - +
cure
Complete
“sterilizing”
cure - + - - -

The next leap forward(?) Not even close!

Current NA treatment is extremely effective, save and increasingly
cheap, and has revolutionized medicine

Virus suppression

Decreased inflammation/fibrosis
Decreased cirrhosis incidence
Decreased HCC incidence
Decreased mortality

Liaw YF et al, N Engl J Med. 2004; Chang et al, Hepatology 2010; Marcellin et al, Lancet 2013;
Hosaka et al, Hepatology 2013; Kim et al, Cancer 2015; Papatheodoridis et al, J Hepatol 2015
 Proportion of Patients Outside the International
Treatment Criteria Developing HCC
Korean retrospective cohort study conducted in 3,624 treatment-naive CHB patients (median
follow-up: 4.6 years)

HCC developed outside treatment criteria HCC developed within treatment criteria

100
Proportion of patients

80 33.5
46.0
64.0
60
Fewer patients developed
(%)

HCC with less stringent 40

EASL 2017 criteria 66.5
54.0
20 36.0
0
EASL 2017 AASLD 2018 APASL 2015
Proportion of patients developing HCC
who were outside or within treatment criteria

Sinn et al. J Viral Hepat. 2019

RETRACT-B Study: Long Term Outcomes After Stopping
Nucs and a Treatment Algorithm Based on qHBsAg

Hepatic decompensation after NA cessation:

• With cirrhosis: 4.3%
• Without cirrhosis: 0.8% patients

Hirode G et al, Gastroenterology 2021;https://doi.org/10.1053/j.gastro.2021.11.002

 Untreated ‘Immune-Tolerant’ Patients have a
Significant Risk for Morbidity and Mortality

Untreated patients (n=413) Treated patients (n=1497)

• Immune tolerant phase • Immune active phase
• HBV DNA ≥20,000 IU/mL • ALT levels ≥80 IU/mL
• No evidence of cirrhosis • Treated with NAs
• Normal ALT levels*

12.7% 2.54 x 6.1% p=0.001

increased risk
10-year risk of HCC

9.7% 3.38 x 3.4% p<0.001

increased risk
10-year risk of death/transplantation
Percentages represent estimated cumulative incidence. *Normal ALT females, <19 IU/mL and males, <30 IU/mL

Kim GA, et al. Gut 2018;67:945–52

 Tenofovir Disoproxil Fumarate Treatment Reduces the Number
of Transcriptionally Active Viral Integrations in CHB

Reduction in viral load with TDF is associated with

with reduced expressed viral integrations and
dysregulated genes

Similar results found by Chow et al (AASLD 2020)

Yao-Chun Hsu et al. AASLD 2020

HBV Treatment Paradigm is Changing
 HBV Vaccination
• Strategies to fight HBV infection
– Treat patients with chronic HBV infection
– Interrupting the route of transmission
– Immunize susceptible individuals
– Birth dose of HBV vaccine <24 hours from birth
preferably < 12 hours, ideally < 2 hours (With
HBIG if mother is HBsAg+)
• Vaccination is the most effective strategy to prevent
individuals from contracting HBV infection
• Preferred vaccine is Heplisav-B, 2 dose regimen,
great safety, efficacy and compliance

Locarnini S, et al. J Hepatol. 2015;62(suppl):S76-S86.

 HBsAg prevalence estimates:
All ages: Vaccine is making a difference
HBsAg all ages pre vaccination 1990

HBsAg all ages 2015 estimates

 Simplified: 6 Pillars of HBV
• Test all adults with triple panel
– Or consider all immigrants, all patients with unknown HBV vaccine status, all
with blood exposure
– Anti-HBc (alone or with anti-HBs)= exposure, no vaccine, educate about
reactivation risk (anti-HBc false + rate is 2/1000 in low risk patients)
• Vaccinate all adults who are triple panel negative

• Treatment Old news

– ALT over ULH (upper limits of healthy) or +fibrosis (APRI, FIB4, TE or bx) and +
DNA over 2000 = Nuc treatment
– New News: treat all HBV DNA + patients including cirhosis

• Treat until HBsAg loss + 12 months consolidation (Quant HBsAg q 12m)

• Treatment changes outcomes !

 Thank You!

Robert Gish MD, FAASLD, AGAF, FAST

Robert G Gish Consultants LLC – Principal
Hepatitis B Foundation - Medical Director
Adjunct Professor of Medicine:
University of Nevada Las Vegas
University of Nevada Reno
UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences