Hepatitis B Diagnosis and Management

Marion Peters

University of California San Francisco

COI

• Spouse works for Hoffmann-La Roche

HBV is a life long, dynamic disease

• Changes over time

• Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults

• Fibrosis can be reversible

• Drugs can decrease fibrosis progression

• HBV can be controlled but not cured

• Reactivation can occur even in those who have lost HBsAg

Prevalence of HBV in HIV-Positive and negative patients

• About 5% to 10% of anti-HCV-antibody–positive patients are HBsAg-positive

• Hepatitis C superinfection of chronic HBsAg carriers is common in HBV endemic regions, such as Southeast Asia

Fernandez-Montero JV, Soriano V. Best Pract Res Clin Gastroenterol. 2012;26:517-530.

Estimated Number of Persons Infected Worldwide, in Millions

HBV350

HIV/HCV/HBV0.5

HIV35

HCV~140

HCV/HBV15

Not to scale.

Geographic Distribution of HBV Genotypes

Ae

B,C,A,D

F2Aa

E

D

DC

B

C

GG

H

BaBjA D

B D

Greenland:

F & HF1, H

Ae, Bj, C,

D, F

A, B, D

B, A/Bj

B3

HBV

HBsAg

DNA

cAg

HBsAg

HBeAg

Dane Particle

Infectious virionSubviral particles

Hepatitis B Virus

HBV Serologic MarkersHBsAg• Acute or chronic infection • First serologic marker to appear• Infection considered chronic if

persistent for > 6 monthsHBeAg• Indicates active replication of virus • Absent if inactive or mutations developAnti-HBc total (HBcAb total)• Present in infection (IgM in acute

infection)• Present in past exposure to HBV• May occur alone when anti-HBs wanes

Anti-HBs• Recovery from HBV with anti-HBc• Detectable alone after immunity

conferred by HBV vaccination• Occasionally seen in chronic

carriers with HBsAg & anti-HBcAnti-HBe• Generally indicates virus is no

longer replicating• Present in those with HBeAg

mutations who have active disease

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

What to do with results?

HBsAg HBsAb HBcAb Management

• + - + refer to care

• - + + past infection*

• - - - vaccinate

• - + - immune (vaccinated)

* latent infection important if immune compromised or chemo BRM

HBV Control

• Inflammatory: normalize serum ALT, biopsy

• Virologic: decrease HBV DNA

• Immune: seroconversion

– HBeAg to anti-HBe

– HBsAg to anti-HBs

• HBV as of 2018 not “cured” but controlled

Who to treat

• Those with inflammation and fibrosis

– Elevated ALT and

– Elevated HBV DNA

• If not clear – Liver biopsy

EASL Guidelines 2017

J Hep 2017

HBeAg positive

Chronic infection Chronic hepatitis

HBsAg High High/intermediate

HBeAg Positive Positive

HBV DNA >107 IU/ml 104-107 IU/ml

ALT Normal Elevated

Liver disease None/minimal Moderate/severe

Old terminology Immune tolerant Immune reactive HBeAg positive

EASL Guidelines 2017HBeAg negative

Chronic infection Chronic hepatitis

HBsAg Low Intermediate

HBeAg Negative Negative

HBV DNA <2,000 IU/ml >2,000 IU/ml

ALT Normal Elevated

Liver disease None Moderate/severe

Old terminology Inactive carrierHBeAg negative chronic hepatitis

J Hep 2017

Monitoring HBV monoinfection• Serum ALT- check every 3 months at first

– If normal for one year, follow labs every 6 months

• (normal ALT <20 for women, <=30 for men)

–Older patients may have cirrhosis with normal serum ALT

• HBV DNA

– If low monitor

– If elevated consider need for therapy

• Over age 40 or family history monitor for HCC

Who should be treated

• Chronic hepatitis (elevated ALT and HBV DNA)

• Cirrhotics- any level ALT, detectable DNA

• HCC

• HIV

• On Chemotherapy or biologics

• Pregnancy – 3rd trimester if HBV DNA >200,000 IU/mL

Approved HBV treatments 2018

• Interferon alfa-2b – 1991

• Lamivudine – 1998

• Adefovir – 2002

• Entecavir – 2005

• Peginterferon alfa-2a – 2005

• Telbivudine – 2006

• Tenofovir Dipivoxil– 2008

• Tenofovir alafenamide- 2017

Long-term Entecavir Treatment Improves Liver Histology and Fibrosis

Chang TT, et al. Hepatology. 2010;52:886-893 CCO Hepatitis.

73

96

0

20

40

60

80

Histologic improvement Fibrosis improvementCoprimary Endpoints

Pati

en

ts (

%)

100

32

88

n = 41 55 158 50

Wk 48Long-term

biopsy >3y

Undetectable HBV DNA Over Time in HBeAg Negative Patients

Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006.

Extended Treatment With Nucleos(t)ide Analogues vs

1 Yr Peginterferon Treatment

Not head-to-head trials; different patient populations and trial designs

Entecavir

Tenofovir

Peginterferon

Un

dete

cta

ble

HB

V D

NA

(%

)

90 93 8791

1 Yr 2 Yrs 3 Yrs

100

80

60

40

20

0

63

15 16

NA

100*

*Single center study.

96

HBsAg Loss Over Time in HBeAg Positive Patients

Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129; Marcellin Gastro 2016

Not head-to-head trials; different patient populations and trial designs

Extended Treatment With Nucleos(t)ide Analogues*

vs 1 Yr Peginterferon Treatment

HB

sA

g L

oss (

%)

2 3 66

100

80

60

40

20

05 88

NA

Entecavir

Tenofovir

Peginterferon

*With sustained undetectable HBV DNA.1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs

5

TDF +PEG 1y 9.3%37.5% geno A

Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683.Marcellin Gastro 2016

HBsAg Loss Over Time in HBeAg Negative Patients

Extended Treatment With Nucleos(t)ide Analogues*

Vs 1 Yr Peginterferon Treatment

Not head-to-head trials; different patient populations and trial designs

Pati

en

ts (

%)

< 1 04

0

100

80

60

40

20

0< 1

9

NA 07

1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs*With sustained undetectable HBV DNA.

Entecavir

Tenofovir

PeginterferonTDF +PEG 1y 5%33% geno A

Types of HBV cureFunctional Cure- clinical

resolutionSustained, off drug:• No inflammation: ALT and

liver biopsy• HBsAg loss• Anti-HBs gain

Complete cure- virological cure• All of above plus• Loss of cccDNA in liver

Inactive state -an interim goal?• No inflammation: ALT and

liver biopsy• HBV DNA low or u/d• HBsAg positive

Viral Life Cycle

ER Budding

Plus strand

synthesis

Minus strand

synthesis

RNApackaging

(encapsidation)Translation

Transcription

Repair

Recycling

Entry

cccDNANucleus

Host RNA pol

Reverse transcriptase

P proteinpre-genomic RNA

S, C, P,e synthesis

HBsAg pos

Viral Life Cycle- “latent or recovered” HBV

ER

cccDNA

Nucleus

HBsAg negAnti-HBsAnti-HBc

Immune system considers this “recovered”BUT cccDNA is template for viral replication

Patients on Immunosuppressive TherapyThere is a high rate of HBV reactivation in immunosuppressed patients:

▪ During chemotherapy

▪ In HIV patients after immune reconstitution

▪ After organ transplant and stem cell transplant

▪ With biologic response modifiers: Rituximab (anti-CD20), TNF-α inhibitors

▪ Rituximab/ stem cell transplant the most potent reactivator of HBV

▪ Prophylax if anti-HBc without HBsAg

All patients should be tested prior to chemotherapy for:

HBsAg, anti-HBs and anti-HBc

Loomba R, et al. Ann Intern Med. 2008;148:519-528;Dong J. Clin Virol. 2013.

Patients on Immunosuppressive Therapy

▪ All patients who are to receive immunosuppressive therapy should be tested for HBsAg and anti-HBc and anti-HBs

▪ If HBsAg positive, initiate antiviral therapy before IS

▪ If anti-HBc positive but HBsAg negative:

▪ Anti-HBV therapy should be administered preemptively for rituximab or stem cell transplant

▪ Consider preemptive anti-HBV therapy for other forms of chemotherapy or close monitoring of HBV DNA if anti-HBV therapy not given

Loomba R, et al. Gastro 2017

HCC and HBV• Increased risk of progression/HCC shown in:

– male sex – younger age of infection – Excess alcohol consumption, NAFLD– High hepatitis B DNA levels (over age 40 years)– Co-infections with HIV, HCV and HDV– Hepatitis B virus genotype C, Aa

• Screen with 6 monthly ultrasound and AFP– If lesion CT or MRI to determine if HCC

McMahon Hep 2009; MMWR Recomm. Rep. 2005;54:1-31Lancet. 2014;384:2053-2063.

Arterial Phase Portal Venous phase

Enhancement “washout”

HCC - RADIOLOGIC CHARACTERISTICSQUAD-PHASE CT OF THE ABDOMEN

Baseline HBV DNA and HCCREVEAL study cohort 3,582

Cu

mu

lati

ve i

ncid

en

ce o

f H

CC

(%)

Year of follow-up

HBV DNA (copies/mL)106

105–<106

104–<105

300–<104

<300

40 1 2 3 5 6 7 8 9 10 11 12 13

14

10

6

4

2

0

16

12

8

14.89%

12.17%

3.57%1.37%

1.30%

Chen et al. JAMA 2006

Relative Risk (95% CI)

10.7 (5.7–20.1)

8.9 (4.6–17.5)

2.7 (1.3–5.6)1.0 (0.5–2.2)1.0 (ref

pink)

Age 45, Male 61%, ALT>45 6%, HBeAg-positive 15%

HCC and HIV survival: 6 monthly AFP and ultrasound

2 yr survival HIV + HIV- p value

• Puoti (R 41) 11% 41% 0.01

• Brau (R 63) 16% 18% 0.6

• Berretta (R 104) 69% 72% 0.048

• Lim (P 23-TB) 44% 60% 0.2

• All note younger age in HIV+ but other factors not common

AIDS 2004; J Hepatol 2007; oncol 2011; JAIDS 2012

HBV and HIV• HIV increases HBV chronicity

• HBV increases antiretroviral-related hepatotoxicity

• HIV/HBV coinfection increases the risk of end stage liver disease compared to HBV alone

• HIV HBV coinfected patients have poorer hospital outcomes, more progression to cirrhosis, HCC and death than either HIV or HBV monoinfected patients

Thio CL, et al. Lancet. 2002: Koziel NEJM 2007; Rajbhandari J Viral Hepat 2016

HBV-HIV Summary

• Immune response predicts HBV outcome

• Flares in HBV/HIV patients are common– Many HIV medications are hepatotoxic

– Other causes of ALT elevations in HBV/HIV should be sought

– Less common causes of flares now are ART without HBV therapy and stopping ART

• Atypical serologies may occur in HIV patients during ART– Reverse seroconversion occurs

• All HBV HIV patients require screening for HCC

Treatment of HBV in Pregnancy

Terrault Hepatology 2016; Zhang. Hepatology. 2014.

Summary▪ Treat if elevated ALT and HBV DNA (and special

considerations)

▪ Comorbidities occur in patients with HBV▪ Check HIV, HCV, HDV, HAV, MS

▪ HBV patients should report to their primary care provider of any

new diagnoses or planned therapies so that considerations for

HBV antiviral therapy can be made, particularly

▪ If receiving high-dose steroids, chemotherapy, or rituximab

▪ If pregnant or wishing to become pregnant

▪ Screen for HCC with 6 monthly imaging and ALF

Strategies to Eradicate HBVVirologic approaches

• Entry inhibitors

• Block cccDNA

• Transcription inhibitors

• RNA interference

• HBV capsid inhibitor

• polymerase inhibitors

• Secretion inhibitors

Host immune approaches

• Interferons• TLR-7• PD-1/ PDL-1• IL-7• Therapeutic vaccines

– Immune complex vaccines

– Nasal HBV (NASVAC) vaccines

– DNA vaccines

– T cell vaccines

– Adenovirus based vaccines (TG1050)

– Yeast based vaccines

RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles

Intracellular Conversion Pathway

cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA

Pre-S1 mRNA Pre-S2/S mRNA

HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION

Precore Protein (p25)

HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION