Update in the Management of Chronic Hepatitis B

Professor of Medicine Division of Gastroenterology and Hepatology

Department of Medicine, NYU Langone HealthNew York University School of Medicine, New York, USA

Calvin Q. Pan MD, FAASLD, FACG, MACP

12TH ANNUAL GASTROENTEROLOGY & HEPATOLOGY SYMPOSIUM, Saturday, February 28-29, 2020 , Anaheim, CA

Company Name DisclosuresGilead Sciences, Inc Advisory Committees, Consulting, Speaker, and

Grant/Research Support

2

Disclosures

3

Outline

What is new in testing for HBV

Whom to treat in 2020

Current therapy and clinical cure

New promising approaches

Potential Diagnostic Markers for Treatment Response and HBV Cure

Lok AS, et al., J Hepatol. 2017 Jul 21. pii: S0168-8278(17)32017-2.

HBV Marker PurposeHBsAg, ultrasensitive assay Lower limit from 0.05 to 0.004 IU/ml and accurate quantitationLarge vs. middle vs. small surface protein

To differentiate complete virions from empty envelope particles

HBsAg-anti-HBs immune complex

To detect residual HBsAg masked by anti-HBs in immune complex

HBcrAg To correlate levels with intrahepatic HBV DNA and predict viral relapse when Rx is stopped

HBV RNA level To predict viral relapse when Rx is stoppedcccDNA To quantify cccDNA, and access transcriptional activity:

pgRNA/cccRNA ratioAntibody response at the single B cell level

To reveal the extent to which neutralizing antibodies are produced by CHB and to predict “cured” of HBV

Can qHBsAg Levels Predict Spontaneous HBsAg Seroclearance?

• Matched case-control study in patients with spontaneous HBsAg seroclearance (n=46)

– Spontaneous HBeAg seroconversion followed by >10 years of persistently normal ALT

– Genotype B: 75%

– Controls: age, sex, and HBV genotype matched

• Decline of HBsAg to <100 IU/mL can predict HBsAg seroclearance in 1 to 3 years

Chen Y-C, et al. Clin Gastroenterol Hepatol. 2012;10:297-302.

PPV: positive predictive value.NPV: negative predictive value.

60

70

80

90

100

Prediction of HBsAg Seroclearance

Perc

ent

PPV

5 years prior3 years prior1 year prior

NPV PPV NPV<200 IU/mL <100 IU/mL

81%79%

82%

68%

81%

100%

82%

87%86%

64%

73%

97%

Based on Decline to a HBsAg Levelin the Years Prior to HBsAg Seroclearance

• HBV DNA

• HBeAg, anti-HBe,

• qHBsAg, HBsAb

• HAV immunity, anti-HAV

• Genotype, Core, PreCore ?

• Anti-HIV

• Anti-HCV

• Anti-HDV

• Chemistry Profile (ALT, Bil, Alb)

Evaluating HBV Patients in 2020

• FibroSure/FibroTest, makers of fibrosis

- APRI, AST/ALT ratio

- Fib4

• Plt count

• Elastography/ Liver biopsy

• US: Liver contour, Spleen size and PV diameter

• AFP/ DCP ALFP3%

• Other imaging study for HCC?

7

Phases of HBV and EASL Terminology

2018 AASLD Guidance: Whom to Treat

Terrault. Hepatology. 2018;67:1560. www.aasld.org.

• AASLD recommendations for antiviral therapy – Adults with immune‐active CHB (HBeAg negative or HBeAg positive) to decrease the risk of

liver‐related complications• Additional factors: age, family history of HCC or cirrhosis, previous treatment history, presence of

extrahepatic manifestations, presence of cirrhosis– Select group of immune‐tolerant adults older than 40 yrs of age with normal ALT and elevated

HBV DNA (1,000,000 IU/mL) and liver biopsy specimen showing significant necroinflammation or fibrosis

If treatment is not indicated, actively monitoras candidacy may change with disease progression

- Propensity Score-Matched Cohorts -

Kim GA, Lim YS, et al. Gut 2018;67:945–952.

Cum

ulat

ive

Inci

denc

e of

HC

C(%

) HCC

Number at risk

0

20

40

60

80

100

Cum

ulat

ive

Inci

denc

e of

D

eath

or T

rans

plan

tatio

n(%

)

0 2 8 104 6

Time (years)Number at risk

Death or Transplantation

0

20

40

60

80

100

0 2 4 6

Time (years)8 10

IT Group, Untreated IA Group, Treated

IT Group, Untreated IA Group, Treated

P = 0.008 P = 0.009

IT Group 397 317 220 163 107 55 IT Group 397 320 228 171 116 62

IA Group 397 347 280 212 160 108 IA Group 397 349 284 214 163 110

Higher Risk of HCC & Death in Untreated Immune Tolerantvs. Treated Immune-Active Phase CHB

Guideline Recommendations: ALT levels for treatment considerations during chronic hepatitis B infection

• Serial monitoring of serum HBV DNA and ALT levels is required in most instances• Typically, a minimum of 2–3 tests are required to confirm diagnosis

• Other causes of ALT elevation should be excluded

• Even after a complete assessment, some subjects may fall into an indeterminate grey area and management needs to be individualized

EASL AASLD Expert Consensus for AsianAmericans with HBV*

Normal ALT levels Approx ≤40 IU/mL Females <25 IU/mLMales <35 IU/mL Laboratory reference

ALT is a catabolic enzyme present in the liver and kidneys. Increased ALT indicates hepatocyte injury. However, different guidelines recommend different cut-off values for normal levels

EASL. J Hepatol 2017;67:370–98; Terrault NA, et al. Hepatology 2018;67:1560–99; *Tong, et Aliment Pharmacol Ther. 2018;1–20.al.

EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis

EASL-ALEH guidelines recommend different TE cut-offs depending on ALT levels…

…however, TE is unsuitable for use in patients with very high ALT levels ( If >

5ULN liver biopsy)

Hepatitis B Treatment-naïve

Normal ALT Elevated ALT but <5x ULN

Consider follow-up TE if HBV DNA >2000 IU/ml

Consider treatment screening for varices and HCC

Liver biopsy if results influence management

Liver stiffness measurement (TE)

Grey area Severe fibrosis/ cirrhosis

Whatever HBV DNA level and

HBeAg status

<6 kPa >12 kPa

Whatever HBV DNA level and

HBeAg status Exclude other causes of

elevated ALT

Consider follow-up TE

Consider treatment screening for varices and HCC

Liver biopsy if results influence management

No significant fibrosis Severe fibrosis/ cirrhosisGrey area

6–9 kPa 6–12 kPa

No significant fibrosis

>9 kPa<6 kPa

EASL-ALEH. J Hepatol 2015;63:237–64

ALEH: Asociacion Latinoamericana para el Estudio del Higado

2017 EASL Guidelines: Indications for Choosing ETV, TAF vs TDF

EASL. J Hepatol. 2017;67:370.VEMLIDY Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; February 2019.: https://www.vemlidyhcp.com/

When to prioritise ETV over TAF:Treatment cost (ETV generic available)Dosing guidelines for CrCl < 15 mL/min

When to prioritise TAF over ETV:Previous nucleoside exposure

Lamivudine with or without adefovir resistanceHIV/HBV coinfectionNo dose adjustment for CrCl ≥ 15 mL/min

Indications for using ETV or TAF over TDF:Aged > 60 yrsBone disease

Chronic steroids or other meds that affect bone History of fragility fracture Osteoporosis

Renal abnormalities (ETV vs. TAF based on CrCl) eGFR < 60 mL/min/1.73 m2

Albuminuria > 30 mg or moderate proteinuria Low phosphate (< 2.5 mg/dL) Hemodialysis

TAF label update(2/2019): End stage renal disease (ESRD; eCrCl <15 mL/min) who are receiving chronic hemodialysis

On days of hemodialysis, administer VEMLIDY after completion of hemodialysis treatment

Updated CHB guidelines -when to stop NUCs

APASL 2016 AASLD 2017 & 2018 EASL 2017

HBeAg+no cirrhosis

HBeAg seroconversion and UD HBV DNA at least 1 year after HBeAg

seroconversion.

Preferably at least 3 years of consolidation therapy

HBeAg seroconversion and UD HBV DNA + ≥ 12 mo

consolidation

An alternative approach is to treat until HBsAg loss

HBeAg seroconversion and UD HBV DNA + ≥ 12 mo

consolidation

Close post-NA monitoring is warranted.

HBeAg-no cirrhosis

HBsAg loss + ≥ 12 mo consolidation or seroconversion to anti-HBs,

orAfter >2 years treatment with HBV DNA-

on 3 occasions 6 mo apart

Indefinite antiviral treatment till HBsAg loss

HBsAg loss or

In selected patients ≥ 3 years UD HBV DNA

Close post-NA monitoring can be guaranteed

Cirrhosis MAY also be considered with a careful off-therapy monitoring plan

DO NOT STOP DO NOT STOP

Sarin SK, et al. Hepatol Int. 2016;10(1):1-98.Terrault NA et al. Hepatology. 2018;67(4):1560-1599.European Association for the Study of the Liver. J Hepatol. 2017;67(2):370-398.

UD= undetectable

Jeng WJ, et al. Hepatology. 2018 Aug;68(2):425-434.

P < 0.001

691 Chinese, HBeAg negative, 44.6% cirrhosis,

Patients with clinical relapse who remained untreated had a 7.34 times higherincidence of HBsAg clearance than those who received retreatment

End of treatment(EOT) HBsAg level < 100 IU/mL significantly related to off-treatment HBsAg loss

Quantitative HBsAg Kinetics in Retreatment Decision for Off-therapy Hepatitis B Flare in HBeAg Negative Patients

Liaw YF, et al. Gastroenterology. 2018;154(8):2280-2281.

Retreatment is required in those with increasing HBsAg levels, whereas retreatment might be unnecessary in those with decreasing HBsAg levels

HBV Life Cycle, from HBV Entry into the Hepatocyte to the Secretion of Newly Produced Virus

A G

Every step of the HBV life cycle could be a therapeutic target for the treatment of HBV, just to name a few:

A. Entry inhibitors: Myrcludex‐B

B. Targeting cccDNA: CRISPRCAS9, HAT inhibitors

C. RNA interference: JNJ‐3989

D. Capsid / core protein modulator: JNJ‐6378

E. Polymerase inhibitors: Nus (ETV, TDF, TAF)

F. Viral Polymerase Ribonuclease H inhibitors

G. NAPs: HBsAg release inhibitors

E

F

DC

B

Pei Y, et al. J Med Chem 2017, 60, 6461‐79

Select Agents Targeting the Viral Life Cycle of HBV and Immune Modulators Presented at EASL 2019

1. Wedemeyer. EASL 2019. Abstr GS‐13. 2. Gao L. et al EASL 2019 Abstract PS‐074. 3. Yuen. EASL 2019. Abstr PS‐080. 4. Ma. EASL 2019. Abstr LB‐06. 5. Yogaratnam. EASL 2019. Abstr FRI‐217. 6. Yuen. EASL 2019. Abstr GS‐12. 7. Hu. EASL 2019. LBP‐25..

Agent MoA Phase Key Findings

Bulevirtide[1] NTCP inhibitor II 6/15 HDV/HBV‐coinfected patients had HBsAg response at Wk 72 with 2 mg bulevirtide + pegIFN.

Orally available ccc_R08[2] cccDNA destabilizer

Pre‐clinical

(Mouse)

Oral ccc_R08 in the HBV circle‐mouse model showed sustainable suppression of HBsAg, HBeAg, HBV DNA, pgRNA levels and reduction of cccDNA.

JNJ‐3989[3] RNA interference II 88% of 40 TN CHB patients achieved HBsAg ≤ 100 IU/mL; 100% gained ≥ 1.0 log10 IU/mL HBsAg decrease after 3 doses; well tolerated.

ABI‐H0731[4] Core protein allosteric modulator IIa

Faster, deeper HBV DNA decline in TN CHB patients with NA combo vs NA alone; HBV DNA undetectable in virologically suppressed patients with NA combo but not NA alone; well

tolerated.

JNJ‐6379[5] Capsid assembly modulator (CAM) I 75 mg QD for 4 wks provided potent antiviral activity,

was well tolerated in 15 TN CHB patients.

Inarigivir[6] RIG‐I agonist II Dose‐dependent response seen in HBeAg‐positive and HBeAg‐negative TN patients (greater response); treatment well tolerated; HBsAg response in 26% of patients.

T101[7] Therapeutic vaccine I Reduced HBsAg and stimulated HBV‐specific T‐cell immune response in CHB patients with HBV DNA < 20 IU/mL on NAs; SC injections well tolerated.

The ccc_R08, First‐in‐Class Small Molecule Eliminates cccDNA in the Liver

Gao L. et al EASL 2019 Abstract PS‐074.

ccc_R08 reduces HBsAg, HBeAg, HBV DNA, and cccDNA in primary human hepatocyte.

Oral ccc_R08 in the HBV circle‐mouse model showed sustainable suppression of HBsAg, HBeAg, HBV DNA, pgRNA levels and reduction of cccDNA.

The molecule was not associated with cytotoxicity, cell cycle inhibition, nor impact on mitochondria DNA level.

JNJ‐3989, a Third‐Generation Subcutaneously Administered RNA Interference (RNAi) Agent

JNJ‐3989 (ARO‐HBV dual iRNA) in eAg pos and eAg neg CHB

- HBsAg declined by 1 log in all patients- No dose‐response from 100‐400mg- 1 Gr 2 ALT elevation, 3 months post‐Rx,

Yuen M-F, et al. EASL 2019, Vienna, Austria. #PS-080

0 1 2 3 4 5 6 7 8

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- 0 . 53 0 0 m g ( C 4 b )

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N U C e x p ( C 9 )

▪ MAD Ph1b (AASLD 2018; EASL 2019) ▪ Phase 1b (AASLD 2019 #PS‐080)- Cohorts 1‐6: 3 doses Q4W- Cohorts 7‐8: 3 doses QW or Q2W

- Doses < 100mg less effective- No more ALT elevations

- Expanded 100–400 mg cohorts- Added low‐dose 25, 50mg cohorts- Longer follow‐up

Gane E, et al. AASLD 2019; #696

‐4

‐3

‐2

‐1

0

0 41 2 3

Time (weeks)

100 mg QD

200 mg BID

300 mg QD

PBO

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400 mg BID

600 mg QD

1000 mg QD

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Yuen M‐F, et al. EASL 2016, Barcelona. LBO6

Oral HBV capsid assembly modulator (CAMs)

Gane E, et al. EASL 2018, Paris. #LBO‐003 Yuen M‐F.EASL 2019, Vienna., #FRI-219

Antiviral effect during 28 days dosing on qHBV DNA

0

–2

–1

–3

1 2 3

Time (weeks)4

100 mg QD200 mg QD400 mg QD600 mg BD

–4

1. NVR3-778 2. JNJ-6379 3. RO7049389 4. ABI-H07310

1200mg2log reductionNo effect on HBsAgSkin rash

250mg2.9 log reductionNo effect on HBsAgOcc ALT elevation

200mg3.2 log reductionNo effect on HBsAgALT elevation in 20%

400mg3.9 log reductionNo effect on HBsAgSkin rash

Yuen M‐F, et al. AASL D2016, San Francisco

PBO QD

25 mg QD

75 mg QD

150 mg QD

250 mg QD

1 2 3

Time (weeks)Zoulim F, et al. EASL 2018, Paris. #LBO‐004

4

‐4

‐3

‐2

‐1

0

HBV Forum 6, Boston Nov 2019

Interim Analyses of 2 Double‐Blind, Placebo‐Controlled Phase 2a Studies of ABI‐H0731 (300 mg QD) Plus Nuc for 12 Weeks

The ABI‐H0731‐201 (201) study enrolled 47 HBeAg positive subjects whose viral load was already suppressed on active Nuctherapy for 24 weeks

The ABI‐H0731‐202 (202) study enrolled 25 treatment naïve HBeAg positive subjects for 24 weeks

Ma. EASL 2019. Abstr LB‐06

Both studies suggest that deeper declines in HBV DNA and HBV RNA are possible with combination therapy.

Summary

Recent advances have been made in using new makers and non‐invasive assessments for CHB, qHBsAg and non‐invasive tests for fibrosis are available.

Treatment indications have been expended including HBeAg positive infection (immune tolerance patients at the age older than 30)

In HBsAg + patients who achieved HBV DNA UD ≥ 3years on Nus, stopping the Nus is feasible, but close post‐Nus monitoring can be guaranteed

The cure for chronic hepatitis B is likely to require combination, we are hopeful that we can cure the disease within the next decade.

Thank You !