Are ALT Flares Associated with

Improved Virological Clearance?

Harry L.A. Janssen MD, PhD

Francis Family Chair of Hepatology

Director Toronto Centre for Liver Disease

Toronto General Hospital

University Health Network

University of Toronto, Canada

November 2019

International HBV Cure Workshop

Toronto

Disclosures

• Grant support: AbbVie, Bristol-Myers Squibb, Gilead

Sciences, Janssen, Medimmune, Merck, Roche

• Consultant: AbbVie, Arbutus, Benitec, Bristol-Myers

Squibb, Gilead Sciences, Glaxo, Janssen, Medimmune,

Merck, Roche, Vir-Bio

• Background

• Flares in PEG-IFN

• Flares in nucleos(t)ide analogues

• Flares in nucleos(t)ide analogue discontinuation

• Flares in new treatment for HBV cure

Content

Introduction

• ALT flares not well defined, depends on frequency of sampling

• In well monitored patients different definitions: serum ALT 2-

3 x baseline/nadir and ALT > 3-10 x ULN

• Flares are associated with hepatocellular damage

• In some situations, flares may herald a transition from active to

inactive HBV disease

• Flares are not well studied: a.in natural history often not or only

partially picked up; b. lack of use of PEG-IFN; c. early start of

treatment with NA during the flare; d no good animal models

1 Liaw, Hepatology 1987; 2 Lok, Hepatology 2007;

Immune Mechanisms of CHB Flare

• As HBV is a non-cytopathic virus, HBV-associated liver

disease pathogenesis is largely immune-mediated

• Critical role for T-cells in animal models: Antiviral CD8 T-cells

kill or cure infected hepatocytes, with a regulatory role of CD4

T-cells and neutralizing antibodies by B-cells

• Due to challenges in clinical studies and limited model

systems, it is unknown what triggers an ALT flare

• Both innate immune effector and regulatory pathways

participate in the pathogenesis of ALT flare

Bertoletti A Gut 2012, Rehermann B Hepatology 2016

HBeAg positives on PEG-IFN+/-LAM

Flares

Host-induced

(Antiviral) FlaresVirus-induced

(Pathogenic) Flares

Flink et al. ,Gut 2005; Janssen et al. Lancet 2005

Flare in 67 of 266 patients treated with PEG-IFN

24 (36%) flares host induced; 25 (38%) virus induced and 17 (26%) were indeterminate

HBeAg Response based on Flare Type and

Timing during PEG-IFN

Flink et al., Gut 2005, Buster et al. , J Hep 2007

P < 0.001

8/24 (33%) patients with host-induced

flares became HBsAg negative

Magnitude of Flares: Mean maximum ALT 20.1 x

ULN in responders vs. 13.2x ULN in non

responders (P=0.036)

P = 0.081

HBeAg Response according to Flares and

HBV Genotype during PEG-IFN

Flink et al., Gut 2005, Buster et al. , J Hep 2007

Incidence of Flares in HBV patients on EntecavirVIRGIL Cohort

Flare defined as at least 3x increase of ALT and at least 3x ULNChi et al., J Gastroenterol Hepatol 2017

• Flare occurred in 30

of 729 patients

• 2 cases of

resistance and 1

documented non-

adherence

Clinical spectrum of Flares during Entecavir Therapy

Chi et al., J Gastroenterol Hepatol 2017

Entecavir treatment (VIRGIL cohort)

Stopping NA Therapy HBeAg negative CHB.

The good, the bad and the indeterminate outcome

Lampertico & Berg Hepatology 2018

Study N Tx duration HBsAg loss Incidence

Chan 53 27 mo 11/53 23% - 5 yrs

Hadziyannis 33 4-5 yrs 13/33 39% - 3 yrs

Chen 105 93 wks 30% - 6 yrs

Patwardhan 33 5.3 yrs ? 30% - 6 yrs

Hung 73 30 mo 20/73 46% - 6 yrs

Yao 119 151 wks 44/119 55% - 6 yrs

Berg 21 (42) >4 yrs 4/21 19% - 144 wks

Jeng 691 156 wks 42/691 13% - 6 yrs

Papatheodoridis 57 5.3 yrs 12/57 25% 1.5 yrs

Summary of studies HBsAg seroclearance after stop NA

Courtesy F. Zoulim EASL PCG 2018; adapted from Jeng WJ et al. Hepatology 2018;68:425

* Estimated Annual HBsAg loss of 1.78%

*

• The cumulative rate of off-therapy flares was high: 61%

developed an ALT>5x ULN and 49% an ALT>10x ULN

• The HBV DNA >10,000 IU/mL at week 4-6 predicts

patients with a high risk of flares

• These patients may need more intensive follow-up and

earlier retreatment

• No relation with HBsAg decline which was very limited

overall

Flares in Toronto NA STOP Study (RCT n=67)

Liem S et al. Gut 2019; Liem S et al. EASL 2019

Profiles of HBVDNA and ALT in with HBsAg loss

Cao J et al. J Infect Dis 2017; 215: 581

HBsAg loss not associated with severe flares

• Fibrosis state

• Retreatment policy

• Serological status: HBsAg < HBeAg neg < HBeAg pos

• Absence of anti-HBe

• Rise of HBV- DNA

• Amplitude of the flare

• AUC of the flare

• Comorbidity

Risk Factors for Dangerous Withdrawal Flares

ALT flare in Novel HBV Cure Treatment

Good

• ALT flare due to host immune clearance, accompanied by decline in HBV DNA and viral proteins

Bad

• ALT flare due to enhanced viral activity, either related to lack of efficacy or drug resistance

Worse

• ALT flare due to undesired effect of drug, either autoimmunity or drug induced liver injury

Potential reasons for ALT flare related to novel

antiviral agents

• Direct acting antiviral agents

– Stimulation of immune system

related to viral suppression leading

to on-treatment hepatitis flare

– Hepatitis reactivation and flare after

stopping treatment

– Drug resistance

– DILI

• Immunomodulatory agents

– Hepatitis flares due to immune

clearance of virus during treatment

– Flare related to insufficient HBV

DNA suppression

– Immune-related adverse events

(hepatitis, skin rash, colitis,

pancreatitis, nephritis, thyroiditis,

adrenal insufficiency, diabetes)

– DILI

Clues to differentiate flares?

1. Hofmann L, et al. European J Cancer 2016;60:190-209

Immune medicated flare Autoimmune hepatitis DILI

Timing of flareUsually within 24 weeks

(interferon)Can be very early with anti-

PD1; 1-4 weeks [1]Any time during treatment

Course of flareUsually self-limiting within

weeksFast and progressive,

respond to steroidStatic or progressive

Association with HBV DNA After HBV DNA decline Unrelated Unrelated

ALP level Normal Normal Normal or elevated

Bilirubin Usually normal Normal or elevatedCan have cholestasis

component

Liver biopsy Not neededMay be needed for

diagnosisCan be non-specific

Antiviral (good) flare vs pathogenic flare

Can we relax the ALT >10x ULN criteria if there is

no hepatic decompensation in new treatment?

• Reduce risk by starting with low risk patients

– Exclude advanced liver fibrosis by non-invasive test

– Can consider combination of both transient elastography and a serum index to

reduce false negative results

• Need to evaluate with viral markers to confirm antiviral flare

• Need to frequent monitoring of liver function and ALT

• Can consider stopping the therapy temporarily and recommence after ALT goes down

Conclusions

• Due to challenges in clinical studies and limited model systems, it is unknown what triggers an ALT flare.

• Flares in PEG-IFN treatment are related to HBeAg and HBsAg response.

• Flares during TDF and ETV mostly due to non-adherence. Antiviral flares

very rare.

• Withdrawal of NA frequently results ALT flares which do not seem to be

related to sustained virologic response and HBsAg loss

• For new compounds important to differentiate antiviral flare vs. HBV

pathogenic flare vs. DILI. Take flares into account when stopping

combination therapy including NA.