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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.