Virological biomarkers in patients stopping Nucsregist2.virology-education.com/presentations/2019/... · ALT during the first 12 months after Nuc discontinuation in patients with/wo

TRANSPLANTATIONSZENTRUM

Virological biomarkers in patients stopping Nucs

Florian van Bömmel

Clinic for Gastroenterology, Hepatology, Pneumology and Infectious Diseases

Division of Hepatology

University Hospital Leipzig


NUc treatment may be discontinued

Endpoints for NUC discontinuation:

• stages of stable immune control over the infection

• characterized by

– undetectable HBeAg and appearance of anti-HBe in formerly HBeAg positive patients

– undetectable HBsAg, which is considered a functional cure of HBV infections

Virological biomarkers in patients stopping Nucs van Bömmel and Berg, Liver International. 2018;38(Suppl. 1):90–96.

Functional cure, sustained immune control and re-treatment rates increasing over time after discontinuing tenofovir treatment

Virological biomarkers in patients stopping Nucs Berg et. al., J Hepatol 2017;67:918-924

Nuc discontinuation


Nuc treatment may be discontinued

Endpoints for treatment with Nucs:

• stages of stable immune control over the infection

• characterized by

– undetectable HBeAg and appearance of anti-HBe in formerly HBeAg positive patients

– undetectable HBsAg, which is considered a functional cure of HBV infections

According to current treatment guidelines: Nuc treatment may be discontinued

• in HBeAg positive patients who achieve HBeAg loss, seroconversion to anti-HBe, and undetectable HBV DNA

• possibility to discontinue long-term Nuc treatment in HBeAg negative patients


Response to NUC discontinuation runs through different phases


Proposed phases of hepatitis B reactivation after NUC discontinuation and

possible long-term outcomes

van Bömmel F, Berg T. Hepatol Communications, submitted

Hadziyannis et al., Gastroenterology 2012;143:629–636

uncontrolled single-center study of post-treatment course of 33 with HBeAg negative patients who had discontinued treatment with adefovir dipivoxil after 3 to 5 years

HBsAg levels at end of treatment (EOT) as predictors for HBsAg loss


number of patients with relapse or HBsAg loss

Sustained response

(HBV-DNA level > 2000 IU/L,

persistently normal level of ALT)

HBsAg loss

Relapser who receive

antiviral re-treatment

Follow upNuc

discontinuation

EOT HBsAg levels


Low HBsAg levels are associated with HBsAg loss after NUC discontinuation

Virological biomarkers in patients stopping Nucs Jeng WJ, et al. Hepatology, Vol. 68, No. 2, 2018

Low HBsAg levels are associated with HBsAg loss after NUC discontinuation

Virological biomarkers in patients stopping Nucs Jeng WJ, et al. Hepatology, Vol. 68, No. 2, 2018

HBsAg levels > 100

IU/mL are rare

HBV RNA levels and viral rebound after NUC discontinuation (ETV)

HBV RNA Viral Rebound No viral rebound Total P-value

positive4 21 0 21

below LOQ 3 9 12 0.001

total 24 9 33

*Chi-Square test; n: number of CHB patient

Virological biomarkers in patients stopping Nucs Wang J, et al. J. Hepatol. 2016:65, 700–710

HBV RNA at EOT associated with clinical relapses after NUC discontinuation following HBeAg seroconversion

127 HBeAg positive patients stopped NA treatment after HBeAg SC during NUC treatment

Clinical relapse was HBV DNA >2000 IU/mL plus ALT >2x ULN.

Virological biomarkers in patients stopping Nucs Fan R, et al. Clinical Gastroenterology and Hepatology 2019

Prediction of clinical relapse by quantitative anti-HBc levels

Virological biomarkers in patients stopping NucsChi H et al. Clin Gastroenterol Hepatol 2018Tseng C-H et al. J Formos Med Assoc 2018; 117: 915

Response to NUC discontinuation runs through different phases

Virological biomarkers in patients stopping Nucs van Bömmel F, Berg T. Hepatol Communications, submitted

Proposed phases of hepatitis B reactivation after NUC discontinuation and

possible long-term outcomes

Role of HBV bio markers:

Early identification of

patients likely to respond

Early identification of

patients at risk

Most patients show HBV DNA relapses after NUC discontinuation


Modified after Karakaya et. al., Antivir Ther. 2017;22:559-570

Increase in HBV relapses >2000 IU/mL

in HBeAg-negative patients after

withdrawal of NA treatment with

entecavir.

After a duration of 48 weeks, a virologic

relapse was seen in almost all patients

Virologic flares trigger immune response after NUC discontinuation


= PD-1 = Other inhibitory receptors

= HBV antigens= Immunosuppressive signals in the liver

NA treatment

Time

HB

V D

NA

A) B)

exhausted

CD8+ T

cell

hepatocyte hepatocyte

activated

CD8+ T

cell

NA treatment

Time

HB

V D

NA

exhausted

CD8+ T

cell

hepatocyte

exhausted

CD8+ T

cell

hepatocyte

van Bömmel F, Berg T. Hepatol Communications, submitted

Relapses in HBV DNA are often followed by ALT flares


HBV DNA

HBsAg

ALT

Time after NA discontinuation

HBV DNA

HBsAg

ALT

Time after NA discontinuation

B) Potentially harmful flareA) Beneficial flare

Beneficial flares trigger a decrease in

HBV DNA and HBsAg

Strong flares are associated with

the risk of severe liver damage

Xie et. al., BMC Infect Dis. 2019 Jul 19;19(1):640.

Extents of HBV DNA and ALT flares are strongly associated

Virological biomarkers in patients stopping Nucs Rinker et. al., J Clin Invest. 2018;128(2):668–681

Patients with hepatic flares (n = 6/19 = 31.6%)

displayed 100 times greater levels of HBV DNA

compared with those that did not flare (n =13/19 =

68.4%)


small uncontrolled single-center study of post-treatment course of 33 with HBeAg negative patients who had discontinued treatment with adefovir dipivoxil after 3 to 5 years

HBV DNA flare are similar in responders and non responders


HBV-DNA during the first 12 months after Nuc discontinuation in patients with biochemical relapse

(n=25)

Relapser who remained without

antiviral therapy (n=10)

Relapser who receive antiviral re-

treatment (n=15), values are shown

until onset of therapy

uncontrolled single-center study of post-treatment course of 33 with HBeAg negative patients who had discontinued treatment with adefovir dipivoxil after 3 to 5 years

ALT flares are not obviously associated with response to NUC discontinuation


ALT during the first 12 months after Nuc discontinuation in patients with/wo biochemical relapse

(n=25)

Relapser who remained without

antiviral therapy (n=10)

Relapser who receive antiviral re-

treatment (n=15), values are shown

until onset of therapy


Profils of HBV markers and ALT in patients with HBsAg loss (n=5)

Virological biomarkers in patients stopping Nucs Cao J et al. J Infect Dis 2017; 215: 581

Stronger virologic and biochemical relapses have weaker associationwith HBSAg loss (samples from FINITE-study)


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415 313 416 414415 415 414 415 413 412414 416 413 416415 314

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RESPONSE ●a ●aHBSAG>50 HBSAG<=50

logHBcrAg

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417 317 417416 418 416 417417417 416 416 416 415 415415 417 414 417416 417 418317 417 417

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417 317 417417 418 415 417417417 415 416 416 414 415416 416 414 417416 417 418317 417 417

50

100

150

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ALT


ALT

Van Bömmel F, ….Berg T. unpublished

Algorithm for planning NUC discontinuation in HBeAg negative chronic HBV infection

Virological biomarkers in patients stopping Nucs van Bömmel and Berg, Hepatology Communications

Conclusion

Virological relapses after NUC discontinuation can be predicted by HBsAg levels, HBV RNA and anti-HBc levels at EOT

• However, virologic flares are possibly the trigger of imunologic response to NUC discontinuation andshoul not be interrupted to early

Low virologic (and biochemical) flares are likely an expression of existing immune controland seen more frequently in patients with HBsAg loss than high flare

Low HBsAg levels at EOT are predictive for HBsAg loss following NUC discontinuation

Lowering HBSAg levels before NUC treatment cessation may represent an interesting goalvfor novel treatments

The value of novel BM for response to NUC dicontinuation needs more research

• Undetectability of HBV DNA and HBV RNA at EOT likely associated with response


Virological biomarkers in patients stopping Nucsregist2.virology-education.com/presentations/2019/... · ALT during the first 12 months after Nuc discontinuation in patients with/wo

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