Discontinuation of Nucleotide or Nucleoside Analogue therapy for Chronic Hepatitis B infection

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1 Discontinuation of Nucleotide or Nucleoside Analogue therapy for Chronic Hepatitis B infection Dr Abid Suddle Institute of Liver Studies King s College Hospital

2 Why consider discontinuation of NA therapy? Long term oral therapy Inconvenient: implications for compliance Cost Adverse effects Bone/ renal disease with TNF Discontinuation may result in an increased chance of functional cure (loss of HBSAg) Only appropriate in certain patients, after careful evaluation

3 Discontinuation of NA treatment Long-term therapy with NAs is usually required HBV eradication is not usually achieved Recommendations Grade of evidence Grade of recommendation NAs should be discontinued After confirmed HBsAg loss (± anti-hbs seroconversion) NAs can be discontinued In HBeAg-positive patients, without cirrhosis, who achieve stable HBeAg seroconversion and undetectable HBV DNA and complete 12 months of consolidation therapy Close post-na monitoring is warranted NAs may be discontinued In selected HBeAg-negative patients, without cirrhosis, who achieve long-term ( 3 years) virological suppression, if close post-na monitoring can be guaranteed II-2 1 II-2 2 II-2 2 EASL CPG HBV. J Hepatol 2017;67:370 98

4 Discontinuation of NA treatment Long-term therapy with NAs is usually required HBV eradication is not usually achieved Recommendations Grade of evidence Grade of recommendation NAs should be discontinued After confirmed HBsAg loss (± anti-hbs seroconversion) NAs can be discontinued In HBeAg-positive patients, without cirrhosis, who achieve stable HBeAg seroconversion and undetectable HBV DNA and complete 12 months of consolidation therapy Close post-na monitoring is warranted NAs may be discontinued In selected HBeAg-negative patients, without cirrhosis, who achieve long-term ( 3 years) virological suppression, if close post-na monitoring can be guaranteed II-2 1 II-2 2 II-2 2 EASL CPG HBV. J Hepatol 2017;67:370 98

5 Discontinuation of NA treatment Long-term therapy with NAs is usually required HBV eradication is not usually achieved Recommendations Grade of evidence Grade of recommendation NAs should be discontinued After confirmed HBsAg loss (± anti-hbs seroconversion) NAs can be discontinued In HBeAg-positive patients, without cirrhosis, who achieve stable HBeAg seroconversion and undetectable HBV DNA and complete 12 months of consolidation therapy Close post-na monitoring is warranted NAs may be discontinued In selected HBeAg-negative patients, without cirrhosis, who achieve long-term ( 3 years) virological suppression, if close post-na monitoring can be guaranteed II-2 1 II-2 2 II-2 2 EASL CPG HBV. J Hepatol 2017;67:370 98

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7 How long do patients need to be suppressed for before attempting discontinuation? Unclear EASL guidelines seem reasonable from a review of available literature.

8 Clinical and Virologic parameters to guide NA withdrawal Sustained Responses and Loss of HBsAg in HBeAg-Negative Patients With Chronic Hepatitis B Who Stop Long-Term Treatment With Adefovir Hadziyannis, Gastro 2012

9 Sustained Responses and Loss of HBsAg in HBeAg- Negative Patients With Chronic Hepatitis B Who Stop Long-Term Treatment With Adefovir Hadziyannis, Gastro 2012

10 Rates and predictors of HBsAg loss after discontinuation of effective long-term entecavir or tenofovir therapy in non-cirrhotic HBeAg-negative chronic hepatitis B patients: Results from the prospective DARING-B Greek study. M Papatheodoridi 1, E Rigopoulou 2, E Hadziyannis 3, K Zachou 2, V Xourafas 1, A Lyberopoulou 2, N Gatselis 2, J, S Manolakopoulos 1,3, GN Dalekos 2, GV Papatheodoridis 1. 1 Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece; 2 Department of Internal Medicine, Thessalia University Medical School, Larissa, Greece; 3 2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokratio General Hospital, Athens, Greece.

11 Study population Inclusion criteria Exclusion criteria CHBe- at NA(s) onset Absence of cirrhosis at NA(s) onset (Ishak s stage 4 or stiffness 10 kpa) NA(s) therapy for 4 years Serum HBV DNA undetectability under NA(s) for 3 years Patients agreement for close followup after NA(s) discontinuation Coinfection with HCV, HDV, or HIV HCC or any other malignancy Liver transplantation Poor compliance to the recommended follow-up during NAs therapy

12 Rate undetectable/low HBsAg (%) Discontinuation of effective ETV/TDF therapy in patients with HBeAg-negative chronic hepatitis B Cumulative rates of undetectable or low levels of HBsAg 100 HBsAg loss HBsAg <10 IU/L HBsAg <100 IU/L HBsAg <1000 IU/L Months after ETV/TDF discontinuation Independent predictors of HBsAg loss HBsAg at Month 0 (per 100 IU/ L): adjusted HR (95% CI 0.587, 0.913), p=0.006 IP-10 at Month 1 (per 10 pg/ml): adjusted HR (95% CI 1.061, 1.274), p=0.001 or ALT at Month 1 (per 10 IU/L): adjusted HR (95% CI 1.089, 1.512), p=0.003 Papatheodoridis M, et al. ILC 2018, #PS-159

13 Cumulative HBsAg seroclearance rate Increased HBsAg seroclearance in HBeAg-negative CHB patients who discontinued NUC therapy vs. natural course HBsAg seroclearance is rare during NUC therapy but may increase after NUC cessation in HBeAg CHB patients Aim: propensity score matched (PSM) study to examine whether the increase is real Methods: Long-term course of 764 HBeAg CHB patients with finite NUC therapy (Off-NUC cohort) was compared with untreated controls from REVEAL- HBV cohort (2916 HBeAg subjects) PSM on age, gender, serum HBV DNA and quantitative HBsAg levels at 1:1 ratio was applied 343 patients in each cohort Results: Cumulative incidence of HBsAg seroclearance after PSM Multivariate Cox regression analysis: higher HBsAg seroclearance in Off-NUC cohort (p=0.0002) Annual incidence of HBsAg seroclearance: 0.91% Off-NUC cohort vs. 0.65% in REVEAL-HBV cohort (log-rank test, p<0.001) after PSM Off-NUC cohort had decreased overall mortality and no increase in HCC incidence Conclusions: the increase of HBsAg seroclearance in HBeAg patients with finite NUC therapy reflects the real effect of finite NUC therapy, in which the risk of adverse outcome(s) is not increased Log-rank test, p< At risk Follow-up duration (years) REVEAL Off-NUC % CI REVEAL Off-NUC cohort Jeng WJ, et al. ILC 2018, #PS-158

14 Clinical and Virologic parameters to guide NA withdrawal A large real world prospective study of stopping NUC therapy in Asian patients with e-ag negative CHB 1,075 patients treated with NUC therapy for 156 (61-430) weeks HBSAg seroclearence during treatment in 6 patients annual incidence 0.15% Median off treatment follow up 155 (2-614) weeks HBSAg seroconversion in 42 patients Annual incidence 1.78% Jeng Hepatology 2018

15 A large real world prospective study of stopping NUC therapy in Asian patients with e-ag negative CHB Predictive factors for HBSAg loss: Shorter time to HBV DNA negativity (<12 weeks) Greater HBSAg reduction during therapy (>1log) Lower EOT HBSAg level (<100) 7 of 308 patients with Cirrhosis suffered hepatic decompensation, 3 died despite retreatment Jeng Hepatology 2018

16 Algorithm for NUC discontinuation in HBeAg negative patients

17 What happens after discontinuation of NUC therapy? Hadziyannis, Gastro 2012

18 - Majority of patients will have flares post discontinuation of NUCs - Flares may trigger immune response or liver damage

19 Distinguishing beneficial and risky flares

20 Retreatment criteria (?) ALT >10x ULN ALT >5x ULN & total bilirubin >2 mg/dl ALT >3x ULN & HBV DNA >100,000 IU/mL ALT > ULN & HBV DNA >2,000 IU/mL on 3 sequential occasions Physician s and patient s decision if HBV DNA >20,000 IU

21 Discontinuation of NA treatment NAs can be discontinued In HBeAg-positive patients, without cirrhosis, who achieve stable HBeAg seroconversion and undetectable HBV DNA and complete 12 months of consolidation therapy Close post-na monitoring is warranted II-2 2 HBeAg seroconversion will remain in the majority (approximately 90%) Virological remission (HBV DNA 2,000 20,000 IU/ml) in >50% 3 years after NAs cessation EASL CPG HBV. J Hepatol 2017;67:370 98

22 Summary In CHB patients, HBSAg seroclearence is the optimal end point for NA treatment Discontinuation may be considered in non-cirrhotic eag positive patients who achieve eag seroconversion Close post discontinuation monitoring NA discontinuation may be considered in selected patients with eag negative CHB Long term virologic suppression?guided by HBSAg at end of treatment/ dynamics Close monitoring Understanding the significance of flares post treatment Expert Doctor, patient who understands rationale