6 November 2019
Stopping Nucleos(t)ide Analogues:
Clinical outcomes of HBs loss, retreatment and flares?
Pietro Lampertico, MD, PhD
Gastroenterology and Hepatology Division
Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico
University of Milan - Italy
Disclosures
Advisory Board/Speaker Bureau for:
- BMS, ROCHE, GILEAD SCIENCES, GSK, ABBVIE, MSD,
ARROWHEAD, ALNYLAM, JANSSEN, SBRING BANK, MYR, EIGER
Discontinuation of NUC therapy
▪ After HBsAg loss / anti-HBs seroconversion
▪ Before HBsAg loss
Discontinuation of NUC therapy
▪ After HBsAg loss /anti-HBs seroconversion
▪ Before HBsAg loss
Can NUC be stopped before achievement of HBsAg loss?
What about patients who want to stop therapy?
* Berg et al. J Hepatology; Chang et al. Liver Int; Chen et al. Clin Microbiol Int; Jeng et al. Hepatology; Papatheodoridis et al. Hepatology
**Chen et al. J Viral Hep; van Boemmel et al. Liver Int; Berg et al. J Hepatol; Wong et al. J Clin Gastroenterol 2018
Pros to stopping
• Considering pregnancy
• Concern about lifelong therapy
• Financial concerns
• Confidence that the data support
this strategy
• Increase rates of HBsAg loss?
PCR: polymerase chain reaction
Cons to stopping
• Therapies are effective, well tolerated
and shown to improve long-term
outcomes – there is no need to stop
• Monitoring is simple
• As HBV causes cancer, patients must
remain PCR-negative to reduce the risk
• There are no predictors to identify
patients who can stop therapy
5 peer-reviewed manuscripts in 2017*
4 peer-reviewed manuscripts in 2018**
HBsAg loss
HBV DNA
<20,000
IU/mL,
(% pts)
Durable biochemical remission: 57%
Pooled HBsAg loss: 1.7%
967 HBeAg neg patients
(17 studies)
Months after NUC discontinuation
HBV DNA
<20,000
IU/mL,
(% pts)
Months after NUC discontinuation
Durable biochemical remission: 76%
Pooled HBsAg loss: 1%
733 initially HBeAg pos patients
(14 studies)
NUC discontinuation before HBsAg loss in CHB
Virological remission - A systematic review
Papatheodoridis G. et al, Hepatology 2016
6 12 24 36 6 12 24 36
Cumulative HBsAg loss rates after stopping NAs in HBeAg-neg CHB
Years after NAs discontinuations
Pts,
%
Hadziyannis S et al, Gastroenterology 2012,143:629-636; Berg T et al, J Hepatol 2017,67:918-24; Papatheodoridis GV et al,
Antivir Ther 2018,epub ahead of print; Chan HL et al, Antiv Ther 2011,16:1249-57; Chen CH et al, J Hepatol 2014,61:515-2;
Hung CH et al, J Viral Hep 2017,24:599-607; Yao CC et al, Sci Rep 2017,7:1839; Jeng WJ et al, Hepatology 2018;68:425-34
Caucasians-
Europeans
East Asians
Pts, n HBsAg levels at EOT (log IU/mL)
33 (no Ci) na
21 (no Ci) 4.7
57 (no Ci) 2.6
53 (34% Ci) 3.2
105 (30% Ci) 2.7
73 (100% Ci) 2.4
119 (24% Ci) 1.6
383 (no Ci)
308 (Ci) 2.6
Finite nucleos(t)ide analog therapy in HBeAg-negative CHB
An emerging paradigm shift – A review
Yun-Fan Liaw, Hepatology International 2019, in press
HBsAg loss increased after stopping NUC therapy
(8 studies)
Higher HBsAg loss rates in patients with non-
retreated off-NUC relapse
NUC discontinuation before HBsAg loss in HBeAg negative CHB
Caucasian studies
Papatheodoridi M et al. AVT 2018Berg T et al, J Hepatol 2017
The FINITE study (RCT) - Germany
HBsAg loss
(19%)
The DARING-B study (cohort) – Greece
(60 patients)
NUC discontinuation before HBsAg loss in CHB from Canada
A RCT study – The Toronto STOP study
67 NUC suppressed patients: age 50, 97% Asian, 92% HBeAg neg. ALT normal, DNA negative, HBsAg 3 log, duration of NUC 7 yrs, Fibroscan 5
Liem KS et al, Gut 2019
Week 72: HBsAg loss: 1 (2.2%) vs 1 (4.5%) p=NS
DNA <20 IU: 1 (2.2%) vs 20 (91%), p<0.005
ALT <ULN: 21 (47%) vs 18 (82%), p=0.01
DNA+ALT: 13 (29%) vs 18 (82%), p<0.005
ALT flares
Fontana RJ et al, JVH 2019 in press
“Beneficial” ALT flare* “Bad” ALT flare*
Different patterns of ALT flares
Yun-Fan Liaw, Hepatology International 2019, in press
Different patterns of ALT flares during and after therapy
After NUC discontinuation in HBeAg neg CHB
*qHBsAg kinetics at peak of ALT
▪ Cumulative retreatment rates were 15%, 22% and 40% at 6, 12 and
24 months after NUC discontinuation.
▪ No patient characteristic was independently associated with the
probability of relapse based on at least two definitions or of
retreatment.
Cumulative rates of virological and biochemical relapses after NUC
discontinuation in 130 non-cirrhotic HBeAg neg CHB pts
Papatheodoridis G et al, Hepatology 2018
Virological relapse Virological and biochemical relapse
TDF-stop group
(n=21)
TDF-continue group
(n=21)
Berg T et al, J Hepatol 2017 Liem KS et al, Gut 2019
NUC discontinuation before HBsAg loss
Off-therapy biochemical and virological patterns
The Toronto STOP study (Canada)The FINITE study (Germany)
Finite nucleos(t)ide analog therapy in HBeAg-negative CHB
an emerging paradigm shift – A review
Yun-Fan Liaw, Hepatology International 2019, in press
Rates of hepatic decompensation
Author’s conclusions:
Off nucleos(t)ide analog (NUC) hepatic decompensation in patients with cirrhosis was at least not more frequent in those
discontinued than those continuing NUC therapy, especially those with poor adherence during long-term NUC therapy
Retreatment
Retreatment criteria after NAs withdrawal in CHB
EASL, AASLD, APASL – No specific criteria
• Same with treatment indications in NA naive
patients?
Indications for retreatment in patients with:
• Flares
• Persistent mild to moderate liver disease activity
(persistently ALT>ULN & HBV DNA >2,000 IU/mL for ≥3-6 months
depending on ALT/HBV DNA levels)
Germany
40%
Retreatment rates after NUC discontinuation in different studies
Greece and Taiwan
Canada Taiwan
40%
Papatheodoridis G et al, Hepatology 2018; Berg T et al, J Hepatol 2017; Liem KS et al, Gut 2019; Jeng WJ et al, Hepatology 2018
NUC discontinuation before HBsAg loss in HBeAg negative CHB
Cumulative HBsAg seroclearance rates in Taiwan
Jeng WJ et al, Hepatology 2018
<100 IU/ml
100-499 IU/ml
>500 IU/ml
The cumulative HBsAg seroclearance rate in overall patients (solid line)，(A) patients with
clinical relapse (CR) and re-treatment (reTx), (B) patients with clinical relapse (CR) but no
re-treatment (no reTx), (C) patients with virologic relapse (VR) but no clinical relapse (CR),
(D) patients with no virologic relapse (no VR) (HBV DNA <2000 IU/mL).
HBsAg loss rates according to ALT flares and re-treatment HBsAg loss rates according to EOT HBsAg levels
0%
18%
Finite nucleos(t)ide analog therapy in HBeAg-negative CHB
An emerging paradigm shift – A review
Yun-Fan Liaw, Hepatology International 2019, in press
HBsAg loss increased after stopping NUC therapy Higher HBsAg loss rates in patients with non-
retreated off-NUC relapse
Can we stop NUC before HBsAg loss ?
Follow-up and retreatment of CHB patients without cirrhosis – A review
Indications for retreatmentIndications for follow-up
M. Papatheodoridi and G. Papatheodoridis, JVH 2019
NUC discontinuation before HBsAg loss - Summary
▪ Significant heterogeneity among studies, few are prospective (2 RCTs)
▪ Variable HBsAg loss rates (1% →30%)
▪ ALT flares: may be significant but they are not associated with decompensation in
non cirrhotic CHB (diagnosis of “non cirrhosis” during long-term NUC?)
▪ ALT flares in compensated cirrhotics: maybe life threatening (safey first !)
▪ Retreatment rates: 40% after 2-3 years
▪ Early retreatment may reduce the likelihood of HBsAg loss (“good flares” ?)
▪ A “stop NUC” control arm may be needed in studies assessing new therapeutics
▪ Which is the “best” endpoint after NUC discontinuation ? Any agreement?
