Predictive immune biomarkers to safely discontinue Nucleos(t)ide

Analogue treatment in HBeAg negative chronic hepatitis B (NUC-B study)

S. PHILLIPS1,2, S. MISTRY1,2, N. HARRIS1,2, C. MOORE3, G. HAHN3, M. ROSARIO3, C. CARR-SMITH4, M. CORTES CARRILLO4, L. ELANGOVAN4,
K. AGARWAL4, J. HAND5, C. SIVELL5, P. KENNEDY5, S. CONGREAVE6, M. BARNES6, S. RYDER6, M. HABIB3, M. THURSZ3, S. CHOKSHI1,2
1
The Roger Williams Institute of Hepatology Foundation for Liver Research London UK, 2School of Immunology and Microbial Sciences King's College London UK, 3St Mary Hospital Faculty of Life
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Sciences and Medicine Digestive Diseases Division Imperial College London UK, 4 Kings college hospital NHS foundation trust London UK, 5 Barts Health NHS trust Royal London hospital London UK, download the

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poster
6
Nottingham University Hospitals NHS trust London UK

INTRODUCTION RESULTS SUMMARY

Discontinuation of long-term nucleos(t)ides analogue (NA)  In the Stop-NA group:
Off Therapy (Stop-NA) Off Therapy (NA/IFN)
treatment can lead to clinical relapse and increased risk of Stop-NA NA/IFN
• A higher proportion of patients experienced exaggerated flares
100 100
hepatic decompensation in patients with HBeAg negative 100 100 17 22 26 26
100 100 100
6
94
6
94
6
94
and needed RTx compared to NA/IFN.
80 83 80

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chronic hepatitis B (CHB)1,2. In others, NA cessation can 78 A) B)

Patients (%)

Patients (%)
74 74 RTx 800
• Patients who need RTx had a lower frequency of IFN-g-specific T
800
60 60 Time: p=0.019

result in functional cure. It is widely believed that Off Therapy

40 40
cells at BL and during follow up. Conversely, one OPP-T cell
restoration of antiviral immunity is key to resolution of CHB 20 20
600 600
PEG-IFN-alpha

subset was higher at BL.

HBcAg (spFC/106)

HBcAg (spFC/106)
and underpins functional cure3,4,5. 0 0

• In patients who remained off therapy: 1) HBV-specific T cell

0
52

TW 8
20

13
7
TW

TW
400 400

TW

TW

TW
FIGURE 2: Patients outcome after NA discontinuation at 130 weeks follow-up. The percentage of patients who

THE INTERNATIONAL
response was detected longitudinally; 2) an increased proportion
AIM
experienced exaggerated flares were 26% and 6% (1 patient) in Stop-NA and NA/IFN groups respectively.

TM
200 200 of patients responded to more than 1 HBV epitope; 3) moderate

LIVER CONGRESS
A) B)
1) To identify immune biomarkers for safe discontinuation
1400 Treatment effect: p=0.04 40 flares were accompanied by a peak in T cell response.
1200 0.0186
of NA treatment in HBeAg negative CHB. 1000
p=0.019 30
0
0 4 -F F -F -F -F -F 24 52
0
HBcAg (spFC/106)

TW -F
TW -F
TW -F
TW 8-F
TW 0-F
TW 2-F
TW 3-F
TW 4-F

TW 6-F
TW 7-F

TW F

TW F

TW 6-F
TW 3-F

TW F
0
TW 4

TW 5-F

TW 8-F

TW 20

TW 24

52
TW TW 10 11 13 14 15 16

TW
TW

-
5
6
7

19

22

43
TW TW

CP (spSFC/106)
800

1
1
1
1
1
1
1
1

2
3
2) To assess the impact of PEG-IFN-alpha treatment on 600
p=0.008 TW TW TW T
Patients
W
visitsT
W TW Patients visits
 In the NA/IFN group:
NA cessation. 20
Px001 Px003 Px006 Px009
400
• One patient needed RTx.
Px005 Px011 Px019 Px020 Px023
10 Px026 Px029 Px045 Px047
200 Px027 Px035 Px037 Px038 Px052

• In patients who remained off therapy, PEG-IFN-alpha treatment

METHOD
0
0
TW0 TW4 TW24 TW52

FIGURE 3: HBV-specific T cell response off

Off Therapy RTxtherapy and during RTx at baseline and during follow up (Stop-
Off Therapy RTx
1400 1400 was associated with: 1) a loss of T cell response including during
1200
NA arm). A) Baseline (BL) HBcAg-specific T cell response was lower in patients who needed retreatment which
Patients virally suppressed for >3 years were randomised persisted during follow up. B) Conversely, the BL T cell response to one core pool (CP) was increased in the RTx 1200 1000 moderate flares; 2) a decline in the proportion of patients
PEG-IFN-alpha
to either stop-NA or discontinue NA for 4 weeks group. Statistics: A) and B) Mann-Whitney non-parametric test.
1000
800
responding to HBV-specific epitopes; 3) a high proportion of

HBsAg (spFC/106)
600

HBsAg (spFC/106)
followed by 16 weeks of PEG-IFN-alpha before 800
400 patients experiencing viral rebound post treatment.
stopping both treatments (NA/IFN) (See Figure 1). 200
150

Off Therapy (Stop-NA) Off Therapy (NA/IFN) 600

Patients with exaggerated flares (ALT>20xULN) were 100 Finally, three T cell subsets at BL were associated with flares in the two
groups.
400
retreated with NAs (RTx). Longitudinal peripheral blood A) 200
C)
200
PEG-IFN-alpha
50

mononuclear cells (PBMCs) (n=459) were collected 150 150

200

DOI: 10.3252/pso.eu.ILC2022.2022
100
from 23 Stop-NA and 18 NA/IFN patients during a 3- 100
spFC/106

0
spFC/106

CONCLUSIONS
p=0.041
50 p=0.027

TW -F

TW -F

TW 0-F

TW 3-F
TW 4-F

TW 7-F

TW F

TW F

TW 6-F
TW 3-F

TW F
0
TW 4

TW 20

TW 24

52
TW -F

TW 8-F

TW 2-F

TW 5-F
TW 6-F

TW 8-F
50 0 4 -F F -F -F -F -F 24 52

TW
TW

-
-

5
6
7

19

22

43
year follow-up. Additional samples were collected during
50 50 TW TW 10 11 13 14 15 16

1
1
1
1
1
1

2
3
1
p=0.045 TW TW
40 40 TW TW TW T W W TW Patients visits
30 30
Patients visitsT

moderate (ALT>2xULN) and exaggerated flares. 20 20

This is the first study to systematically characterise the HBV-specific T-

10 10
Px001 Px003 Px006 Px009
0 0 Px005 Px011 Px019 Px020 Px023

PBMCs were stimulated with 15 overlapping genotype- TW0 TW4

Patients visits
TW24 TW52 TW0 TW4 TW20
Patients visits
TW24 TW52
Px026 Px029 Px045 Px047 Px027 Px035 Px037 Px038 Px052
cell responses during NA withdrawal and assess the impact of PEG-
specific peptide pools (OPP), HBV core, surface CP1 CP2 CP3 CP4 CP5 CP1 CP2 CP3 CP4 CP5 FIGURE 6: Longitudinal HBV-specific T cell response off therapy during moderate flares (2XULN <ALT>20XULN) in the
2 strategy arms. A) In the Stop-NA group, patients who remained off therapy had a peak in their T-cell response during IFN-alpha therapy post-NA cessation on antiviral immunity.
(HBcAg/HBsAg) and recall antigens. Ex-vivo frequency CP6 CP7+CP8 CP6 CP7+CP8 moderate flares. B) In the NA/IFN group, moderate flares occurred when T cell response was diminished. Each line represents a
of HBV-specific IFN-gamma (IFN-g) producing T-cells B) D)
single patient. Patients experienced flares at different time point (TW-F). Statistics: Mixed effect model with post hoc Tukey. The findings reveal that epitope-specific T-cells may effectively predict
100
was assessed by ELISpot assays, validated and 100
31
38
47 31 >9pp
44 31 19
7
13
25 >9pp
5-9pp
CHB patients that can safely discontinue NA treatment.
5-9pp 80
standardised at GCLP. 80 50
Patients (%)

1-4 pp
Patients (%)

45 1-4 pp 67 38
63 44 60 38
60
Virological and clinical parameters were correlated with
31
50 0PP
20 0PP
40
40
immunological assessments. 38 38

REFERENCES
31 31
33 20 19
20 19 Off Therapy (Stop-NA) Off Therapy (NA/IFN)
0 6
13
6 0 6 13
A) B)
p=0.005

FIGURE 4: W
0
LongitudinalW
4 24
T HBV-specific
52
T cell response off therapy in the 2 Patients from the TW
0 4
TW TW TW TW
strategy arms.
20 24 52 40 600 PEG-IFN-alpha
1500 PEG-IFN-alpha 1(Hadziyannis, Sevastianos et al. 2012)
T TW TW p=0.035
2(Seto, Hui et al. 2015)
500 p=0.013
Stop-NA group who remained off therapy: A) HBV-specific T cell response to CP was detected; B) The percentage
30 p=0.007 400
of patients who responded against more than 1 epitope increased. Patients from the NA/IFN group who remained 1000

off therapy: C) HBV-specific T cell response to CP was lost during PEG-IFN-alpha treatment and started to recover 300 3 (Evans, A et al. 2008)
spSFC/106

spSFC/106
p=0.011

spSFC/106
post treatment; D) During PEG-IFN-alpha treatment, there was an increase in the percentage of patients who did 20 200 500
4(Phillips, s et al. 2010)

Sandra Phillips
Basic Science
300
not response and a decrease in the percentage of patients who responded to >5 pp. Statistics: A and B) Mixed 150

effect model with post hoc Tukey. 10 100

p=0.040

200
5(Phillips, S et al. 2017)
50 100
0 0
0
100 Clinical relapse 0 4 20 24 52
4
0

24

52

TW TW
TW

TW

CONTACT INFORMATION
6
TW TW TW

20

24

52
TW

TW

(HBV DNA>2000 IU/mL; elevated ALT)

TW

TW

TW

TW

TW
23
80 63 Virological relapse (grey zone)
Off-Therapy No Flare Off-Therapy Flare Off-Therapy No Flare Off-Therapy Flare
Off-Therapy No Flare Off-Therapy Flare
(HBV DNA>2000 IU/mL; normal ALT)
Patient (%)

18
60
HBeAg- Chronic Infection
FIGURE 7: HBV-specific T cell response in patients off therapy who flared or did not flare in the 2 strategy arms at
s.phillips@researchinliver.org.uk
40 59 (HBV DNA<2000 IU/mL; normal ALT for 1 year)
baseline and during follow up. A) In the Stop-NA arm, patients who remained off therapy and experienced flares had a lower
31

THU--178
20 BL frequency of one OPP-specific T cell subset. B) In the NA/IFN group, patients who remained off therapy and experienced
flares had a higher BL frequency of two OPP-specific T cell subsets Statistics: Mann-Whitney non-parametric test. s.chokshi@researchinliver.org.uk
0
FIGURE 5: Virological markers of Off
patients
Therapyoff
Off therapy
Therapy at TW130. In the Stop NA group, 59% of patients who
remained off therapy met the HBeAg (Stop-NA) (NA/IFN)infection criteria. In the NA/IFN group, 63% experienced viral
negative chronic
rebound against 18% in the Stop-NA group.
FIGURE 1: NUC-B study design.

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