1. Efficacy of antiviral therapy in reactivation prophylaxis in patients with Hepatitis B (HBV) infection treated with different immunosuppressive agents
Deutsch M1, Manolakopoulos S1,Papadopoulos N2, Tsironi E3, Solomou A3, Skondra M1, Giannouli S1, Theohari M1 , Papatheodoridis GV1, Pectasides D1, Koskinas J1
12nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Greece
21st Department of Internal Medicine, 401 General Army Hospital of Athens, Greece
3 Gastroenterology Department, “Metaxa” General Hospital of Athens, Greece
Abstract Mo1030

2. Background I HBV reactivation
→ represents the result of the loss of HBV immune control due to immunosuppression in a patient with inactive or “resolved” HBV infection
→ abrupt reappearance or increase in viral replication (rise in HBV DNA ± return of HBeAg) with liver damage (ALT increase → mild or very dramatic)
→ may progress to liver failure/death
→ depends on the initial HBV status, disease and the type of immunosupressive therapy
→ a special warning is issued in patients receiving anti-CD20 monoclonal antibodies ( Rituximab, Ofatumumab)

3. Background II Major societies management guidelines
Agency
Subspecialty
Whom to screen
Proposed screening
AASLD
Liver diseases
All
HBsAg, anti-HBc, anti-HBs
EASL
HBsAg, anti-HBc
ACR
Rheumatologists
High risk patients
before MTX or LEF
No specific
recommendations
Expert Consensus
Before anti-TNF/rituximab
ASCO
Oncologists
Only high risk patients or high risk therapy
HBsAg
Consider anti-HBc
AAD
Dermatologists
Patients on anti-TNF
APAGE
Gastroenterologists
According to local practice
(HBsAg, anti-HBc, anti-HBs)
ECCO
AGA
Moderate to high risk patients

4. AGA guidelines (2015) of the prevention and treatment of hepatitis B reactivation during immunosupressive therapy – risk stratification
VERY HIGH RISK (>20%)
- HBsAg (+) + antiCD20 / HSCT
HIGH RISK (11-20%)
- HBsAg (+) + high dose CS / cytokine inhibitors (eg. antiCD52)
MODERATE (1-10%)
- HBsAg (+) + TNFs, cytotoxic without CS, anti-rejection Rx - HBsAg (-)/anti-HBc (+) + Rx with antiCD20 / HSCT
LOW (<1%)
- HBsAg (+) + MTX, AZA - HBsAg (-)/anti-HBc (+) + high dose CS / cytokine inhibitors (eg. antiCD52)
VERY LOW (rare)
- HBsAg (-)/anti-HBc (+) + TNFs, cytotoxic without CS, anti-rejection Rx, MTX, AZA
Prophylaxis YES
Prophylaxis NO

5. Choice of Antiviral Therapy as prophylaxis
Background III
Choice of Antiviral Therapy as prophylaxis
Lamivudine (LAM) is still recommended in patients with low initial viral load (<2000IU/ml) and short duration (<12 mo) of immunosupression
During LAM the emergence of resistant mutants in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of HBV occur in 24% of immunocompetent patients (first year), 70% ( 5 years) and in 7.7% of immunosuppressed (1 year prophylactic therapy)
Entecavir (ENT) and tenofovir disoproxil fumarate (TNF) can be considered in patients with initially high levels of HBV-DNA or those who will receive lengthy and repeated cycles of immunosupression
The experience in this setting with ENT and TDF is limited

6. Aim
The aim of the present study was to investigate the efficacy of prophylactic antiviral treatment with lamivudine (LAM), entecavir (ENT) or tenofovir (TDF) in patients receiving different immunosuppressive agents

7. Patients
110 immunosupressed patients retrospectively/prospectively included
At least 6 months follow up
HBV profile: HBsAg positive or HBsAg negative / anti-HBc positive with negative or positive anti-HBs
Immunosuppressive therapy
1) conventional chemotherapy
2) therapy containing corticosteroids
3) containing monoclonals (rituximab/ofantumumab/alemtuzumab)
Exclusion: HCV/delta or HIVco-infections
NA’s →administered once daily in patients with normal renal function or dose adjusted according to the glomerular filtration rate (GFR)

8. Methods
HBV DNA was measured with real time PCR (cut off 45 IU/ml) at presentation, at six months and at various times during follow-up along with liver biochemistry tests.
HBV reactivation was defined as:
>1 log increase in HBV DNA, or
HBV DNA >2000 IU/ml if no baseline value was available, or
Reverse-Seroconversion, with HBsAg detection when previously negative
with or without acute hepatitis

9. Results Baseline characteristics of the patients
Age, years
63.19±13
Gender (males), n(%)
60 (54.5)
Median duration of follow-up, months
14,85 (6-156)
Monoclonal regimens, n(%)
47 (43)
Corticosteroids without monoclonal regimens, n(%)
23 (21)
Conventional chemotherapy/other, n(%)
40 (36)
HBV status
HBsAg(+), n(%)
73 (66.5)
antiHBc(+)/antiHBs(-), n(%)
20 (18)
antiHBc(+)/antiHBs(+), n(%)
12 (11)
not available, n(%)
5 (4.5)

10. Results: Patients without prophylaxis N=24 (22%)
reactivation, n(%)
21 (87.5)
Not screened n(%)
12 (50)
HBsAg (+) n(%)
5 (20,8)
HBsAg (-) n(%)
7 (29,2)
Anti HBc (+) antiHBs(-)
3 (12,5)
Anti HBc (+) antiHBs(+)
4 (16,7)
Reverse seroconversion, n(%)
6 (66.5)
2 (8,3%) deaths
HBsAg (+) with asthma receiving corticosteroids
HbsAg (-) with chronic lymphocytic leukemia receiving Rituximab

11. Results: 21 patients with reactivation and no prophylaxis → treatment regimen%
1 death
1 death

12. Patients with prophylaxis: N=86 (78%): outcomes
Results
Patients with prophylaxis: N=86 (78%): outcomes
ENT/TDF rescue
1 death (14%)

13. Results
Patients who received prophylaxis : Characteristics according to the type of immunosuppression
Treatment regimen
HBV status
Total=84*
Conventional chemotherapy
N=33
Corticosteroid based therapies without monoclonal
N=22
Corticosteroid based therapies with monoclonal
N=29
ENT/TDF
HBsAg(+)/HBsAg(-)
19/2
13/3
7/12
ENT/TDF failure
LAM
9/0
4/2
LAM failure
3/0
2/2
*2/86 patients received other immunosuppressive therapy and are not included

14. Characteristics(N% or mean±SD) antiHBc(+)antiHBs(+)
Comparative data in patients receiving monoclonals versus other
Characteristics(N% or mean±SD)
Monoclonal YES N=45
Monoclonal NO N=65 P
Gender M/F
32/13
28/37
0,08
Age
64,7±14,6
62,14±12
0,32
Reactivation
14 (31%)
10 (15,4%)
0,013
LAM failure
4 (15,8%)
3 (9,7%)
0,01
HBsAg (+)
26(31,6%)
58 (83,9%)
0,00
antiHBc(+) only
13(47,3%)
2 (3,2%)
antiHBc(+)antiHBs(+)
5(21,1%)
3 (12,9%)
0,04
Follow up (months)
14±12
9,3±11,6
0,26
Patients with past HBV receiving monoclonals were statistically more often treated with prophylactic antivirals

15. Conclusions
HBV reactivation may occur even in patients considered “low risk”(e.g : HBsAg negative treated with antiCD52)
TDF and ENT are effective in prophylaxis and rescue treatment of HBV reactivation in patients receiving immunosupressive therapy
LAM should not be the first choice especially in patients receiving monoclonal antibodies or corticosteroids even if they have initially negative HBsAg.

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