Reactivation of hepatitis B virus (HBV) can occur when a patient with resolved or inactive HBV undergoes immunosuppression. This document discusses the definition, causes, incidence, risk factors, clinical manifestations, outcomes, prevention and treatment of HBV reactivation. Key points include: screening patients for HBV before immunosuppression, using prophylactic antiviral therapy for high risk patients, and monitoring or using pre-emptive therapy for moderate risk patients. Entecavir is recommended over lamivudine or tenofovir for prevention due to lower resistance risk. Therapy should begin before and continue after immunosuppression.

1. BY
PROF. YOSRY ABDELRAHMAN
THEODOR BILHARZ RESEARCH INSTITUTE
Reactivation of Hepatitis B

2. Definition
Abrupt rise or reappearance of hepatitis
B virus (HBV) DNA in the serum of a patient with
previously inactive or resolved HBV infection
Hoofnagle J, Hepatology, ,2009,vol 49,N 5,S156-165

3. Hwang and Lok ,Nat Rev Gastroenterol Hepatol. 2014 April ; 11(4): 209–219

4. Causes of Reactivation
 Spontaneous
 Progressive Immunodeficiency (HIV Infection)
 Sudden Withdrawal of AntiviralTherapy
 Cancer Chemotherapy
 Immunosuppression for Autoimmune or Allergic Conditions
 Solid OrganTransplantation (Kidney, Heart, Lung)
 LiverTransplantation (Reactivation in Graft)
 Bone MarrowTransplantation
 superimposed infections with other hepatotropic viruses
Hoofnagle J,2009, Hepatology,vol 49,N 5,S156-165

5. Incidence of Reactivation
 poorly defined
 depend on many factors including :
host characteristics
underlying disease
type of immunosuppressive therapy
received
baseline HBV status
Hwang and Lok ,Nat Rev Gastroenterol Hepatol. 2014 April ; 11(4): 209–219

6. Risk factors for reactivation
 Host:
Male sex
 Disease:
Lymphoma, breast cancer
 immunosuppressive therapy:
Rituximab, steroids
 viral:
HBsAg positive, high HBV DNA level
before immunosuppressive therapy

7. HBV Reactivation in Patients with HCC
36%
6%
24%
35.00%
17.50%
0%
5%
10%
15%
20%
25%
30%
35%
40%
S Chem LAT TAI TACL TACE
Reactivation
Reactivation

8. Clinical Manifestations
Phase Feature Diagnostic Comments
markers
1 Increase inViral Repl. HBV DNA Rise of > 1 log10 IU/ml
HBeAg In HBeAg negative
HBsAg Reverse seroconversion
2 Appearance of Dis. ALT Rise > 3 times baseline
symptoms severe injury
jaundice
3 Recovery HBV DNA fall to baseline values
ALT fall to baseline values
HBsAg may be cleared late
Hoofnagle J,2009, Hepatology,vol 49,N 5,S156-165

9. Outcomes of reactivation
 Resolution : return to baseline
 Cure: loss of HBsAg positivity
 Persistence: HBV DNA level is higher or
HBsAg remains positive (in HBsAg-negative patient
at baseline) ≥6 months after onset of
reactivation
 death or liver transplantation

10. Prevention of reactivation
 HBV screening
 Preventative antiviral therapy:
Prophylactic antiviral therapy
Pre-emptive antiviral therapy
 Therapeutic antiviral therapy:

11. HBV screening
 which patients should be screened?
 Should screening tests include both HBsAg
and anti-HBc?

12. Preventative antiviral therapy
Prophylactic vs Pre-emptive antiviral therapy
Lau GK, et al. Gastroenterology 2003;125:1742-1749.
Reactivation Hepatitis B Fatality
Prophylaxis 0% 0% 0%
Therapy 53% 47% 7%
0%
10%
20%
30%
40%
50%
60%
NofCases
Lamivudine in HbsAg+ patients

13. Preventative antiviral therapy
Prophylactic vs Pre-emptive antiviral therapy
Hsu C, et al. HEPATOLOGY 2008;47:844-853.
Reactivatio
n
Hepatitis B
severe
hepatitis
fatality
Prophylaxis 12% 8% 0% 0%
Therapy 56% 48% 36% 0%
0%
10%
20%
30%
40%
50%
60%
Nofcases
Lamivudine in HbsAg+ patients

14. Preventative antiviral therapy
Prophylactic vs Pre-emptive antiviral therapy
Huang YH, et al. J Clin Oncol. 2013; 31:2765–72
0%
5%
10%
15%
20%
Reactivation
Entecavir in anti Hbc + patients
prophylactic
therapy

15. Prevention of reactivation
 Which patients should be offered prophylaxis
against reactivation?
 Which antiviral agent should be used? And for
how long?
 Using what tests to monitor therapy for both
efficacy and safety

16. Risk stratification for HBV reactivation
Hwang and Lok ,Nat Rev Gastroenterol Hepatol. 2014 April ; 11(4): 209–219
Antiviral therapyHBsAg – and
Anti Hbc + *
HBsAg +
ProphylaxisChemotherapy for
haematological
malignancies
Anti-CD20 and/or anti-CD52
agents
Chemotherapy
Anti-CD20 and/or anti-
CD52 agents
IST for transplantation
(stem cell,solid organ)
Steroids in combination
with other IST
High risk
Prophylaxis or
pre-emptive
Chemotherapy for solid
tumours‡;
IST for transplantation
(stem cell, solid organ)‡;
Steroids in combination with
other IST‡
Anti-TNF agents;
Maintenance low dose
steroids alone;
Other IST without steroids‡
Moderate risk
No prophylaxisAnti-TNF agent‡;
maintenance on low-dose
steroids alone‡;
other immunosuppressive
therapy without steroids
Steroids alone for a few
days‡
Low risk

17. A management algorithm for patients with HBV infection
prior to starting immunosuppressive therapy.
Hwang and Lok ,Nat Rev Gastroenterol Hepatol. 2014 April ; 11(4): 209–219

18. Antiviral Agents
Li HR, et al. J Viral Hepat. 2011; 18:877–83
6%
0%
6%
27%
12%
20%
0%
5%
10%
15%
20%
25%
30%
Hepatitis HBV
Reactivation
chemotherapy
interruption
Entecavir
Lamivudine

19. Recomendations
 screening all patients about to start immunosuppressive therapy with
HBsAg and anti-HBc tests.
 prophylactic antiviral therapy for all patients who are deemed to be at
high risk of HBV reactivation.
 Patients considered to be at moderate risk can receive prophylactic
antiviral therapy, or they can be closely monitored and pre-emptive
antiviral therapy initiated if there is evidence of HBV reactivation.
 Patients at low risk of HBV reactivation can receive usual medical care,
and pre-emptive antiviral therapy initiated if there is evidence of HBV
reactivation.
 entecavir use is better than tenofovir because of the lack of
nephrotoxicity.

20. Recomendations
 Lamivudine could be used in patients with undetectable serum HBV DNA before
the start of immunosuppressive therapy and if the anticipated duration of use is
short (for example, <12 months) to avoid resistance.
 starting prophylactic antiviral therapy as soon as possible, preferably before the
start of immunosuppressive therapy.
 it is necessary to delay the start of immunosuppressive therapy except in
patients with high baseline serum HBV DNA levels (for example, >4 log10 IU/ml);
for these patients, the benefit of delaying immunosuppressive therapy until HBV
DNA level is suppressed must be weighed against the risk of progression of the
underlying medical condition.
 Continuing preventative antiviral therapy for at least 6 months after the
completion of immunosuppressive therapy and even longer (11months) for
those who receive rituximab or who had high serum HBV DNA levels before the
start of immunosuppressive therapy
Hwang and Lok ,Nat Rev Gastroenterol Hepatol. 2014 April ; 11(4): 209–219