Hepatitis B Related Serological Events In Hematopoietic Stem Cell Transplant Patients

and Efficacy Of Lamivudine Prophylaxis Against Reactivation

Alok Gupta, MD1*, Bhausaheb Bagal, MD, DM.1*, Jayant Gawande, MD, DM1*, Sachin Punatar, MD1*, Bharat Chauhan, MD1*, Libin Mathew1*, Vivek

Bhat, MD2*, Sadhana Kannan, MSc3* and Navin Khattry, MD, DM.1*

1Bone Marrow Transplant Unit, ACTREC, Tata Memorial Centre, Mumbai, India; 2Microbiology, ACTREC, Tata Memorial Centre, Mumbai,

India; 3Biostatistics, ACTREC, Tata Memorial Centre, Mumbai, India

Hepatitis B Infection

Remote Hepatitis B

Infection (RHBI)

Background

• Remote Hepatitis B infection (RHBI) is characterized by the persistence of Hepatitis B virus (HBV) genome at very low levels of replication in the hepatocytes and/or peripheral blood mononuclear cells.

• Prevalence: 4-18 % in non-endemic areas to 55 % in endemic areas.

• HBsAg, HBeAg and HBV DNA in serum are negative while anti-HBs and/or anti-HBcIgG are positive.

• Reactivation of RHBI is an important cause of morbidity in patients undergoing hematopoietic cell transplant (HCT).

Aim

To determine the prevalence of RHBI and HBV reactivation,

the role of lamivudine in preventing HBV reactivation and

pattern of change in serological markers at reactivation in

patients undergoing HCT.

Definitions

RHBI: Defined as positive anti-HBcIgG and/or anti-HBs

(without history of HBV vaccination) with negative HBsAg

and anti-HBcIgM and normal liver function.

HBV reactivation: Defined as increase in transaminases ≥ 3

times the ULN with HBV DNA and/or anti-HBs and/or anti-

HBcIgG and/or HBsAg positivity (anti-HBcIgM being

negative).

Study design

• Retrospective study

• Study Period: March 2010 to May 2013

• Study centre: Bone Marrow Transplant Unit, ACTREC, Tata Memorial Centre, Mumbai, India

• Patients: 205 patients who underwent HCT (autologous- 103, allogeneic- 102) were included.

Methods

• Virological testing

Pre-transplant: All patients were tested by ELISA for HBsAg, anti-HBs, anti-HBcIgM and anti-HBcIgG within 1 month prior to transplant.

Post transplant: At the time of deranged liver function, patients were tested for HBsAg, Anti-HBs, Anti-HBc IgM, Anti-HBc IgG, Anti-HCV, Anti-HEV and Anti-HAV by ELISA. HBV DNA and HCV RNA were tested by PCR.

All BMT donors were tested for HBsAg, anti-HBs, anti-HBcIgM and anti-HBcIgG within 1 month prior to transplant.

Methods

• Patients diagnosed with RHBI were divided into 2 groups based on the use of lamivudine prophylaxis.

1. Prophylaxis Group: All but one patient with anti-HBcIgGpositivity (irrespective of anti-HBs status).

2. No Prophylaxis Group: Patients with only anti-HBs positivity.

Results

RHBI14% (n=28)

No RHBI 86% (n=177)

Prevalence of Remote Hepatitis B Infection (RHBI)

N=205

Distribution of patients

Total patients n=205

Patients with RHBI

n=28 (14%)

Prophylaxis group

n=15

Reactivation rate 0/15 (0%)

No prophylaxis group

n=13

Reactivation rate

12/13 (92.30%)

Patients without RHBI

n=177 (86%)

All in no prophylaxis

group

Reactivation rate

9/177 (5.08%)

Clinical and virological characteristics of Remote Hepatitis B Infection and outcome of lamivudine prophylaxis

Characteristic Prophylaxis Group

(n=15)

No-prophylaxis group

(n=13)

Total- RHBI

(n=28)

Median Age in years (range) 34 (10-55) 30 (5-49) 29 (5-55)

Gender M/F 12/3 7/6 19/9

Diagnosis

AML 3 7 10

ALL 1 2 3

CML 0 2 2

Lymphoma 4 1 5

Multiple myeloma 4 0 4

Aplastic anemia 3 1 4

Type of transplant

Autologous 8 1 9

Allogeneic 7 12 19

Pre-transplant HBV serology

HBsAg positive 0 0 0

anti-HBcIgG positive * 14 1 15

anti-HBs positive * 8 11 19

Developed HBV reactivation 0 12 P <0.001

* Pretransplant anti-HBcIgG and anti-HBs not available in one patient in No-prophylaxis group

Reactivation10% (n=21)

No reactivation90% (n=184)

Incidence of HBV reactivationN=205

Distribution of patients

Total patients n=205

Patients with RHBI

n=28 (14%)

Prophylaxis group

n=15

Reactivation rate 0/15 (0%)

No prophylaxis group

n=13

Reactivation rate

12/13 (92.30%)

Patients without RHBI

n=177 (86%)

All in no prophylaxis

group

Reactivation rate

9/177 (5.08%)

Clinical and virological characteristics of HBV reactivation

Characteristic HBV reactivation

No. of Patients 21/205 (10%)

Median Age in years (range) 30 (5-49)

Gender M/F 12/9

Diagnosis

AML 12

ALL 5

CML 3

Lymphoma 1

Multiple myeloma 0

Aplastic anemia 0

Type of transplant

Autologous 1

Allogeneic 20

Serological profile Pre-transplant At reactivation

HBsAg positive 0 1

anti-HBcIgG positive 1 7

anti-HBs positive 11 7

HBV DNA positive 0 7

All markers negative 9 0

anti-HBcIgG *positive5% (n=1)

anti-HBs positive

52% (n=11)

All markers negative

43% (n=9)

Pre-transplant serological profile of patients with HBV reactivation (N=21)

*All patients with anti HBcIgG positive received lamivudine prophylaxis except 1

HBsAg positive4% (n=1)

anti-HBcIgGpositive

32% (n=7)

anti-HBs positive

32% (n=7)

HBV DNA positive

32% (n=7)

Post-transplant serological profile of patients with HBV reactivation (N=21)

Changes in serological profile at reactivation (N=21)

Pattern of change No. of patients (%)

Reverse seroconversion (HBsAg negative to

HBsAg positive)

1 (5%)

Loss of antibody 5 (24%)

anti-HBcIgG (positive to negative) 1

anti-HBs (positive to negative) 4

Gain of antibody 8 (39%)

anti-HBcIgG (negative to positive) 7

anti-HBs (negative to positive) 1

HBV viremia 7 (33%)

Patients responded to lamivudine therapy (%) 20 (95)

Median time to response 17 days

Lamivudine therapy at reactivation

Pre-transplant Serological profile of patients with HBV viremia at reactivation (N=21)

Serological profile HBV viremia

(n=7)

No HBV viremia

(n=14)

HBsAg positive 0 0

anti-HBcIgG positive 1 0

anti-HBs positive 0 10 (p=0.023)

All markers negative 5 4

Conclusions1. Incidence of RHBI in patients undergoing HCT is high in our

setting.

2. Lamivudine prophylaxis protects against HBV reactivation post

transplant.

3. We recommend lamivudine prophylaxis not only in patients with

anti-HBcIgG positivity but also in those with isolated anti-HBs

positivity given the high rate of HBV reactivation in these

patients.

4. HBV Serology does not identify all cases of RHBI.

5. Therefore, all serological markers for HBV should be repeated at

the time of deranged liver functions post transplant.

Thank You