Management of HBV in Challenging Populations

K. Rajender Reddy, M.D. Ruimy Family President’s Distinguished Professor in Medicine

Professor of Medicine in Surgery Director of Hepatology

Director, Viral Hepatitis Center Medical Director, Liver Transplantation

University of Pennsylvania

Chronic Hepatitis B in Special Populations

• Pregnancy

• HBV Reactivation

1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004, 3. WHO/WPRO data.

HBsAg Prevalence (%)1

8: High

2–8: Intermediate <2: Low

Country HBsAg+ (%)

China 5.3-122

South Korea 2.6-5.12

Pakistan/

India 2.4-4.72

Taiwan 10-13.82

Vietnam 5.7-102

Japan 4.4-133

Africa 5-192

Russia 1.4-82

US/Europe 0.3-122

Geographic Distribution of Chronic HBV Infection

Chronic HBV Potential Mechanisms of MTCT

• Antenatal transmission (rare) – Trans placental

– Placental leakage/threatened abortion

– Amniocentesis

• Natal (predominant) – Vaginal exposure during delivery

• Postnatal – Breastfeeding: not a risk

YI S, J Hepatol 2014; 60: 523-9 Deng M, Virol J 2012;9:185

Rac MW, Obstet Gynecol Clin North Am 2014;41:573-92

Management of Mothers with HBV

• Many patients with CHB are immune tolerant when pregnant

• Mandatory testing of mothers for HBsAg

• HBIG for infants born to HBsAg positive mothers within 12-24 hours of birth

• HBV vaccine for all infants first dose, with subsequent vaccination at 1 and 3-6 months of age

– >95% of children then immune to HBV

Managing HBV in Pregnancy Differing Clinical Scenarios

• Pregnant and already on antiviral treatment

• Pregnant and not on treatment

– Potential risk of mother-to-child transmission

Unique clinical setting of balancing risks:

Mother Baby

Case

• 28 yr F who is pregnant, 12 weeks

• On treatment with entecavir 0.5 mg daily for 2 years for chronic HBV

• HBsAg +ve, HBeAg +ve, ALT 18

• HBV DNA undetectable

1. Stop HBV treatment because of risk to the baby?

2. Continue entecavir with no changes ?

3. Switch to tenofovir?

Options in Women on Treatment Who Become Pregnant

• Stop treatment and resume post-partum

– Risk of flare with treatment withdrawal

• Continue treatment but with full discussion of benefits and potential risks

– Change to drug with safety profile suitable for pregnancy

Safety of NA in Pregnancy and Breastfeeding

Drugs Pregnancy category

APR data* (Defects / live births)

Breast feeding

Lamivudine C 344 / 11,678 (2.9%) Biologically significant conc. in breast milk

Telbivudine B 0 / 20 No data

Tenofovir B 77 / 3,442 (2.2%) Significant conc. in breast milk (but poor oral bioavailability in infants)

Adefovir C 0 / 48 No data

Entecavir C 2 / 60 (3.3%) No data

CAT-C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks CAT-B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women *Antiretroviral Registry: accessed April 2015

Safety of NA in Pregnancy and Breastfeeding

Drugs Pregnancy category

APR data* (Defects / live births)

Breast feeding

Lamivudine C 322 / 11,982 (2.7%) Biologically significant conc. in breast milk

Telbivudine B 0 / 18 No data

Tenofovir B 95 / 4,419 (2.2%) Significant conc. in breast milk (but poor oral bioavailability in infants)

Adefovir C 0 / 48 No data

Entecavir C 2 / 60 (3.3%) No data

CAT-C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks CAT-B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women *Antiretroviral Registry (exposure in the 1st-2nd trimester): Up to July 2016

Risk of Birth Defects Among Women Exposed to Antivirals During Pregnancy

1st Trimester 2nd/3rd Trimester

Registry Drugs # Live Births

Prevalence % (95% CI)

# Live Births

Prevalence (%) 95% CI

APR* (US)

All antivirals 5555 3.0 (2.5-3.4)

7483 2.7 (2.4-3.1)

Lamivudine 3864 3.1 (2.5-3.7)

6230 2.7 (2.3-3.1)

Tenofovir 1092 2.4 (1.6-3.5)

639 2.0 (1.1-3.5)

MACDP (European)

All antivirals

880 2.0 (1.2-3.2)

1765 1.2 (0.7-1.8)

UK/Ireland All antivirals

3190 3.0 (2.4-3.6)

7323 2.8 (2.4-3.2)

Brown R, J Hepatol 2012;57:953-9

*Antiretroviral Pregnancy Registry (www.APRegistry.com) Not significantly different for exposed women from unexposed

women: CDC population-based data: 2.72%, (2.68–2.76%)

Case

• 20 yr F who is pregnant with first child, 20 weeks

• HBsAg +ve, HBeAg +ve, ALT 12

• HBV DNA >108 log or 100 million copies/mL

1. Start HBV treatment now to prevent MTCT?

2. No need to treat during pregnancy as ALT normal?

3. Consider treatment 28-32 weeks if HBV DNA still elevated?

Treatment of Women in the Last Trimester of Pregnancy

• Rationale:

– Higher risk of prophylaxis failure in mothers with high levels of HBV DNA at delivery

– Prophylactic therapy of infants reduces risk of transmission

• Significant variability in delivery of immunoprophylaxis

• Issues: – Risks to infant – Risks to mother post-partum with drug withdrawal – Breastfeeding concerns

HBV: Mother-to-Child Transmission

• Risk Factors – HBeAg positive

– High HBV-DNA

– Aminocentesis

– Prolonged uterine contractions

– Threatened abortion

– Preterm Labor

HBV-DNA log copies/ml

8-10%

5

10

0

< 6 log

< 1%

3%

6-6.99 log 7-7.99 log ≥ 8 log

7-8%

Imm

un

op

rop

hyl

axis

fa

ilure

rat

e (

%)

Piratvisuth T. Liver Int 2013;33(S1):188-94 Zou H, et al. J Viral Hepatol 2012;19:e18-e25

Controlled Studies: Efficacy of NA During Pregnancy to Reduce MTCT

Study N Drug (time of Rx) Control HBeAg HBV-DNA MTCT rate

Xu 2009 89 LAM (wk 32) Yes Pos >9 log c/ml 7% vs 15%

Han 2011 135 LdT (wk 20-32) Yes Pos >7 log c/ml 0% vs 8%

Pan 2012 53 LdT (2nd-3rd trim.) Yes Pos >6 log c/ml 0% vs 8.6%

Zhang 2014 661 LdT vs LAM (wk 28) Yes Pos >6 log c/ml 1.9% vs 3.7%

Han 2015 454 LdT (2nd-3rd trim.) Yes Pos >6 log c/ml 0% vs 9.3%

Wu 2015 450 LdT (wk 24-32) Yes Pos >6 log c/ml 0% vs 14.7%

Chen 2015 118 TDF (wk 30-32) Yes Pos >7.5 log c/ml 1.5% vs 10.7%

Pan 2016 197 TDF (wk 30-32) Yes Pos >6 log c/ml 0% vs 7%

Xu WM, et al. J Viral Hepat 2009; Han GR, et al. J Hepatol 2011 Pan CQ, et al. Clin Gastro Hepatol 2012; Zhang H, et al. Hepatology 2014

Han GR, et al. J Viral Hepat 2015; Wu Q, et al. Clin Gastroenterol Hepatol 2015 Chen HL, et al. Hepatology 2015; Pan CQ, et al. NEJM 2016

Systematic Review of Antiviral Therapy for Prevention of Perinatal Transmission

Outcome N RR 95% CI P Value

Infant HBsAg seropositivity at 6-12 months post-partum

737 (8 RCTs)

0.26 0.16-0.44 (P<0.05)

Infant HBsAg seropositivity at 6-12 months post-partum

1190 (5 observational

studies)

0.21 0.12-0.38 (P<0.05)

~75-80% reduction in risk of perinatal transmission with use of antiviral therapy

Brown R, Hepatology 2016;63(1):319-3

26 studies with a total of 3622 pregnant women were included in the analysis: 10 studies were RCTs and 16 studies were nonrandomized studies

Most of the studies (92%) were conducted in China, and none were conducted in the United States

Rationale:

– Higher risk of failure of prophylaxis in mothers with high levels of HBV

DNA at delivery – ~10% on average

– Risk of prophylaxis failures is related to HBV DNA level in mother at the

time of delivery

– Antiviral therapy could reduce HBV DNA levels to reduce risk of

prophylaxis failure

Treatment of Women in the Last Trimester of Pregnancy

AASLD HBV Treatment Guideline 2016 Hepatology 2016;63;261-83

Tenofovir for Prevention of MTCT of HBV

• RCT of N=200 women HBeAg and HBV DNA level >200,000 IU/mL

• 1:1 randomization to SOC (not antivirals) or TDF

• TDF 300 mg/day started 30-32 wks gestation postpartum wk 4

• Mean duration of TDF before delivery = 8.57±0.53 weeks

• All infants received vaccination and HBIG

Pan C, N Engl J Med 2016.

Timing of Antiviral Therapy to Prevent HBV Transmission

Treatment started Week 20-32 weeks

Han, GR. J Hepatol. 2011;55:1215-21

Treatment started Week 30-32 weeks

8.19

4.67 4.66

3.52

7.73

8.18 8.01

Pan C, N Engl J Med 2016;374:2324-34.

36%of women had HBV DNA >200,000 IU/mL Average 8.6 weeks therapy

6% of women had HBV DNA >1,000,000 IU/mL Average 11.4 weeks therapy

Some Variability in Recommendations by Society Guidelines

AASLD APASL EASL

Antiviral Choices Tenofovir

Telbivudine

Lamivudine

Tenofovir

Telbivudine

Lamivudine

Tenofovir

Telbivudine

Lamivudine

HBV DNA criteria >200,000 >106-7 >106-7

Starting treatment 28-32 wks 28-32 wks 28-32 wks

Stopping treatment Delivery – 4 wks post Delivery – 4 to 12 weeks post

Within the first 3 mos post

Breastfeeding Not contraindicated Discouraged Not contraindicated

C-section Insufficient data to recommend

-- --

APASL HBV Guidelines Hepatol Int (2016) 10:1–98 EASL HBV Guidelines, J Hepatology 2017

AASLD HBV Guidelines Hepatology 2016;63;261-83

C-Section vs Vaginal Delivery?

Chang M, Can J Gastroenterol Hepatol, 2014

N= 10 studies: n=2352 C-section compared with n=2739 vaginal delivery

But …. minimal benefit if use infant HBIG prophylaxis plus treatment of high viremia mothers

Insufficient evidence to recommend

What is the Risk to the Mother with Stopping Antivirals Post-Partum?

• ALT “flares” frequent post-partum

– Up to 45% of women

– Not predicted by HBV DNA level or HBeAg status

• ALT flares may be more frequent in women receiving 3rd trimester antivirals, but ALT >10 times ULN rare

– Most women are in immune tolerant phase low fibrosis

Tagawa et al, Nippon Sanka Fujinka Gakkar Zasshi, 1987 Soderstrom et al, Scand J Inf Dis, 2003

Ter Borg et al, J Viral Hepatitis 2008 Zhang H et al, Hepatology, 2014

Risk of Flares When Prophylactic Antiviral Therapy Stopped

Higher frequency of ALT elevations in the TDF group after stopping treatment than controls (45% in the TDF group vs. 30% in the control group, P = 0.03).

None clinically significant

Pan C, N Engl J Med 2016.

Suggested Management of HBsAg-Positive Women During Pregnancy

- Continue antiviral therapy post partum

- Breastfeeding not contraindicated

- Discontinue antivirals at delivery or up to 3 months post-partum

- Breastfeeding not contraindicated

* TDF is preferred drug. Initiate therapy ≤28 wks if HBV VL very high to allow time for viral load reduction to <200,000 IU/mL

Treatment of HBV in Pregnancy Summary

HBIG plus vaccination remains the mainstay of prevention of perinatal transmission High maternal viremia increases risk of transmission despite

immunoprophylaxis

Treatment in the 3rd trimester (starting 28-32 weeks of gestation) reduces the risk of perinatal transmission

Tenofovir, telbivudine and lamivudine are options Tenofovir preferred due to minimal risk of resistance

Breastfeeding is not contraindicated on therapy

C-section in those with HBV diagnosis is not indicated

Chronic Hepatitis B in Special Populations

• Pregnancy

• HBV Reactivation

HBV Reactivation (HBVr): Overview • Clinical syndrome characterized by an increase in HBV DNA and

ALT/AST with or without symptoms or jaundice

• Occurs in pts with active (HBsAg+) and resolved/occult (HBsAg-, anti-HBc+) HBV infection

• Wide clinical spectrum for HBVr

– Ranges from silent to liver failure

• Can occur during treatment with many immunosuppressive agents, DAA, HIV, organ transplant

– May also occur up to 12 months after event or treatment

• Preventable by antiviral prophylaxis

Di Bisceglie AM, et al. Hepatology. 2015;61:703-711.

Perrillo RP, et al. Gastroenterology. 2015;148:221-244.

Definitions

• Virologic increase of 1 log IU/ml or de novo appearance of HBV DNA when previously non detectable

Proposed: 2 log increase or de novo or reappearance of HBV DNA to a level of at least 100 IU/mL (AASLD Emerging Trends Conference on HBV Reactivation, March, 2013)

In absence of HBV DNA measurements, reappearance of

HBeAg or HBsAg is reasonable evidence • Increase of 3 fold or greater in ALT levels if BSL levels

normal or 2 fold or greater increase over BSL if initially abnormal.

Case

• 60 yr Asian male with diagnosis of NHL • Plan is to start R-CHOP • HBsAg -ve, HBcAb +ve, HBsAb -ve

1. Start HBV prophylaxis before starting

chemotherapy? 2. No need to treat during chemotherapy as risk is

low ? 3. Consider treatment 28-32 weeks if HBV DNA still

elevated?

Weeks after Exposure

0 4 8 12 16 20 24 28 32 36 52 100

ChemoRx and/or

Steroids Or HCV DAAs

Or Liver SOT

HBV DNA

IMMUNE change or

SUPPRESSION RECOVER

Acute hepatitis

ALT

IMMUNE REBOUND

Recovery of neutropenia or

steroid withdrawal

Natural History of HBV Reactivation During Chemotherapy

Acute liver failure

Death

Chronic hepatitis

Cirrhosis

Liver Transplant

Reactivation of Hepatitis B Following Rituximab Treatment Case on Lymphoma

Rituximab Tenofovir

HBsAg (-) Anti-HBc IgM (-) Anti-HBs (-)

HBsAg (-) HBV DNA (-)

HBsAg (+) HBV DNA 5.46 Log IU/mL

0

100

200

300

400

500

600

700

May

-14

Jun

-14

Jul-

14

Au

g-1

4

Sep

-14

Oct

-14

No

v-1

4

De

c-1

4

Jan

-15

Feb

-15

Mar

-15

Ap

r-1

5

May

-15

Jun

-15

Jul-

15

Au

g-1

5

Sep

-15

Oct

-15

No

v-1

5

De

c-1

5

Jan

-16

Feb

-16

Mar

-16

Ap

r-1

6

May

-16

Jun

-16

Jul-

16

Au

g-1

6

Sep

-16

Oct

-16

No

v-1

6

De

c-1

6

Jan

-17

Feb

-17

Mar

-17

Ap

r-1

7

May

-17

Jun

-17

Jul-

17

Au

g-1

7

Sep

-17

Oct

-17

U/L

ALT

AST

Case: 55-Yr-Old Chinese Woman With Stage II Breast Cancer

• Treated with doxorubicin, paclitaxel, dexamethasone, and cyclophosphamide

ALT

Total bilirubin

20

15

10

5

0

4000

3000

2000

1000

0 0 20 40 60 80

Days Following Initiation of Chemotherapy

Tota

l Biliru

bin

(mg/d

L)

Seru

m A

LT

(IU

/L)

Pt dies

Entecavir

initiated

Chemotherapy

discontinued

First abnormal ALT

Courtesy of Dr. Perrillo

HBV may reactivate in anyone who is Anti-HBc+

HBsAg Anti-HBc total

Anti-HBs Anti-HBc IgM

What it means

_ _ _ _ Never exposed

_ _ + _ Vaccinated

_ + + _

Chronic HBV + + _ _

Exposure, Occult, Cleared disease “Isolated core”

_ _ _ _

_ + _ _

+ + _ + Acute HBV

(rare during active/chronic disease)

A

B

C

D

E

F

Exposure, Occult, Cleared disease

Immunosuppressive Therapy (IST) Reported to Cause HBV Reactivation

Immunoodulatory Therapy

Anti-TNF

(Infliximab, adalimumab, etanercept)

Anti-Metabolite (Methotrexate)

Purine Analogues (Azathioprine/6MP)

Steroids (Prednisone, budesonide)

Other

(Rituximab, cyclosporine)

Loomba R, Liang JT Gastroenterology 2017:152;1297-09

HBV lifecycle and targets for Immunosuppressive therapy

High risk for HBVr (>10%)

B-cell depleting agents (rituximab, ofatumumab)

HBsAg + core +

30 – 60%

HBsAg - core +

17%

Anthracycline derivatives (e.g.,doxorubin / epirubicin)

15 – 30%

Categories of confidence in the estimate: (A) High confidence that the estimate lies within group risk boundaries (B) Moderate confidence that the estimate lies within group risk boundaries (C) Little or no confidence that the estimate lies within group risk boundaries

Corticosteroids for > 4 wks (> 10 mg prednisone)

> 10%

Confidence in estimate

A

A

B

Moderate risk (1% - 10%)

TNF-alpha inhibitors (etanercept, adalimumab, certolizimab, infliximab)

HBsAg + core +

1 – 10% (B)

Other cytokine & integrin inhib. (abatacept, ustekinimab, natalizumab, vedolizumab)

1 – 10% (C)

Corticosteroids for > 4 weeks 1 – 10% (B) (low dose: <10 mg)

Tyrosine kinase inhibitors (imatinib, nilotinib)

1 – 10% (B)

HBsAg - core +

1% (C)

1% (C)

1% (C)

1 – 10% (C) (>10 mg)

Anthracycline derivatives (e.g.,doxorubin / epirubicin)

1% (C)

Low risk group (<1%)

Traditional immunsupp. agents (azathioprine, 6-mercaptopurin, methotrexate alone)

HBsAg + core +

<1% (A)

Intra-articular corticosteroid <1% (A)

Corticosteroids for > 4 weeks

Corticosteroids for ≤ 1 week <1% (B)

HBsAg - core +

<<1% (A)

<<1% (A)

<<1% (A)

<1% (B) (low dose: <10 mg)

Categories of confidence in the estimate: (A) High confidence that the estimate lies within group risk boundaries (B) Moderate confidence that the estimate lies within group risk boundaries (C) Little or no confidence that the estimate lies within group risk boundaries

High Risk of Reactivation

with Hematologic Malignancy

48

22

4 4

0

20

40

60

80

100

% o

f H

BsA

g P

ati

en

ts

HBV Reactivation

Jaundice Non-Fatal Liver Failure

Death

100 patients with NHL undergoing CHOP 27 HBsAg +ve

Lok et al, 1991

HBV Reactivation With Rituximab in Pts With Hematologic

Malignancies

• Single-center study of HBsAg-

negative anti-HBc–positive pts

receiving rituximab-containing

chemotherapy (N = 62)

– Baseline HBV DNA

undetectable (< 10 IU/mL)

– No previous HBV treatment

– No chronic liver disease

• 24.2% of patients experienced

HBV reactivation within 9 months

– Reactivation occurred early

(86.7% within 6 months)

• Lower baseline anti-HBs levels associated with subsequent HBV reactivation (P = .015)

Seto WK, et al. 2014.

HBV Reactivation

No HBV Reactivation

100

75

50

25

0

Pa

tie

nts

(%

)

P = .015 Anti-HBs Levels, mIU/mL

≥ 300

100 - < 300

10 - < 100

< 10

Rituximab-Associated HBV Reactivation

in Lymphoproliferative Disorders

• Meta-analysis and review of FDA

safety profiles

– Case reports (n=27)

– Case series reports (n=156)

• Onset post last rituximab dose

– Median: 3 months (range: 0-12

months)

– >6 months: 29%

• Reactivation in anti-HBc positive

patients receiving rituximab

versus no rituximab

– Odds ratio: 5.73 (P=0.0009)

Evens AM, et al. Ann Oncol. 22:1170-1180, 2011

Hui (n=233)

Tsutsumi

(n=47)

Targhetta (n=319)

Yeo

(n=50)

Fukushima (n=48)

Overall (n=697)

HBV Reactivation Risk:

Rituximab-Treated Lymphoma Patients

0.32 1.0 3.16 31.62

Odds Ratio

12.44

5.24

3.38

9.39

1.60

5.64

(2.18-14.54)

Anti-TNF Agents and HBV Reactivation

Disease Studied

No. Patients

HBsAg + HBcAb +

HBsAg – Anti-HBc +

Multiple 257 39% 5%

IBD 88 9/25 (36%) 0%

Rheumatologic 122 12% N/A

Rheumatologic 468 N/A 2%

• TNF-a: proinflammatory cytokine that inhibits HBV replication • Anti-TNF agents associated with HBV reactivation

• Utilized in IBD, psoriasis, rheumatoid arthritis

Perez-Alvarez et al, 2011; Loras et al, 2010; Lee et al, 2013; Lee et al, 2013;

• Antiviral prophylaxis warranted for all HBsAg+ on TNFi • Low risk of HBVr in anti-HBc + only

• Consider monitoring for HBVr • Higher risk may be associated with addition of other IST

Bone Marrow Transplantation: Increased Risk of Reactivation

• Markedly increased rate of reactivation (HBsAg +ve)

– Up to 75%1

– Long-term complications: cirrhosis 10%2

• Reverse seroconversion common if anti-HBc +ve

– Up to 50% become HBsAg +ve3

– May occur very late

1 Lau BMT 1997, 2 Hui Blood 2005, 3 Onozawa Transplantation 2005

Value of Pre-Emptive Antivirals

48

8

36

0

20

0 08

0

20

40

60

80

100

% o

f H

BsA

g P

ati

en

ts

On-Demand Pre-emptive

• Pre-emptive group - start LAM 1 day prior to CHOP

• On-demand - start LAM if ALT>1.5 x ULN

Hepatitis Flare Jaundice

ALT >10xULN

Death (after chemoTx)

Pre-emptive antivirals decrease HBV reactivation

HBsAg +ve pts with NHL treated with CHOP

Randomized ‘Pre-emptive’ vs ‘On-Demand’ Lamivudine

Meta-analysis shows survival benefit to this approach - Loomba Ann Int Med 2008

Hsu et al Hepatology 2008; Lau et al Gastroenterology 2003

Randomized, Controlled Trials of HBV Prophylaxis

P = .001

70

60

40

20

0

50

30

10

HB

V R

eactivation (

%)

Lymphoma,

HBsAg+

(N = 30)

HCC,

HBV DNA+

(N = 76)

Lymphoma,

HBsAg+

(N = 52)

Breast

Cancer,

HBsAg+

(N = 42)

Lymphoma,

HBsAg-

Anti-HBc+

(N = 80)

Lymphoma,

HBsAg-

Anti-HBc+

(N = 30)

Lymphoma,

HBsAg+

(N = 121)

Control

Lamivudine

Control

Entecavir

Control

Tenofovir

Lamivudine

Entecavir

53

P = .002

0 0 0

P < .001 P = .001

P = .02

P = .03 P = NS

41

3

12

56

29

18

2

17

30

7

Perrillo RP, et al. Gastroenterology. 2015;148:221-244.

Choosing an Antiviral for HBV Prophylaxis

• Drugs with high genetic barrier to resistance (tenofovir, entecavir) preferred[1]

• Lamivudine associated with resistance[1]

– Entecavir prophylaxis associated with a significantly lower incidence of HBV reactivation vs lamivudine in randomized controlled trial[2]

• Adefovir less potent than tenofovir for treating HBV[3]

• Lamivudine plus adefovir may be an option[4]

1. Reddy KR, et al. Gastroenterology. 2015;148:215-219. 2. Huang H, et al. JAMA. 2014;312:2521-2530.

3. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. 4. Vassiliadis TG, et al. J Gastroenterol Hepatol.

2010;25:54-60.

AGA Institute Guidelines on Hepatitis B Reactivation ( HBVr) Clinical Decision Support Tool

High Risk (reactivation risk > 10%)

HBsAg-positive/anti-HBc-positive or HBsAg-negative/anti-HBc-

positive

Patients taking B cell depleting agents (e.g.,

rituximab, ofatumumab)

Patients taking anthracycline derivatives (e.g., doxorubicin,

epirubicin)

GRADE – Strong Recommendation, moderate quality of evidence.

Antiviral prophylaxis for at least 12 months after

discontinuation of immunosuppressive therapy

Antiviral prophylaxis for at least 6 months after discontinuation of immunosuppressive therapy

HBsAg-positive/anti-HBc-positive

Patients taking moderate dose ( 10-20 mg prednisone daily or

equivalent ) or high dose ( > 20 mg prednisone daily or equivalent)

corticosteroids daily for ≥4 weeks

Reddy KR et al Gastroenterology 2015 ;148(1):215-9

Moderate Risk (reactivation risk 1-10%)

Patients taking TNF alpha inhibitors

(e.g., etanercept, adalimumab, certolizumab,

infliximab)

Patients taking moderate dose ( 10-20 mg prednisone daily or equivalent ) or high

dose ( > 20 mg prednisone daily or equivalent) corticosteroids daily for ≥4

weeks. Patients taking anthracycline derivatives (e.g., doxorubicin, epirubicin)

Patients taking other cytokine or integrin

inhibitors (e.g., abatacept,

ustekinumab, natalizumab, vedolizumab)

GRADE – Weak Recommendation, moderate quality of evidence

Suggest antiviral prophylaxis for at least 6 months after discontinuation of immunosuppressive therapy*

AGA Institute Guidelines on Hepatitis B Reactivation ( HBVr) Clinical Decision Support Tool

* Patients who place a higher value on avoiding the long-term use of antiviral therapy and cost associated with its use and a lower value on avoiding the small risk of reactivation (particularly in those who are HBsAg-negative), may reasonably select no prophylaxis over antiviral prophylaxis

HBsAg-positive/anti-HBc-positive or HBsAg-negative/anti-HBc-positive

HBsAg-negative/anti-HBc-positive

Patients taking tyrosine kinase inhibitors (e.g.,

imatinib, nilotinib )

HBsAg-positive/ anti-HBc-positive

Patient taking low-dose ( < 10 mg prednisone daily

or equivalent) corticosteroids daily for

duration of ≥4 weeks

Reddy KR et al Gastroenterology 2015 ;148(1):215-9

Low Risk (reactivation risk <1%)

HBsAg-positive/anti-HBc-positive or HBsAg-negative/anti-HBc-positive

Patients taking traditional immunosuppressive agents

(e.g., azathioprine, 6-mercaptopurine, methotrexate)

Patients taking low dose ( < 10 mg prednisone or equivalent) corticosteroids for ≥ 4 weeks

Patients taking intra-articular corticosteroids.

Patients taking any dose oral corticosteroids daily for duration of

≤ 1 week

GRADE – Weak Recommendation Moderate quality of evidence

Suggest not to use routine antiviral prophylaxis in patients undergoing immunosuppressive drug therapy and are at low risk for HBVr

AGA Institute Guidelines on Hepatitis B Reactivation ( HBVr) Clinical Decision Support Tool

HBsAg-negative/anti-HBc-positive

Reddy KR et al Gastroenterology 2015 ;148(1):215-9

HBV Reactivation Associated with DAA Therapy for HCV

• Case reports of 2 patients:

• Flare of HBV temporally related to initiation of SOF/SMV

• 2 additional cases of ALF in anti-HBc-positive patient on antiviral therapy

Ende et al, 2015; Collins et al, 2015; DeMonte et al, 2016

HBsAg+ HBcAb + only

Safety WARNING: HBV Reactivation and DAAs October, 2016

HBV Reactivation in Pts Receiving DAAs: Postmarketing Cases Reported to FDA

• Case reports of HBV reactivation in pts receiving DAAs

– Reactivation: increase in HBV DNA or seroconversion to HBsAg positive

• 29 confirmed cases in ~ 3 yrs (November 2013 to October 2016)

– Pts from Japan (n = 19), US (n = 5), other (n = 5)

– Usually occurred within 4-8 weeks (mean 52 days)

– 2 deaths, 1 transplant, 6 hospitalizations, 10 DAA discontinuations

Bersoff-Matcha SJ, et al. Annals Intern Med 2017.

HBV Reactivation (N = 29)

Not reported, uninterpretable, or undetectable HBV DNA w/o

HBsAg status

Detectable HBV DNA

HBsAg+, undetectable HBV DNA

HBsAg-, undetectable HBV DNA

31% (n = 9)

38% (n = 11)

21% (n = 6)

10% (n = 3)

FDA Recommendations for Monitoring During DAA Therapy

• To decrease the risk of HBV reactivation in patients co-infected with HBV and HCV, health care professionals should:

• • Screen all patients for evidence of current or prior HBV infection before initiating treatment with DAAs by measuring HBsAg and anti-HBc. In patients with serologic evidence of HBV infection, measure baseline HBV DNA prior to DAA treatment.

• Monitor patients who show evidence of current or prior HBV infection for clinical and laboratory signs (i.e., HBsAg, HBV DNA, serum aminotransferase levels, bilirubin) of hepatitis flare or HBV reactivation during DAA treatment and post- treatment follow-up.

• Consult a physician with expertise in managing hepatitis B regarding the monitoring and consideration for HBV antiviral treatment in HCV/HBV co- infected patients.

Jan 2014-Sept 2016 62,290 Veterans completed DAA

HCV therapy

85.5% (53,784/62,920) had HBsAg Test

0.70% (377/53,784)

were HBsAg (+)

84.6% (53,237/62,920) had anti-HBs test

42.2% (22,479/53,237)

were anti-HBs (+)

64.2% (40,383/62,920)

had anti-HBc test

45.7% (18,462/40,383)

were anti-HBc (+)

39.5% (7,295/18,462)

were isolated anti-HBc (+)

Reactivation in 9 cases

8 in HBsAg (+)

1 in anti-HBc alone (+)

Defined reactivation as >1000 IU/ml increase in HBV DNA or HBsAg detection in previously (-)ve case

Evaluation of Hep B Reactivation Among Veterans Treated with Oral Hep C Antivirals

Belperio, P. et al. Hepatology 2017;66:27-36

AASLD Guidance on HBV Reactivation in Pts Receiving HCV DAA Therapy

• HBV vaccination recommended for all susceptible individuals (eg, no previous immunization, no evidence of immunization response, anti-HBc (-)

• All pts starting HCV DAA therapy should be assessed for HBV infection (HBsAg, anti-HBs, and anti-HBc testing)

– If HBsAg+, assess HBV DNA prior to, during, and immediately after HCV DAA therapy

• For active HBV infection, initiate HBV therapy before or simultaneously with HCV DAA therapy

• For low or undetectable HBV DNA, monitor for HBV reactivation during HCV DAA therapy

– Insufficient data to provide recommendations for pts who are HBsAg- and anti-HBc+ or anti-HBs+/anti-HBc+

AASLD/IDSA HCV Guidelines. September 2016.

Summary-HBVr

• ALL patients undergoing chemotherapy should be tested for HBsAg, HBsAb and HBcAb

• All patients who are HBsAg+ should receive prophylaxis prior to chemotherapy – in select cases anti-HBc alone is an indication for

prophylaxis

• Rituximab use and in those with Stem cell transplant: all patients with current or past HBV should receive prophylaxis.

• HBV reactivation on DAA therapy is rare - reactivation in anti-HBc alone cases is even rarer and controversial