Management of HBV in Challenging Populations

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

Geographic Distribution of Chronic HBV Infection Country HBsAg+ (%) China 5.3-12 2 South Korea 2.6-5.1 2 Pakistan/ India 2.4-4.7 2 Taiwan 10-13.8 2 Vietnam 5.7-10 2 Japan 4.4-13 3 Africa 5-19 2 Russia 1.4-8 2 US/Europe 0.3-12 2 HBsAg Prevalence (%) 1 8: High 2 8: Intermediate <2: Low 1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004, 3. WHO/WPRO data.

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) Lamivudine C 344 / 11,678 (2.9%) Breast feeding 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) Lamivudine C 322 / 11,982 (2.7%) Breast feeding 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 1 st -2 nd trimester): Up to July 2016

Risk of Birth Defects Among Women Exposed to Antivirals During Pregnancy Registry Drugs # Live Births APR* (US) MACDP (European) 1 st Trimester 2 nd /3 rd Trimester Prevalence % (95% CI) All antivirals 5555 3.0 (2.5-3.4) Lamivudine 3864 3.1 (2.5-3.7) Tenofovir 1092 2.4 (1.6-3.5) All antivirals 880 2.0 (1.2-3.2) UK/Ireland All antivirals 3190 3.0 (2.4-3.6) # Live Births Prevalence (%) 95% CI 7483 2.7 (2.4-3.1) 6230 2.7 (2.3-3.1) 639 2.0 (1.1-3.5) 1765 1.2 (0.7-1.8) 7323 2.8 (2.4-3.2) *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%) Brown R, J Hepatol 2012;57:953-9

Case 20 yr F who is pregnant with first child, 20 weeks HBsAg +ve, HBeAg +ve, ALT 12 HBV DNA >10 8 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 Rationale: Trimester of Pregnancy 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

Immunoprophylaxis failure rate (%) HBV: Mother-to-Child Transmission Risk Factors HBeAg positive High HBV-DNA Aminocentesis Prolonged uterine contractions Threatened abortion Preterm Labor 10 7-8% 8-10% 5 0 < 1% < 6 log 3% 6-6.99 log 7-7.99 log 8 log HBV-DNA log copies/ml 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 (2 nd -3 rd 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 (2 nd -3 rd 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 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 Outcome N RR 95% CI P Value Infant HBsAg seropositivity at 6-12 months post-partum Infant HBsAg seropositivity at 6-12 months post-partum 737 (8 RCTs) 1190 (5 observational studies) 0.26 0.16-0.44 (P<0.05) 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

Treatment of Women in the Last Trimester of Pregnancy 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 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 Treatment started Week 30-32 weeks 36%of women had HBV DNA >200,000 IU/mL Average 8.6 weeks therapy 8.18 8.01 8.19 7.73 4.67 4.66 3.52 6% of women had HBV DNA >1,000,000 IU/mL Average 11.4 weeks therapy Han, GR. J Hepatol. 2011;55:1215-21 Pan C, N Engl J Med 2016;374:2324-34.

Some Variability in Recommendations by Society Guidelines Antiviral Choices AASLD APASL EASL Tenofovir Tenofovir Tenofovir Telbivudine Telbivudine Telbivudine Lamivudine Lamivudine HBV DNA criteria >200,000 >10 6-7 >10 6-7 Lamivudine 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? 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 Chang M, Can J Gastroenterol Hepatol, 2014

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 - Discontinue antivirals at delivery or up to 3 months post-partum - Breastfeeding not contraindicated - Continue antiviral therapy 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 3 rd 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?

Natural History of HBV Reactivation During Chemotherapy Liver Transplant ChemoRx and/or Steroids Or HCV DAAs Or Liver SOT HBV DNA Recovery of neutropenia or steroid withdrawal ALT Acute liver failure Chronic hepatitis Acute hepatitis Death Cirrhosis IMMUNE change or SUPPRESSION IMMUNE REBOUND RECOVER 0 4 8 12 16 20 24 28 32 36 52 100 Weeks after Exposure

U/L Reactivation of Hepatitis B Following Rituximab Treatment Case on Lymphoma May-14 Jun-14 Jul-14 Aug-14 Sep-14 Oct-14 Nov-14 Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep-15 Oct-15 Nov-15 Dec-15 Jan-16 Feb-16 Mar-16 Apr-16 May-16 Jun-16 Jul-16 Aug-16 Sep-16 Oct-16 Nov-16 Dec-16 Jan-17 Feb-17 Mar-17 Apr-17 May-17 Jun-17 Jul-17 Aug-17 Sep-17 Oct-17 700 600 Rituximab Tenofovir 500 400 300 ALT AST 200 100 HBsAg (-) Anti-HBc IgM (-) Anti-HBs (-) HBsAg (+) HBV DNA 5.46 Log IU/mL HBsAg (-) HBV DNA (-) 0

Serum ALT (IU/L) Case: 55-Yr-Old Chinese Woman With Stage II Breast Cancer Treated with doxorubicin, paclitaxel, dexamethasone, and cyclophosphamide 4000 Pt dies 20 3000 2000 1000 ALT Total bilirubin First abnormal ALT Entecavir initiated Chemotherapy discontinued 15 10 5 Total Bilirubin (mg/dl) 0 0 20 40 60 80 0 Days Following Initiation of Chemotherapy Courtesy of Dr. Perrillo

HBV may reactivate in anyone who is Anti-HBc+ A B C D E F HBsAg Anti-HBc Anti-HBc Anti-HBs total IgM _ + + + + + _ + + + + _ What it means Never exposed Vaccinated Exposure, Occult, Cleared disease Acute HBV (rare during active/chronic disease) Chronic HBV Exposure, Occult, Cleared disease Isolated core

Immunosuppressive Therapy (IST) Reported to Cause HBV Reactivation Other (Rituximab, cyclosporine) Anti-TNF (Infliximab, adalimumab, etanercept) Immunoodulatory Therapy Anti-Metabolite (Methotrexate) Steroids (Prednisone, budesonide) Purine Analogues (Azathioprine/6MP)

HBV lifecycle and targets for Immunosuppressive therapy Loomba R, Liang JT Gastroenterology 2017:152;1297-09

High risk for HBVr (>10%) HBsAg + core + HBsAg - core + Confidence in estimate B-cell depleting agents (rituximab, ofatumumab) 30 60% 17% A Anthracycline derivatives (e.g.,doxorubin / epirubicin) 15 30% A Corticosteroids for > 4 wks (> 10 mg prednisone) > 10% B 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

Moderate risk (1% - 10%) TNF-alpha inhibitors (etanercept, adalimumab, certolizimab, infliximab) Other cytokine & integrin inhib. (abatacept, ustekinimab, natalizumab, vedolizumab) Tyrosine kinase inhibitors (imatinib, nilotinib) Corticosteroids for > 4 weeks Anthracycline derivatives (e.g.,doxorubin / epirubicin) HBsAg + core + 1 10% (B) 1 10% (C) 1 10% (B) 1 10% (B) (low dose: <10 mg) HBsAg - core + 1% (C) 1% (C) 1% (C) 1 10% (C) (>10 mg) 1% (C)

Low risk group (<1%) Traditional immunsupp. agents (azathioprine, 6-mercaptopurin, methotrexate alone) Intra-articular corticosteroid Corticosteroids for 1 week Corticosteroids for > 4 weeks HBsAg + core + <1% (A) <1% (A) <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

% of HBsAg Patients High Risk of Reactivation with Hematologic Malignancy 100 100 patients with NHL undergoing CHOP 27 HBsAg +ve 80 60 48 40 22 20 4 4 0 HBV Reactivation Jaundice Non-Fatal Liver Failure Death Lok et al, 1991

Patients (%) HBV Reactivation With Rituximab in Pts With Hematologic Malignancies Single-center study of HBsAgnegative 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) 100 75 50 P =.015 Anti-HBs Levels, miu/ml 300 100 - < 300 10 - < 100 < 10 25 Seto WK, et al. 2014. 0 HBV Reactivation No HBV Reactivation

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) HBV Reactivation Risk: Rituximab-Treated Lymphoma Patients Hui (n=233) Tsutsumi (n=47) Targhetta (n=319) Yeo (n=50) Fukushima (n=48) Overall (n=697) 1.60 3.38 5.24 9.39 5.64 (2.18-14.54) 12.44 0.32 1.0 3.16 31.62 Odds Ratio Evens AM, et al. Ann Oncol. 22:1170-1180, 2011

Anti-TNF Agents and HBV Reactivation TNF-a: proinflammatory cytokine that inhibits HBV replication Anti-TNF agents associated with HBV reactivation Utilized in IBD, psoriasis, rheumatoid arthritis 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% 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 Perez-Alvarez et al, 2011; Loras et al, 2010; Lee et al, 2013; Lee et al, 2013;

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 +ve 3 May occur very late 1 Lau BMT 1997, 2 Hui Blood 2005, 3 Onozawa Transplantation 2005

% of HBsAg Patients Hsu et al Hepatology 2008; Lau et al Gastroenterology 2003 Value of Pre-Emptive Antivirals HBsAg +ve pts with NHL treated with CHOP Randomized Pre-emptive vs On-Demand Lamivudine On-Demand Pre-emptive 100 80 60 40 20 0 Pre-emptive group - start LAM 1 day prior to CHOP On-demand - start LAM if ALT>1.5 x ULN 48 8 Hepatitis Flare 36 0 ALT >10xULN 20 Jaundice 0 0 8 Death (after chemotx) Pre-emptive antivirals decrease HBV reactivation Meta-analysis shows survival benefit to this approach - Loomba Ann Int Med 2008

HBV Reactivation (%) Randomized, Controlled Trials of HBV Prophylaxis 70 60 50 40 30 20 10 0 53 P =.002 Lymphoma, HBsAg+ (N = 30) P <.001 41 HCC, HBV DNA+ (N = 76) Control Lamivudine 56 Lymphoma, HBsAg+ (N = 52) P =.001 12 P =.02 29 Breast Cancer, HBsAg+ (N = 42) Control Entecavir P =.03 18 Lymphoma, HBsAg- Anti-HBc+ (N = 80) Control Tenofovir P = NS 17 3 2 0 0 0 Lymphoma, HBsAg- Anti-HBc+ (N = 30) Lamivudine Entecavir P =.001 30 7 Lymphoma, HBsAg+ (N = 121) 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-HBcpositive HBsAg-positive/anti-HBc-positive Patients taking B cell depleting agents (e.g., rituximab, ofatumumab) Patients taking anthracycline derivatives (e.g., doxorubicin, epirubicin) 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 Antiviral prophylaxis for at least 12 months after discontinuation of immunosuppressive therapy Antiviral prophylaxis for at least 6 months after discontinuation of immunosuppressive therapy GRADE Strong Recommendation, moderate quality of evidence. Reddy KR et al Gastroenterology 2015 ;148(1):215-9

AGA Institute Guidelines on Hepatitis B Reactivation ( HBVr) Clinical Decision Support Tool Moderate Risk (reactivation risk 1-10%) HBsAg-positive/anti-HBc-positive or HBsAg-negative/anti-HBc-positive HBsAg-positive/ anti-hbc-positive HBsAg-negative/anti- HBc-positive Patients taking TNF alpha inhibitors (e.g., etanercept, adalimumab, certolizumab, infliximab) Patients taking other cytokine or integrin inhibitors (e.g., abatacept, ustekinumab, natalizumab, vedolizumab) Patients taking tyrosine kinase inhibitors (e.g., imatinib, nilotinib ) Patient taking low-dose ( < 10 mg prednisone daily or equivalent) corticosteroids daily for duration of 4 weeks 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) Suggest antiviral prophylaxis for at least 6 months after discontinuation of immunosuppressive therapy* GRADE Weak Recommendation, moderate quality of evidence * 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 Reddy KR et al Gastroenterology 2015 ;148(1):215-9

AGA Institute Guidelines on Hepatitis B Reactivation ( HBVr) Clinical Decision Support Tool Low Risk (reactivation risk <1%) HBsAg-positive/anti-HBc-positive or HBsAg-negative/anti-HBc-positive HBsAg-negative/anti-HBc-positive Patients taking traditional immunosuppressive agents (e.g., azathioprine, 6- mercaptopurine, methotrexate) Patients taking intra-articular corticosteroids. Patients taking any dose oral corticosteroids daily for duration of 1 week Patients taking low dose ( < 10 mg prednisone or equivalent) corticosteroids for 4 weeks Suggest not to use routine antiviral prophylaxis in patients undergoing immunosuppressive drug therapy and are at low risk for HBVr GRADE Weak Recommendation Moderate quality of evidence 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 HBsAg+ HBcAb + only Ende et al, 2015; Collins et al, 2015; DeMonte et al, 2016

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 31% (n = 9) 21% (n = 6) HBV Reactivation (N = 29) 10% (n = 3) 38% (n = 11) Not reported, uninterpretable, or undetectable HBV DNA w/o HBsAg status Detectable HBV DNA HBsAg+, undetectable HBV DNA HBsAg-, undetectable HBV DNA Bersoff-Matcha SJ, et al. Annals Intern Med 2017.

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.

Evaluation of Hep B Reactivation Among Veterans Treated with Oral Hep C Antivirals Jan 2014-Sept 2016 62,290 Veterans completed DAA HCV therapy 85.5% (53,784/62,920) had HBsAg Test 84.6% (53,237/62,920) had anti-hbs test 64.2% (40,383/62,920) had anti-hbc test 0.70% (377/53,784) were HBsAg (+) 42.2% (22,479/53,237) were anti-hbs (+) 45.7% (18,462/40,383) were anti-hbc (+) 39.5% (7,295/18,462) were isolated anti- HBc (+) Reactivation in 9 cases Defined reactivation as >1000 IU/ml increase in HBV DNA or HBsAg detection in previously (-)ve case 8 in HBsAg (+) 1 in anti-hbc alone (+) 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