Pr Raymond Sayegh
The problem Brief background on HBV Definitions of HBV reactivation The treatment The role and timing of antiviral therapy Special situations Lone anti-hbcpositive, rituximab, BMT, reactivation in nononcology settings
Immunotolerance HBV DNA Immune Clearance Immune Control (Nonreplicative) HBeAg+ HBsAg+ ALT HBeAg- HBeAb+ HBsAg- HBsAb+ 5-30 Yrs Mos-Yrs Infection Yim HJ, et al. Hepatology. 2006;43:S173-S181. Mos-Yrs
Immunotolerance HBV DNA HBeAg+ HBsAg+ ALT Immune Clearance Immune Control (Nonreplicative) Most Oncology Patients Normal ALT Low/undetectable HBV DNA HBsAg+ and HBeAg- or HBsAg-, anti-hbc+ HBeAg- HBeAb+ HBsAg- HBsAb+ 5-30 Yrs Mos-Yrs Infection Yim HJ, et al. Hepatology. 2006;43:S173-S181. Mos-Yrs
cccdna Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
cccdna Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
T cell cccdna T cell T cell Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
T cell cccdna T cell HIV Steroids Chemotx T cell Immune control can be lost Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
T cell cccdna T cell HIV Steroids Chemotx T cell Immune control can be lost Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Clearance HBV DNA ALT Infection 5-30 Yrs Mos-Yrs Hoofnagle JH. Hepatology. 2009;49(5 suppl):s156-s165. Mos-Yrs
HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Clearance Immune Suppression HBV DNA ALT Infection 5-30 Yrs Mos-Yrs Hoofnagle JH. Hepatology. 2009;49(5 suppl):s156-s165. Mos-Yrs
HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Clearance Immune Suppression Immune Reconstitution HBV DNA ALT Infection 5-30 Yrs Mos-Yrs Mos-Yrs Hoofnagle JH. Hepatology. 2009;49(5 suppl):s156-s165.
Definition Loss of HBV immune control in a patient with inactive or resolved HBV infection Abrupt reappearance or increase in viral replication with liver damage occurring during and/or following immune reconstitution Clinically Range from subclinical to severe/fatal hepatitis Rise in HBV DNA ±return of HBeAg ALT increase (may be mild or very dramatic) May progress to liver failure/death despite antiviral therapy Hoofnagle JH. Hepatology. 2009;49(5 suppl):s156-s165.
Class Corticosteroids Antitumor antibiotics Plant alkaloids Alkylating agents Antimetabolites Monoclonal antibodies Others Agents Dexamethasone, methylprednisolone, prednisolone Actinomycin D, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin-c Vinblastine, vincristine Carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide Azauridine, cytarabine, fluouracil, gemcitabine, mercaptopurine, methotrexate, thioguanine Alemtuzumab, rituximab Colaspase, docetaxel, etoposide, fludarabine, folinic acid, interferon, procarbazine Yeo W, et al. Hepatology. 2006;43:209-220.
25 HBV DNA Bilirubin ALT Hepatology consulted 3000 20 Chemotherapy Lamivudine 2500 HBV DNA (Log IU/mL) Bilirubin (mg/dl) 15 10 2000 1500 1000 ALT (IU/L) 5 500 0-2 0 4 8 12 16 18 20 22 24 26 Wks Despite introduction of lamivudine, patient died of liver failure 0
Hepatitis May be severe or even fulminant Occasionally may miss HBV DNA spike because HBV DNA may fall when ALT rises This may lead to misdiagnosis and, ultimately, may result in subsequent flares of HBV By the time ALT rises... may be too late to bring under control Interruption of chemotherapy Potential for poorer cancer-related outcome Yeo W, et al. Hepatology. 2006;43:209-220.
HBsAg-positive breast cancer patients receiving chemotherapy Rate of HBV-associated acute hepatitis: 21% [1] With careful HBV DNA monitoring, up to 41% with HBV reactivation [2] HBV DNA may be undetectable by time of ALT peak Limited data on other solid tumors Of those who flare [2] : 35% chemotherapy interruption 35% premature termination of chemotherapy 1. Kim MK, et al. Korean J Intern Med. 2007;22:237-243. 2. Yeo W, et al. J Med Virol. 2003;70:553-561.
100 patients with NHL undergoing CHOP; 27 HBsAg positive 100 80 HBsAg Patients (%) 60 40 20 48 22 0 HBV Reactivation Jaundice 4 4 Nonfatal Liver Failure Death Lok AS, et al. Gastroenterology. 1991;100:182-188.
Malignancy NHL: 40% to 58% of HBsAg positive Breast cancer: up to 41% of HBsAg positive Chemotherapy Prednisone, anthracyclines, rituximab increased risk Potency of immunosuppression HBV DNA HBV DNA > 3 10 5 copies/ml Elevated if HBeAg positive Demographics Men > women Yeo W, et al. Hepatology. 2006;43:209-220.
50 patients with NHL who were HBsAg positive randomized to epirubicin, cyclophosphamide and etoposide (ACE) ± prednisolone (P) HBsAg Patients (%) 100 80 60 40 20 0 38 73* HBV Reactivation 13 44* ALT > 10 x ULN 4 Jaundice * 28* 35 46 Complete Remission 36 68 Survival at 4 Yrs ACE PACE *P <.05 Cheng AL, et al. Hepatology. 2003;37:1320-1328. Prednisolone increased risk and severity of HBV reactivation but trend toward improved NHL outcome
HBsAg-positive patients with lymphoma treated with high-dose chemotherapy randomized to preemptive vs on-demand lamivudine Survival Free From Hepatitis Due to HBV Reactivation Pts at Risk, n Preemptive LAM On-demand LAM 100 Lau GK, et al. Gastroenterology. 2003;125:1742-1749. 75 50 25 P=.002 by log-rank test Preemptive LAM On-demand LAM (if HBV DNA increased) 0 0 10 20 30 40 Wk 15 12 10 9 6 15 13 10 4 2
HBV DNA (Log IU/mL)/ Bilirubin (mg/dl) 10 9 8 7 6 5 4 3 2 Cycloph/doxo Lamivudine Paclitaxel 200 180 160 140 120 100 80 60 40 ALT (IU/L) HBV DNA Bilirubin ALT Hepatology consulted 1 20 0-2 0 2 6 10 14 18 20 22 24 26 28 30 32 36 0 Wks Uninterrupted chemotherapy with no hepatitis flare
HBsAg-positive patients with NHL treated with CHOP randomized to preemptive vs on-demand lamivudine HBsAg Patients (%) 100 80 60 40 20 0 Hsu C, et al. Hepatology. 2008;47:844-853. On-demand group: start LAM if ALT > 1.5 x ULN Preemptive group: start LAM on Day 1 of CHOP 48 8 HBV Reactivation and Hepatitis Flare 36 0 HBV Reactivation and ALT >10 x ULN HBV Reactivation and Jaundice Preemptive antivirals decrease HBV reactivation 20 0 0 8 Death (After ChemoTx)
Choice of therapy affected by HBV DNA level HBV DNA < 2000 IU/mL: any therapy can be used (including lamivudine) HBV DNA > 2000 IU/mL: entecavir or tenofovir Choice of therapy affected by duration of therapy > 12 mos: entecavir or tenofovir HBV DNA and ALT should be monitored every 3 mos EASL. J Hepatol. 2009;50:227-242. Lok AS, et al. Hepatology. 2009;50:661-662.
When to start Ideally before or together with chemotherapy Do not delay start of chemotherapy When to stop If baseline HBV DNA > 2000 IU/mL: high risk of withdrawal flare Continue therapy as for chronic HBV infection If baseline HBV DNA < 2000 IU/mL 6-12 mosafter end of chemotherapy Monitor for withdrawal flares with monthly HBV DNA and ALT EASL. J Hepatol. 2009;50:227-242. Lok AS, et al. Hepatology. 2009;50:661-662.
Indicates exposure to HBV Usually persists lifelong but may lose after yrs May be false positive if truly no HBV risk factors No guidelines for management Risk for reactivation Low risk for most standard solid tumor regimens Consider preemptive HBV therapy if cirrhosis Consider preemptive HBV therapy if the following treatment strategies are used Rituximab Bone marrow/stem cell transplantation Manzano-Alonso ML, et al. World J Gastroenterol. 2011;17:1531-1537.
Monoclonal antibody against CD20 (B-cell marker) Reduces B-cell numbers and antibody levels Increasingly used as part of CHOP-R, EPOCH-R Increased risk of HBV reactivation, including HBsAgnegative patients Reverse seroconversion: reappearance of HBsAg in previously HBsAg-negative patient due to loss of immune control Yeo W, et al. Hepatology. 2006;43:209-220. Papamichalis P, et al. Clin Res Hepatol Gastroenterol. 2012;36:84-93.
Patients with diffuse large B-cell lymphoma HBsAg-negative, anti-hbc positive individuals treated with CHOP or CHOP-R Proportion of Anti-HBcPositive, HBsAg-Negative Patients (%) 40 30 20 10 HBV Reverse Seroconversion Yeo W, et al. J Clin Oncol. 2009;27:605-611. 0 24 0 0 HBV-Related Death CHOP (n = 25) CHOP-R (n = 21) Risk of reactivation with rituximab significant in anti-hbc positive 5
Reverse HBV seroconversion [1] Among 5 patients who reactivated, 1 during fifth cycle of chemotherapy; 3 median of 98 days AFTER last rituximab cycle; can occur early as well Median peak ALT: 809 U/L (362-3499) Median peak bilirubin: 65 µmol/l (19-249) Risk Factors for reactivation 1. Men >> women (almost all cases) 2. Anti-HBs negative (or low titer) 3.? increased age (> 50 yrs) Yeo W, et al. J Clin Oncol. 2009;27:605-611.
Markedly high rate of reactivation (HBsAg positive) Up to 54% [1] need preemptive antiviral therapy! Long-term complications: cirrhosis in 10% [2] Reverse seroconversion common if anti-hbc positive [3] Up to 50% become HBsAg positive use preemptive antivirals May occur very late HBV status of donor important [1,4] If natural immunity (anti-hbs, anti-hbc): may clear HBsAg If vaccinated (anti-hbs): possibly some protection 1. Lau GK, et al. Bone Marrow Transplant. 1997;19:795-799. 2. Hui CK, et al. Blood. 2005;106:464-469. 3. Onozawa M, et al. Transplantation. 2005;79:616-619. 4. Lau GK, et al. J Infect Dis. 1998;178:1585-1591.
HBV reactivation not uncommon in HBsAg-positive individuals treated with standard chemotherapy HBV may reactivate even in those with an apparent resolved infection (anti-hbc positive, HBsAg negative) Greatest risk factor for HBV is country of origin Highest reactivation risk with rituximab and stemcell/bmt HBV reactivation can be effectively prevented with preemptive antiviral therapy
Preemptive therapy requires preemptive screening, which is highly cost-effective Screening recommended by CDC, EASL, AASLD, and IOM Patients to receive Standard chemotherapy Screen HBsAg (± anti-hbc) Patients to receive Complex chemotherapy (eg, rituximab/ BMT) Screen HBsAg, anti-hbc, anti-hbs Management of lone anti-hbcpositive controversial; follow-up required
HBsAg Significance Action HBV infection Prophylaxis indicated Anti-HBs alone Immunity to HBV None Anti-HBc + anti-hbs - Exposure to HBV If HBsAg negative, low risk for standard chemotherapy If BMT or rituximab, consider prophylaxis HBV DNA Undetectable < 2000 IU/mL 2000 IU/mL Very low HBV DNA Low HBV DNA High HBV DNA Lamivudine adequate Lamivudine adequate Consider more potent agent
Increasing use of biologics and immunomodulatory therapies Rheumatology (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc) Dermatology (psoriasis, pemphigus) Gastroenterology (irritable bowel syndrome, autoimmune hepatitis) Data on incidence and management limited Case reports only
Anti-TNF (infliximab, adalimumab, etanercept) Other (rituximab, cyclosporine) Antimetabolite (methotrexate) Immunomodulatory Therapy Steroids (prednisone, budesonide) Purine Analogues (azathioprine/6mp) Roche B, et al. Liver Int. 2011;31(suppl 1):104-110.
HBsAg+ HBV DNA Screen all patients HBsAg, anti-hbc, anti-hbs Positive HBsAg-, anti-hbc+ HBV DNA < 2000 IU/mL 2000 IU/mL Positive Negative LAM x 6-12 mos posttherapy ETV/TDF until HBV endpoints Test HBsAg q mo HBV DNA q 3 mos Until 6-12 mos posttherapy Watch for withdrawal flares *Caveats: If concern about monitoring err on side of treatment High risk: anti-hbs negative older men consider up-front treatment
Increased use of immunomodulatorytherapy in nononcology fields HBV reactivation reported with many agents but absolute risks unclear Recommend screening all for HBsAg and anti-hbc HBsAg-positive patients should receive preemptive antiviral therapy Lone anti-hbcpositive: management less clear