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HBV Curbside consultation and case discussion in special populations

HBV Curbside consultation and case discussion in special populations. Brenda Appolo PAC, MHS University of Pennsylvania, Perelman School of Medicine. HBV: Special Populations. Pregnancy HBV and Risk of Reactivation HBV and HIV co-infection Decompensated cirrhosis Hepatitis D

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HBV Curbside consultation and case discussion in special populations

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  1. HBVCurbside consultation and case discussion in special populations Brenda Appolo PAC, MHS University of Pennsylvania, Perelman School of Medicine

  2. HBV: Special Populations Pregnancy HBV and Risk of Reactivation HBV and HIV co-infection Decompensated cirrhosis Hepatitis D HBV and HCV co-infection Resistant HBV HBV in Liver Transplant Recipients

  3. Clinical Profiles of Chronic HBV Infection HBeAg, hepatitis B e antigen.*Expert opinions vary as to this value . Adapted from Hoofnagle JH et al. Hepatology. 2007;45:1056-1075.

  4. Therapeutic Endpoints Improvedsurvival Anti-HBs+ Improvedhistology Loss of HBsAg Anti-HBe+ Loss of HBeAg Loss of HBV DNA = HBeAg seroconversion TIME

  5. Approved Therapies for Chronic HBV \.

  6. Case #1 • 33 F presents for initial HBV consultation • Moved from Belgium with husband 8 yrs ago to US; she was born in China • 21 wks pregnant with first child; no complications • Meds: Prenatals; never treated for HBV in past • Exam: unremarkable for stigmata of liver disease • Labs • CBC wnl • ALT 19; AST 16; T bil 0.9; AlkPhos 189; Albumin • INR 1.0 • HBV s Ag +; HBV e Ag +; HBV e Ab neg • HBV > 170,000,000 iu/ml

  7. Case #1 • What other history is pertinent • FHx: Mother HBV +; Sister HBV ?; Father HBV ?; Maternal Uncle HBV + / HCC • Husband HBV per patient “negative” • What other labs / imaging at this point? • What is risk of vertical transmission to baby? • Should we treat mom? • Why? Why not? • What should we advise mom and OB/neonatology colleagues if anything? • HBV Vaccination & HBIg IM w/in 12 hours of birth • HBV vaccination: Birthday, 2m, 6m • Confirm Ab at one year of age

  8. HBV and Pregnancy

  9. Treatment of CHB in Women Considering Pregnancy Options: Treat prior to pregnancy - finite treatment course Defer treatment until post-partum Main consideration is risk to mother in absence of treatment May be deferring for years if planning >1 pregnancy Defer treatment until after first trimester 1st trimester is period of greatest risk for developing fetus Reduction of viral load may reduce risk of transmission to infant

  10. Risk-Benefit AssessmentTreatment During Pregnancy Possible Benefits Prevent disease progression during pregnancy Prevent flares in association with abrupt withdrawal of therapy Reduce risk of pre-term labor 1, 2 Prevent intrauterine transmission Possible Risks Adverse outcome of pregnancy 1 Tse et al. J Hepatology 2005 2 Su et al. World J Gastroenterol 2004

  11. Antiviral Medications and Pregnancy Risk

  12. Pregnancy Categories – Drug Safety

  13. Antiretroviral Pregnancy Registry Data http://www.apregistry.com – 1 January 1989 through 31 January 2012

  14. Estimated Risk of Perinatal HBV Transmission(without prevention) Chronic HBV infected mothers Acute hepatitis HBV infected mothers 80-90% 90% Risk of Transmission to Infants(%) 10-40% 10%

  15. Lamivudine in Late Pregnancy to Prevent Perinatal Transmission ITT analysis 46% P=0.003 20% • Double-blind, RCT in China • N = 141 • HBsAg+ pregnant women • HBV-DNA >109 copies/ml • LAM 100 mg/D vs placebo; from • GA 32 wk to 4 wk after delivery • All received HBIG + HBV vaccine • High drop-out rate • (LAM 13%, placebo 31%) % Infant with HBV-DNA positive at age 1 yr Based on those tested P=NS 15% 7% Xu WM et al. J Viral Hepat 2009;16:94-103

  16. Efficacy of Telbivudine in Late Pregnancy for Prevention of Vertical HBV Transmission P=0.002 • Open-labeled prospective study • N = 141 (all Chinese) • HBsAg+ pregnant women • HBeAg+ • HBV-DNA >109 copies/ml • LdT 600 mg/D vs untreated • control • from GA 20-32 wk to delivery • All received HBIG+HBV vaccine % Infant with HBsAg+ at age 7 months 8% 0% Han GR, et al. J Hepatol 2011;55:1215-21

  17. Tenofovir for Prevention of HBV Vertical Transmission • Retrospective analysis • 11 HBV infected mothers with HBeAg positive; median HBV-DNA 9 (7.7-9.4) log10 copies/ml • TDF was started at the median GA of 29 (28-32) wk • Maternal outcomes • HBV-DNA significantly reduced at delivery compared to BL • 6/11 pt. had HBV-DNA < 6 log10 before delivery • No significant changes in serum creatinine • TDF was stopped soon after delivery in 8 pt; no ALT flare • Infant outcomes • All infants were HBsAg negative at 28-36 wk of age • No congenital defect • All infants received HBIG+HBV vaccine Pan CQ, Mi LJ, Bunchorntavakul C, et al. Dig Dis Sci 2012;57:2423-9

  18. Proposed Algorithm for HBV Management During Pregnancy Buchanan C, Tran TT. Clin Liver Dis 2010;14:495-504

  19. Case #1 – wrap up • Should we treat mom? • How long should therapy continue? • Is she breastfeeding • HCC surveillance?

  20. Case #2 • 56 yr old F present to ED with new onset jaundice, malaise • PMHx – CD20-positive diffuse large B-cell non-Hodgkin's lymphoma; completed treatment 6 weeks prior (rituximab + CHOP) • SHx – no alcohol, previous IVDU 20 yrs ago • Meds: levothyroxine • Exam: Scleral icterus; exam otherwise unremarkable • Pretreatment labs • Per patient LFTs normal • ED Labs • ALT 333; AST 235; T bil 5.4; AlkPhos 241; Albumin 3.0

  21. Case #2 • What is your DDx? • What patient history is most pertinent? • Viral serologies • HAV IgM negative; HAV total + • HCV Ab +; HCV RNA negative • HBV core Ab Total +; HBV IgM equivocal • HBV s Ag + • HBV DNA 545,000

  22. HBV and Immunosuppressed States : Chemotherapy and Corticosteroids

  23. Natural History of HBV Reactivation During Chemotherapy ChemoRx and/or steroids Acute hepatitis HBV DNA IMMUNE SUPPRESSION RECOVER 0 4 8 12 16 24 28 32 52 100 20 36 Recovery of neutropenia or steroid withdrawal Death Acute liver failure Chronic hepatitis Cirrhosis ALT IMMUNE REBOUND Weeks after Exposure

  24. Reactivation of Hepatitis B Infection Among Cancer Patients Large database from MD Anderson examined to determine HBV screening rates for patients who received chemotherapy 87 HBsAg 87 HBsAg- 17% patients screened 1 HBsAg+ anti-HBc- 34 HBV Reactivation 1,665 HBsAg and anti-HBc 70,737 new patients 1,787 screened 10,729 chemotherapy 25 HBsAg+ anti-HBc+ 123 HBsAg- anti-HBc+ 1/5 with HBV risk screened 2% of screened 23% of positive 35 anti-HBc 2 anti-HBc+ Hwang JP, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 172.

  25. Results of Prophylaxis or Treatment of 34 Patients with Reactivation Fisher’s Exact Test, p<0.05 71% 72% 22% Reactivation Chemotherapy • Conclusion: Persons at risk for HBV are not being adequately screened prior to chemotherapy, resulting in preventable reactivation and mortality Hwang JP, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 172.

  26. Risk Factorsof HBV Reactivation Mindikoglu AL, Regev A, Schiff ER. Clin Gastroenterol Hepatol 2006;4:1076-81 Manzano-Alonso ML, Castellano-Tortajada G. World J Gastroenterol 2011;17:15-1537

  27. Efficacy of Lamivudine Prophylaxis for Chemotherapy-Induced HBV Reactivation % 54% • Review of 10 RCTs & prospective case series • Total N=173 • LAM dose 100mg/D • AEs : LAM=placebo 31% 9.2% 8.7% Kohrt HE, Ouyang DL, Keefe EB. Aliment PharmacolTher 2006;24:1003-16

  28. HBV: Management of Patient Undergoing Immunosuppressive Therapy HBsAg negative *Anti-HBs + Anti-HBc - Anti-HBs - Anti-HBc - Anti-HBs ± Anti-HBc + Prior vaccination with appropriate immune response HBV vaccination is recommended(double-dose ?) • Monitor HBV-DNA q 1-3 mo during and until 6 moafter immunosuppressive Rx • Antiviral prophylaxis, if HBV-DNA positive *Anti-HBs+ is considered when titer ≥10 mIU/ml Check anti-HBs at 1-2 mo after vaccination Adapted from Bunchorntavakul C, Reddy KR. Medical treatment of hepatobiliary diseases associated with ulcerative colitis. In: Lichtenstein G. editor. Medical Therapy of Mucosal Ulcerative Colitis. Springer Publishing, New York, USA; 2012 [in press]

  29. HBV: Management of Patient Undergoing Immunosuppressive Therapy HBsAg positive HBV-DNA <2,000 IU/ml Normal ALT HBV-DNA ≥2,000 IU/ml Normal or elevated ALT • Start antiviral prophylaxis before initiation of immunosuppressive Rx and continue for 6 mo after discontinuing all immunosuppressive Rx (12 mo for rituximab) • LAM can be used, if the anticipated Rx duration is <12 months • ETV or TDF is preferred, if longer duration of Rx is anticipated • HBV treatment • Delay immunosuppressive Rxuntilanti-HBV is initiated and HBV DNA negative Adapted from Bunchorntavakul C, Reddy KR. Medical treatment of hepatobiliary diseases associated with ulcerative colitis. Springer Publishing. [in press] and Lok ASF, McMahon BF. AASLD Practice guideline 2009

  30. Case #3 • 49 yr old male presents with self reported history of Hepatitis A,B,C • His only complaint is fatigue; referred by area health clinic • Exam notable for temporal muscle wasting; trace icterus, + fluid wave • He has high risk behaviors including IV drug use, multiple sexual partners; “alcohol was never my thing” • Labs: T bil 2.1; AST 119; ALT 242; Albumin 3.0; AlkPhos 245; INR 1.3 • You have no medical records or labs otherwise • You order “viral hepatitis panel” • HCV Ab positive • HBV s Ag positive • HBV IgM negative • Now what? • What is the likely hood this patient actually has chronic, active HBV and HCV • What other co – infections should we screen for in ALL our patients?

  31. HBV and HIV Co-infection

  32. Prevalence of HBV-HIV co-infections by Geography and Route of Infection Thio CL. Hepatology 2009;49:S138-S145

  33. Liver-Related Mortality Liver-related mortality rate (per 1,000 person-years) • Multicenter prospective cohort study of 5293 men who had sex with men (in USA) Thio CL, et al. Lancet 2002;360:1921-6

  34. Influence of HIV on HBV Lower rates of clearance of HBeAg Increased serum HBV DNA viral load 1 Reactivation of hepatitis in asymptomatic carriers Increased liver injury Faster fibrosis cirrhosis and HCC Higher mortality and morbidity (1) Perillo RP, Regenstein FG, et al. Chronic hepatitis B in asymptomatic homosexual men with antibody to the human immunodeficiency virus. Ann Intern Med 1986:105:382-3

  35. Influence of HBV on HIV CONFLICTING DATA Increased rate of HIV progression to AIDS ? 1 No change in progression ? 2 Cohort studies suggest that HBV does not appear to influence the progression of HIV. (1) Eskild A, Magnus P, et al. Hepatitis B antibodies in HIV-infected homosexual men are associated with more rapid progression to AIDS. Aids 1992:6:571-4 (2) Diamondsstone LS, Blakly SA, et al. Prognostic factors for all-cause mortality among hemophiliacs infected with human immunodeficiency virus. Am J Epidemiol 1995:142:304-13

  36. HBV and HIV Therapies * ADV at dose 10mg/D has negligible activity against HIV (activity against HIV started at dose 30mg/D) †LdT has no activity against HIV, but should not be used in HIV/HBV co-infectionbecause risk of selection of M204I mutation in YMDD motif of HIV

  37. HBV-DNA ↑, ALT ↑ (Liver biopsy is considered in pt. with fluctuating or mildly elevated ALT) Not on HAART and treatment for both HIV and HBV in planned Start antiviral Rx that is active against both viruses (combination Rx is preferred) Lamivudine or Emtricitabine + Tenofovir When HAART regimens are altered, drugs that are effective against HBV should not be discontinued without substituting another drug that has activity against HBV AASLD Practice Guideline 2009

  38. Hepatitis D

  39. RCT, 31 HDV patients HBV-DNA levels decreased at wk 48 and rebounded at week 72 in all patients Treatment of Hepatitis D: Peginterferon Versus Adefovir P=0.02 P=0.003 P=0.006 P=0.004 Patients (%) Results at 72 weeks FU Wedermayer H, et al. N Eng J Med 2011;364:322-31

  40. HBV Decompensated Cirrhosis

  41. Lamivudine significantly reduced the incidence of hepatic decompensation and HCC Multicenter, DB-RCT in Asian populations, N=651 P=0.001 P=0.047 Liaw YF, et al. N Engl J Med 2004;351:1521-31

  42. Entecavir and Tenofovir in Advanced Cirrhosis DB-RCT, N=112 CTP and MELD scores improved in all groups 300 mg 0.5 or 1 mg P=NS, across treatment groups Tolerability failure = increased Cr ≥ 0.5 mg/dl from BL or serum phosphate <2 mg/dl x2 consecutive visit % patients (at 48 weeks analysis) Liaw YF, et al. Hepatology 2011;53:62-72

  43. Summary & Curbside Thoughts • Prenatal HBV screening does not always lend way to linkage to care • HBV monitoring during pregnancy and post pregnancy / life long appropriate • Hepatitis B core – check it! • Chronic HBV infection (sAg+) and Chronic HCV infection (+RNA) rare --- treatment paradigm will change in era of HCV DAAs for HCV • Delta screening – one time – for all; patients tend to have evidence of advanced disease; low HBV DNA titers • Always treat HBV in HBV s Ag and clinical or histological evidence of cirrhosis • Chronic HBV infection – a carcinogen! • Yearly HCC surveillance at 40 for males; 50 for females • Earlier age surveillance if FHx HCC or African • If cirrhosis semi annual surveillance

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