Hematopoietic stem cell transplantation in HBV-infected patients

1. Hematopoietic stem cell transplantation in HBV-infected patients Francesco Paolo Russo, MD PhD Gastroenterology/Multivisceral Transplant Unit Department of Surgery Oncology and Gastroenterology University Hospital Padova, Italy francescopaolo.russo@unipd.it epatitivirali.aopd@aopd.veneto.it

2. Outline • Case report • Introduction to HSCT • Prevalence of HBV in HSCT • Risk of HBV reactivation • Possible use of HSC from positive HBV donors

3. Outline • Case report • Introduction to HSCT • Prevalence of HBV in HSCT • Risk of HBV reactivation • Possible use of HSC from positive HBV donors

4. Case report: Thinking Long-term • 54-yr-old woman with multiple myeloma • Allogeneic stem cell transplantation from her sister • Pretransplantation • ALT: 17 U/L • Bilirubin: 8 umol/dL • Albumin: 38 g/dL • INR: 1.0

5. Case: Evolution • At 18 mosposttransplantation, patient presents with GI and skin graft-vs-host disease • ALT found to be 162 U/L

6. Treat GVHD • Skin and GI GVHD ultimately responded with improvement in ALT • Repeated similar bouts of GVHD treated identically with apparent good clinical responses

7. Conduct Workup for ALT Elevation • Workup revealed HBsAg positive, HBeAg positive • HBV DNA 1.5 x 106 IU/mL • HCV, CMV, EBV all negative • Liver biopsy shows active HBV hepatitis with minimal fibrosis • Treated with entecavir with good response • No recurrence of myeloma 6 yrs later

8. Outline • Case report • Introduction to HSCT • Prevalence of HBV in HSCT • Risk of HBV reactivation • Possible use of HSC from positive HBV donors

9. HSCT - definition Definition any procedure where hematopoietic stem cells of any donor and any source are given to a recipient with intention of repopulating/replacing the hematopoietic system in total or in part

10. first successful HSCT in treatment of acute leukaemia Thomas ED et al. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 1957.

11. HSCT • Allogeneic HSCT • syngeneic • from sibling/related donor • from unrelated donor • Autologous HSCT

12. Indication for HSCT • Neoplastic disorders • Haematological malignancies • Lymphomas (Hodgkin and non-Hodgkin) • Leukaemia (acute and chronic) • Multiple myeloma • MDS • Solid tumors • Non-neoplastic disorders • Aplastic anaemia • Autoimmune diseases • Immunodeficiency • Inborn errors of metabolism

13. Conditioning regimens • Principles • „space-making” (controversial) • immunosuppression • disease eradication • Strategy • Ablative therapy • radio/chemo • Reduced intensity therapy • radio/chemo • Non-myloablative therapy • radio/chemo

14. Factors influencing the outcome of HSCT • Disease factors • stage • Patient - related factors • Age • Viral status • Donor - related factors • Histopompatibility (HLA) • Sex • Viral status • Peri-transplant factors • Conditioning • GVHD prevention • Stem cell source and content • Post-transplant factors • GVHD

15. Allogeneic Early infection aGVHD bleeding toxicity graft failure Late chGVHD infection relapse gonadal failure secondary malignancy toxicity Autologous Early infection bleeding toxicity Late relapse infection gonadal failure secondary malignancy toxicity Complications

16. Outline • Case report • Introduction to HSCT • Prevalence of HBV in HSCT • Risk of HBV reactivation • Possible use of HSC from positive HBV donors

17. Global prevalence and genotype distribution of hepatitis B virus infection in 2016: a modelling study Lancet Gastro Hep2018

18. Prevalence in HSCT recipients InfectiousDiseasesWorking Party (IDWP) 3.1% Locasciulli et al BMT 2003

19. Outline • Case report • Introduction to HSCT • Prevalence of HBV in HSCT • Risk of HBV reactivation • Possible use of HSC from positive HBV donors

20. HBV Reactivation Risk Assessment Drug Immunosuppression Potency Low High Immune Control Risk of Reactivation Anti-HBs Anti-HBc Positive Negative Negative Positive HBsAg Negative Low Level High Level HBV DNA ResolvedInfection OccultInfection InactiveHBsAg Carrier Immune ActiveChronic Hepatitis B Perrillo RP, et al. Gastroenterology. 2015 Bessone F, et al. World J Hepatol. 2016

21. Do You Ever Really Get Rid of HBV? • Immune control—not clearance • “Resolved HBV” a misnomer—still HBV DNA in liver cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004

22. Do You Ever Really Get Rid of HBV? • Immune control—not clearance • “Resolved HBV” a misnomer—still HBV DNA in liver cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004

23. T cell T cell T cell Do You Ever Really Get Rid of HBV? • Immune control—not clearance • “Resolved HBV” a misnomer—still HBV DNA in liver cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004

24. T cell T cell T cell Along comes immune suppression • Immune control can be lost • Immune-mediated liver damage with immune reconstitution HIV Steroids Chemotx cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004

25. T cell T cell T cell Along comes immune suppression • Immune control can be lost • Immune-mediated liver damage with immune reconstitution HIV Steroids Chemotx cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004

26. AASLD Survey: HBV Reactivation by Cancer Type • Survey of AASLD members regarding HBV reactivation experiences during cancer chemotherapy (N = 188 pts described) HBV Reactivation HCC SolidHematologic Unknown Breast, n = 17Lung, n = 4 Colon, n = 2 Lymphoma, n = 88Leukemia, n = 30 Other, n = 8 Hwang JP, et al. J Viral Hep. 2015

27. HBV reactivation after HSCT and rituximab-containing chemotherapy: a 12-year experience at a single center Hwang JP, et al. J Viral Hep. 2015

28. Hepatitis B Reactivation in Occult Viral Carriers Undergoing Hematopoietic Stem Cell Transplantation: A Prospective Study Setoet al. Hepatology 2017

29. Risk of hepatitis B surface antigen seroreversion after allogeneic hematopoietic SCT Viganòet al. BMT 2012

30. Cumulative rates of HBV reactivation Setoet al. Hepatology 2017

31. HBV Reactivation and HSCT HSCT, and in particular allogeneic HSCT (allo-HSCT) is associated with a high risk for HBV reactivation. Higher rate reported in HBsAg-positive recipients • HBsAg-positive auto- and allo-HSCT recipients • Auto- and allo-HSCT recipients with ?resolved’ HBV infection • HBV-negative allo-HSCT recipient with an anti-HBV-positive donor Sarmatiet al. Clin Micr Inf. 2017

32. HBsAg-positive auto- and allo-HSCT recipients • All HBsAg-positive HSCT recipients should be treated independent of the presence or the level of HBV DNA (strong recommendation, moderate quality of evidence). • Antiviral treatment should be conducted with last generation nucleos/tide analogue (strong recommendation, moderate quality of evidence) • Antiviral drugs should be started at least a week before the HSCT procedure and should be continued for at least 1 year (strong recommendation, moderate quality of evidence). Sarmatiet al. Clin Micr Inf. 2017

33. Auto- and allo-HSCT recipients with resolved HBV infection • All anti-HBc-positive HSCT recipients should receive prophylaxis with lamivudine, independent of the presence of HBV DNA, for a time period of at least 18 months (strong recommendation, moderate quality of evidence). • Ideally, the duration of antiviral prophylaxis should be based on immune recovery (i.e. increased CD4 counts above 200-400 cells/cubic millimeter), which can take years after allo-HSCT. • Close monitoring of viraemic rebound and seroreversion should be performed when prophylaxis is discontinued. The timing of monitoring is not actually defined. Sarmatiet al. Clin Micr Inf. 2017

34. Outline • Case report • Introduction to HSCT • Prevalence of HBV in HSCT • Risk of HBV reactivation • Possible use of HSC from positive HBV donors

35. HBV-negative allo-HSCT recipient with an anti-HBV-positive donor • All HBV-negative allo-HSCT recipients with anti-HBc-positive/anti-HBs-positive or -negative (HBV DNA negative) donors should receive prophylaxis with lamivudine (weak recommendation, moderate quality of evidence). • The lamivudine prophylaxis duration is not defined (no recommendation, knowledge gap ). Sarmatiet al. Clin Micr Inf. 2017

36. Vaccination in HBV in patients with haematologic malignancies and/or patients who underwent HSCT • All these patients should undergo HBV vaccination • Anti-HBs titre should be periodically monitored (strong recommendation, low quality of evidence). • HBV vaccination of HBV-negative auto- or allo-HSCT patients should be performed before beginning the conditioning regimen. • In the allo-HSCT setting, vaccination of donors for HBV-positive recipients is also suggested, with the goal that the adaptive immune response from the HBV-vaccinated donor could protect the recipient from HBV reactivation Sarmatiet al. Clin Micr Inf. 2017

37. Hepatitis B virus reactivation in patients treated with immunosuppressive drugs: a practical guide for clinicians Koffaset al. ClinScience. 2018

38. Conclusions • Markedly high rate of reactivation (HBsAg positive) • Up to 54% → need preemptive antiviral therapy • Long-term complications: cirrhosis in 10% • Reverse seroconversion common if anti-HBc positive • Up to 50% become HBsAg positive → use preemptive antivirals • May occur very late • Risk factors for reactivation: chronic disease, GVHD, age>50 • HBV status of donor important • If natural immunity (anti-HBs, anti-HBc): may clear HBsAg • If vaccinated (anti-HBs): possibly some protection