Hematopoietic stem cell transplantation in HCV-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

Outline Prevalence of HCV in HSCT recipients HCV positive donors Chronic hepatitis C in HSCT recipients

Outline Prevalence of HCV in HSCT recipients HCV positive donors Chronic hepatitis C in HSCT recipients

Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study Lancet Gastro Hep 2017

Prevalence in HSCT recipients Infectious Diseases Working Party (IDWP) 6 % Locasciulli et al BMT 2003

Risk of hepatitis reactivation in HCV-infected patients undergoing allogeneic (a) vs autologous (b) HSCT Locasciulli et al BMT 2003

Outline Prevalence of HCV in HSCT recipients HCV positive donors Chronic hepatitis C in HSCT recipients

The HCV-RNA-positive donor -American recommendations- HCV infection in donors should not be an absolute contraindication for HSCT (class I, level C). The risk of HCV transmission is extremely low when HCV-RNA- candidates receive HSCT from anti-HCV+/HCV-RNA- donor (class I, level C). In case of HCV-RNA+ donor, antiviral therapy should be started, ideally attaining undetectable HCV-RNA before stem cell harvest (class I, level C). Biology of Blood and Marrow Transplantation 2015

HCV-related liver disease of donors HCV-infected donors should be assessed for advanced chronic liver disease and other extrahepatic manifestations of HCV to recommend an optimal management of their disease (class I, level C). Biology of Blood and Marrow Transplantation 2015

The HCV-RNA-positive donor -European recommendations- In general, HCV-RNA-positive donors should not be considered, because they will transmit HCV to the recipient. But it could be considered if other donor options are inferior. In this case, the donor should be treated with new direct-acting antivirals (DAAs) (class III, level B) Lancet Infection Disease 2016

Outline Prevalence of HCV in HSCT recipients HCV positive donors Chronic hepatitis C in HSCT recipients

Chronic hepatitis C in recipient of HSCT They are at high risk for liver complications: viral reactivation acute hepatitis accelerated liver disease progression veno-occusive disease Ramos et al Haematologica 2009

Physiopathology of liver lesions in HSCT recipients with chronic hepatitis C Physiopathology of liver lesions in Stem cell transplant recipients with chronic hepatitis C. There are specific factors due to the allogeneic and immunosuppressed context that are responsible for quicker fibrosis progression: Pre-transplant liver toxicity: the conditioning may directly support the liver injury, as well as inflammatory cytokines. Iron overload (transfusions) is also responsible for liver fibrosis. Immediate post-transplant period: the HCV replication rate exceeds largely the kinetics of the immune response. The virus extension is rapid to a high number of hepatocytes. Insulino resistance, steatosis and/or obesity are now recognized as important risk for fibrosis progression. Immune recovery: NK compartment is the first to recover after transplant. HCV is able to inhibit NK cell cytotoxicity and cytokine production. Specific humoral immune response takes time and is limited after HCT. Reconstitution of the immune system after a period of depressed cellular immune responses increases inflammatory activity in the liver, with enhanced HCV-specific immune responses. Long-term outcome: a more rapid rate of liver fibrosis progression is observed in HCV-infected HCT patients with an expected median time to cirrhosis of about 18 years after HCT Peffault de Latour et al. J Hep 2008

Monitoring HCV in HSCT Recipients with Chronic HCV Infection -American recommendations- In HSCT recipients with chronic HCV infection, ALT level should be evaluated at entry into care, 2 to 8 weeks after completion of the conditioning regimen, every 2 to 8 weeks during maintenance chemotherapy or immunosuppressive treatment, and every 3 to 6 months thereafter (class II, level C). In HSCT recipients with chronic HCV infection, routine monitoring of HCV RNA is not recommended. However, viral load should be considered for patients who have an unexplained elevation of ALT (class II, level C). HCV RNA should be measured in all patients at entry into care, and monitoring of viral load should be performed in patients receiving HCV treatment according to the AASLD-IDSA HCV guidance (http://www.hcvguidelines.org/) (class I, level C).

Severe hepatitis C reactivation as an early complication of hematopoietic cell transplantation Oliver et al. BMT 2017

Long-term outcome A more rapid rate of liver fibrosis progression is observed in HCV-infected HSCT patients vs HCV patients, with an expected median time to cirrhosis of about 18 vs 40 years, respectively. Peffault de Latour et al. J Hep 2008

Timing of antiviral treatment in the HCV+ recipient DAAs should be considered before HSCT. The alternative is to treat the recipient after HSCT using DAAs after immune reconstitution. It is urgent for: patients with fibrosing cholestatic hepatitis patients with cirrhosis whose condition is deteriorating

fewer relapse of non-Hodgkin lymphomas, 20% vs 86%, p=.015 Hepatitis C virus infection in patients undergoing hematopoietic cell transplantation in the era of DAAs 64 HCV-infected patients underwent allogenic and autologous HSCT 2009-2015 Treated patients had: fewer relapse of non-Hodgkin lymphomas, 20% vs 86%, p=.015 higher 5-year survival, 75% vs 39%, p=.02 trend toward lower rate of progression to cirrhosis, 5% vs 21%, p=.06 Kyvernitakis et al. BMT 2017

13% HCV-RNA negative after HSCT Hepatitis C virus infection in patients undergoing hematopoietic cell transplantation in the era of DAAs SVR in 32% of cases with IFN-based and 85% with DAA-based antiviral therapy. 13% HCV-RNA negative after HSCT HCV seropositivity can be lost post-HSCT posing a diagnostic challenge Kyvernitakis et al. BMT 2017

Drug–Drug Interactions in HCV-Infected HCT Candidates and Recipients Receiving DAAs and Conditioning Regimens or Immunosuppressive Agents DDI can be pharmacokinetic, resulting in changes in drug concentrations, or pharmacodynamic, resulting in additive, synergistic, or antagonistic effects on efficacy or toxicity  Physicians should frequently assess for DDI in HCV-infected HCT recipients (class I, level C). HCT candidates should not receive DAAs concomitantly with the chemotherapy preparative regimen if the potential for DDI exists (class I, level C).

2015

Successful treatment of hepatitis C virus infection with DAAs during hematopoietic cell transplant Cunningham et al. Transpl Infect Dis 2019

Successful treatment of hepatitis C virus infection with DAAs during hematopoietic cell transplant Delaying HCT to complete antiviral therapy presented an unacceptable risk for AML relapse Untreated infection during chemotherapy or HCT is associated with accelerated liver disease, HCV exacerbation, and increased mortality Cunningham et al. Transpl Infect Dis 2019

Conclusions Very high prevalence of viral reactivation HCV represents a significant cause of morbidity and mortality in HSCT recipients. Treatment of HCV infection should be offered to donors and recipients, because it improves outcomes, increases overall survival, and lowers relapse rates. Those patients can be safely treated with DAAs, with monitoring for potential drug-drug interaction.