Il trapianto di cellule staminali emopoietiche nel paziente portatore di virus epatitici Anna Locasciulli Ematologia e Trapianto di Cellule Staminali Emopoietiche Ospedale S.Camillo, Roma
Il trapianto di cellule staminali emopoietiche nel paziente portatore di virus epatitici Anna Locasciulli Ematologia e Trapianto di Cellule Staminali Emopoietiche Ospedale S.Camillo, Roma
Viruses and liver disease Hepatotropic viruses = acute and chronic disease that exclusively or primarily involve the liver Other viruses = possible cause of clinically significant liver damage as part of a systemic disease
Hepatitis viruses and HSCT patients Before HSCT - latent infection with no liver disease - chronic asymptomatic hepatitis - acute,clinically overt hepatitis (rare) Following HSCT - reactivation of latent infection ± LD - de novo infection ± LD - unmodified ongoing chronic hepatitis
HBV and HCV infection in HSCT Pre-SCT HBV/HCV infected patient HBV/HCV infected donor HBV/HCV infected patient and donor post-sct de novo HBV/HCV infection ± hepatitis HBV/HCV hepatitis reactivation
Host variables λ Underlying disease λ Degree of immune competence λ Presence of other causes for liver disease λ Age λ Type of SCT
Type of SCT - autologous Liver disease is likely to mimic what has been seen during standard chemotherapy Other hepatotoxic agents (other infections, drugs, TPN)
Type of SCT - allogeneic Donor immune status Post-SCT immunosuppression VOD Liver GVHD Other hepatotoxic agents (other infections, drugs, TPN)
Epidemiology Prevalence HBV HCV Donors 2.6 2 SCT candidates 3.1 6 Post-SCT de novo infection 3.6 7 Transplantation, 1999
Risk for death of liver failure %r isk of death in LF 100 90 80 70 60 50 40 30 20 10 0 A= Autologous: n pts 54 5% B= Allogeneic: n pts 36 7% p=0.34 12 24 Months from BMT
% risk of death in LF 100 90 80 70 60 50 40 30 20 10 0 Risk for death of liver failure A=HBV n=33 3% B=HCV n=57 8% P=0.6 12 24 Months from BMT
Post-SCT liver disease in AUTO SCT with HBV or HCV infection 70 60 50 40 30 20 HBsAg+ HCV+ 10 0 no LD unchang. reactiv F/subAH liver disease (%): no LD = absent or resolved; unchang= unmodified by SCT; reactiv= acute flare;f/subah= fulminant or subacute
Post-SCT liver disease in ALLO SCT with HBV or HCV infection 50 45 40 35 30 25 20 15 10 5 0 no LD unchang. reactiv. F/subAH HBsAg+ HCV+ liver disease (%): no LD = absent or resolved; unchang= unmodified by SCT; reactiv= acute flare;f/subah= fulminant or subacute
Post-SCT liver disease in ALLO SCT with donor HBV or HCV infection 80 70 60 50 40 30 20 10 0 no LD unchang. de novo F/subAH HBsAg+ HCV+ liver disease (%): no LD = absent or resolved; unchang= unmodified by SCT;de novo = new post-sct infection;f/subah= fulminant or subacute
Post-SCT liver disease in ALLO SCT: donor + pat HBV or HCV infection 100 90 80 70 60 50 40 30 20 10 0 no LD unchang. reactiv. F/subAH HBsAg+ HCV+ liver disease (%): no LD = absent or resolved; unchang= unmodified by SCT; reactiv= acute flare;f/subah= fulminant or subacute
Virus mutations Cyclic emergency of escape mutant virus under the pressure of the host immune response. HBV pre-core mutants HCV hypervariable region mutations
Superinfections with other viruses Hepatitis Delta Virus HBV Hepatitis A Virus HCV Virus mutation and superinfection both modify the course of established liver disease ( fulminant evolution, cyclic flares
HBV/HCV infected SCT candidate What are the infection characteristics? Long-lasting carrier status? With / without liver disease? Suspicion of recent infection? (serologic profile (e.g. anti-hbc IgM+); acute hepatitis concomitant to documented seroconversion (e.g.: from HCV-RNA - to HCV-RNA+)
Assessment of Liver Disease in HBV/HCV infected SCT candidate What happened to the liver function during the chemotherapy? For example pattern and timing of : ALT elevation, clinically overt hepatitis, ALT flares? If the hepatitis exacerbated during the time-intervals between CT courses or following its withdrawal, post- SCT reactivation is likely to occur.
HBV/HCV infected SCT candidate Histologic assessment : fibrosis inflammatory activity iron deposition
Contraindication for SCT: Absolute Clinically decompensated liver disease ascites splenomegaly ± thrombocytopenia hepatic encephalopathy portal hypertension liver failure
Contraindication for SCT: relative If there is a clinically compensated cirrhosis - older age - underlying disease
Management of HBV λ Before SCT λ Early after SCT λ Long-term
Effect of HBV vaccination on HBV infection after BMT Previous HBV vaccination Total N (%) HbsAg positivity donor recipient in BMT Pts N (%) no no 74 (67) 3/74 (4) yes no 6 ( 5) 1/6 (17) yes yes 25 (22) 0/25 (0) no yes 6 ( 5) 0/6 (0) Blood,97
Therapy of HBV infection In case of normal or slightly abnormal ALT at SCT, and no reactivation during chemotherapy: Monitoring of LFT s, especially after engraftment and from 3-6 months post SCT (immune restoration) Careful tapering of immunosuppressive therapy posttransplant, with monitoring of clinical and biochemical parameters and serum viral markers and viral load. If there is no post-sct liver disease, no therapy is required
Therapy of HBV infection In case of ALT deterioration during follow-up together with documented HBV-DNA in serum or increased viral load: Lamivudine 100 mg/day (12 months?) Hepatitis B IgG, 5000 U/day i.v. per dose, given at the following time-intervals : day 0, +14, +28, followed by monthly infusions of the same dosage for 6 months
Current therapies for chronic HBV hepatitis Interferon alpha 10 MU thrice weekly or 5 MU /day for 4-6 mths Sustained response 20-40% Nucleotide Analogues (lamivudine, famciclovir, ganciclovir, adefovir) -----> can decrease HBV-DNA up to negativity in 70-90% but erradication is rarely achieved reactivation often occurs at therapy withdrawal
Treatment of chronic B hepatitis in SCT recipients Interferon, with or without nucleotide analogues, may be proposed in patients with with stable engraftment and no evidence of recurrence of the underlying disease, autoimmune diseases and chronic GVHD, In cases of iron overload, phlebotomy or chelating agents should be administered prior to interferon therapy.
Management of HCV λ Before SCT λ Early after SCT λ Long-term
Before SCT λ How strong is the SCT indication? λ Is there time to treat the HCV before SCT? λ Prefer BMT rather than PBSCT ( risk of cgvhd) λ To prevent hepatitis A virus co-infection, consider HAV vaccine prior to SCT λ If the SC- donor is anti-hav negative, consider HAV vaccine
Prophylaxis and preemptive therapy Ribavirin????
Allo SCT in patients with HCV-RNA+ (with or without anti-hcv) In case of normal or slightly abnormal ALT at SCT and no reactivations during chemotherapy: Monitoring of LFT s, especially after engraftment and from 3 to 6 months after SCT (immune restoration). If there is no post-sct liver disease, no particular measures are required.
Allo SCT in patients with HCV-RNA+ (with or without anti-hcv) In case of ALT deterioration during follow-up together with documented increased viral load or clinical hepatitis: Add immunosuppressive therapy with corticosteroids 2 mg/kg/day Careful tapering of immunosuppressive therapy posttransplant, with monitoring of clinical and biochemical parameters and serum viral markers and viral load.
Current therapy for chronic HCV Interferon Alpha 3-6 MU thrice weekly for 12 months Rate of sustained response 10 % - 30 % depending on genotype and pretreatment virus load Addition of Ribavirine 3 fold increased sustained response rate
Treatment of chronic C hepatitis in SCT recipients Interferon, with or without ribavirin, may be proposed in patients with with stable engraftment and no evidence of recurrence of the underlying disease, autoimmune diseases and chronic GVHD, In cases of iron overload, phlebotomy or chelating agents should be administered prior to interferon therapy.
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