Infective hepatic complications in HSCT patients. Simone Cesaro. Pediatric Hematology Oncology Verona, Italy. Session II: organ specific complications

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1 Session II: organ specific complications Infective hepatic complications in HSCT patients Simone Cesaro Pediatric Hematology Oncology Verona, Italy

2 Liver complications after HSCT - Hepatic dysfunction can occur up to 80% of patients - 5%-15% of TRM is related to post-transplant liver disease

3 Liver complications after HSCT - Hepatic dysfunction can occur up to 80% of patients % of TRM is related to post-transplant liver disease Main causes: - GVHD - VOD -- virus: CMV, EBV, HHV6, ADV - HBV, HCV hepatitis - fungi: Candida, Aspergillus, Fusarium - iron overload

4 Liver complications and hepatitis Recipients: - Pre-HSCT AST increase RR of fulminant hepatis of 4.6 fold (McDonald 1993) - Pre-HSCT ALT increase and HCV + RR of severe VOD of 9.6 (Strasser 1999)

5 Liver complications and hepatitis Recipients: - Pre-HSCT AST increase RR of fulminant hepatis of 4.6 fold (McDonald 1993) - Pre-HSCT AST increase and HCV + RR of severe VOD of 9.6 (Strasser 1999) Donor: - pre-harvest ALT increase RR of fulminant hepatis/vod in the recipient of 6.3 fold (Strasser 1999)

6 Impact of HBV or HCV positivity of donor or recipient on related allo-hsct Retrospective study, related allo-hsct seronegative pts with a seropositive donor, 128 seropositive patients with a seronegative donor 256 matched controls, Tomblyn et al Transplant Infect Dis 2012

7 Impact of HBV or HCV positivity of donor or recipient on related allo-hsct Retrospective study, related allo-hsct seronegative pts with a seropositive donor, 128 seropositive patients, 256 matched controls Variable/ probability R-HBsAg (N=28) R-HBcAb (N=27) R-HCV pos (N=29) D-HBsAg (N=14) D-HBcAb (N=7) D-HCV pos (N=12) R/D HBV or HCV pos (N=44) Controls (N=256) agvhd II-IV y cgvhd y TRM y-OS Liver toxic VOD liver agvhd Liver cgvhd Tomblyn et al Transplant Infect Dis 2012

8 Impact of HBV or HCV positivity by donor or recipient on related allo-hsct Retrospective study, related allo-hsct seronegative pts with a seropositive donor, 128 seropositive patients, 256 matched controls Variable/ probability R-HBsAg (N=28) R-HBcAb (N=27) R-HCV pos (N=29) D-HBsAg (N=14) D-HBcAb (N=7) D-HCV pos (N=12) R/D HBV or HCV pos (N=44) Controls (N=256) agvhd II-IV y cgvhd y TRM y-OS Liver toxic VOD liver agvhd Liver cgvhd Tomblyn et al Transplant Infect Dis 2012

9 Impact of HBV or HCV positivity by donor or recipient on related allo-hsct Retrospective study, related allo-hsct seronegative pts with a seropositive donor, 128 seropositive patients, 256 matched controls Variable/ probability R-HBsAg (N=28) R-HBcAb (N=27) R-HCV pos (N=29) D-HBsAg (N=14) D-HBcAb (N=7) D-HCV pos (12) R/D HBV or HCV pos (N=44) Controls (N256) GVHD II-IV y cgvhd y TRM y-OS Liver toxic VOD liver agvhd Liver cgvhd Prior exposure to HBV or HCV by the donor or the recipient is not an absolute controindication to HSCT

10 HBV worldwide - 2 billion people have been infected with HBV - Chronic HBV infection affects 350 million people WHO 2009

11 HBV worldwide 2 billion people have been infected with HBV Chronic HBV infection affects 350 million people HBV may: - Cause fulminant hepatitis (1%) - progress to chronic HBV hepatitis (20%-40%) - increase the risk of HCC (300-fold) WHO 2009

12 HBV in Europe Incidence of notification in Europe: 1.29/ Highest in Bulgaria (8.17), Latvia (6.16), Estonia (3.95), Romania (5.9) Italy & Sweden (1.8), Germany (1.4), Spain (1.1), France (0.29)

13 HBV in HSCT - Recipients HBsAg pos (seropositive) - Recipient HBsAg neg, HBcAb pos (previous exposure) - Recipient HbsAg neg, HBcAb neg (seronegative) with HBV seropositive donor

14 HBV seropositive patient -The prevalence of HbsAg positive recipient varies between 1% and 28%, depending on geographic aerea - An EBMT study showed that 3% (6/193) of patients are HbsAg pos before HSCT (data collected before 2000) -The risk of acute exacerbation of hepatitis is > 60% at 24 months post-hsct: 81% for allo-hsct, 66% for auto-hsct - Risk factors are: steroids, GVHD, unrelated HSCT, CMV infection, HBV neg donor - The risk of fulminant hepatitis is 3% - The probability of sero-reversion to HBsAb is 25% Locasciulli et al.transplantation 2003 ; Brugger et al Lancet 1997; Lau et al Crit Rev Oncol Hematol 1993 Lau et al Bone marrow Transplnt 1997

15 HBV seropositive recipient Preventative and Treatment measures - Strict monitoring for LFTs and HBV DNA during HSCT - Prophylaxis with lamivudine 100 mg/d for 6-12 months or more -Use steroids in case of acute hepatitis (ALT flare > 500 U/l) and Iper-immune IgG - Prednisone 2 mg/kg for 2 weeks, then slow tapering or - Prednisone 60 mg/day for 4 day or until PT normalized, than taper 10 mg every 4 days, until 30 mg, followed by mg tapering every 2 weeks -IgG HBV 5000 U every 2 weeks for 3 times, then monthly for 6 monts (limited data) -Switch to adefovir + lamivudine to prevent resistance or to entecavir Locasciulli Medit J Hematol Infect Dis 2009; Strasser et al Clin Transplant 2006; Liang R.Blood 2009;

16 Recipient with previous HBV exposure (HBsAb and HBcAb pos) - The phenomenon acute HBV hepatitis in HBcAb pos pts is called reverse seroconversion: described in 6%-86% of patients - In a recent retrospective study, previous HBV exp. was found in 4.4% (61/1386) of patients - 12 of 61 (20%) patients had HBV reactivation at a median time from HSCT of 17.5 m. (range 4-44) - Chronic hepatitis was observed in 10/12 patients and in 6 of them the clinical diagnosis different from chronic HBV hepatitis - Fulminant hepatitis: 8% (1/12) Hammond et al. Biol Blood Marrow Transplant 2009

17 Recipient with previous HBV exposure (HBsAb and HBcAb pos) - The phenomenon is called reverse seroconversion: described in 6%-86% of patients - In a recent retrospective study, previous HBV exp. was found in 4.4% (61/1386) of patients - 12 of 61 (20%) patients had HBV reactivation at a median time from HSCT of 17.5 m. (range 4-44) - Chronic hepatitis was observed in 10/12 patients and in 6 of them the clinical diagnosis different from chronic HBV hepatitis - Fulminant hepatitis: 8% (1/12) - Cumulative probability of HBV reactivation was 9% at 1 y, 22% at 2 y, 30% at 3 y, 43% at 4 y - Risk factors: pre-hsct titer of HBsAb < 10mIU/ml (RR 4.6) extensive cgvhd (RR 7.2) -Virological Response Rate with adefovir + lamivudine or entecavir of 64% (7/11) and 3 pts recovered completely Hammond et al. Biol Blood Marrow Transplant 2009

18 HBV seronegative recipient with seropositive donor - de novo infection with HBsAg and HBV-DNA seroconversion occurs in 3% of HSCT (Locasciulli et al Transplantation 1999) -In the era of blood product screening the main cause is a HBsAg pos donor -Seroconversion to HBsAg of the recipient is observed in 22% but only in 5% the infection became chronic -Liver failure in the recipient was observed in 21% of HbsAg seroconverted recipients - Recipients with HBsAb had less seroconversion rate and no liver failure - Recipients HbeAb pos. are at higher risk of liver failure Locasciulli et al.. Blood 1995

19 HBV seronegative recipientprevention measures - HBV seronegative recipient vaccination before HSCT (limited efficacy) - Donor treatment with lamivudine before harvest/pbsc collection - Iper-immune Ig in the first 6 months after HSCT, 5000 U every 2 weeks for 3 times, then monthly for 6 monts(limited data) - Lamivudine prophylaxis in the recipient or - Strict monitoring of recipient for HBV-DNA and HbsAg, if positive treat with lamivudine and adefovir or entecavir/tenofovir Locasciulli Medit J Hematol Infect Dis 2009; Strasser et al Clin Transplant 2006; Liang R.Blood 2009;

20 HCV infection worldwide HCV prevalence > 10% % % WHO estimate: 140 million people affected, 2.2% of world population High prevalence in asiatic, latino-american and subsaharian countries USA (2003): 4 million people affected, Incidence of 0.4/ Italy (2004): 5 million people affected, incidence of 0.5/

21 HCV infection in Europe < 0.5 % 0.5-1% % % % > 3.6% HCV prevalence North Europe: 0.1-1% Central Europe: % South Europe, Eastearn europe countries: % Ukraine, Rumenia: > 3.6%

22 HCV: early morbidity and mortality after HSCT (I) - Frequent cause of liver dysfunction in the first 3 months after HSCT with ALT increase up to 5-10 times - Risk factor for VOD: debated issue To day: HCV is not considered a risk for VOD if Fludarabin-RIC based, targeted BU, low-dose TBI are used

23 HCV: early morbidity and mortality after HSCT (I) - More frequent differential diagnosis is GVHD, then fungal infection, TPN, drug toxicity iron overload: a) Non-invasive method: PAI-1 b) Invasive method: liver biopsy In the post-transplant period the increase of ALT > 500 U/l and of HCV viral load requires the add/augment of steroid dose and a very slow tapering to avoid fulminant hepatitis Be careful: fulminat hepatitis is associated with HAV-HCV co-infection

24 HCV: impact on survival (II) - 31 HCV + adult patients, allo-hsct (68% related donor; 68% RIC), median f-up 34 m vs 31 matched controls (median f-up 27 m.) and 1800 cohort-controls (median f-up 29 m) - period y OS: HCV + 29% vs. 56%, HR 3.1 CI-NRM: HCV + 43% vs 23% and 24%, HR 3.3 Multivariate analysis for survival: HCV + (HR 3.1), High-risk disease (HR 1.9) RIC (HR 0.7), MSD (HR 0.6) Ramos et al. Haematologica 2008

25 HCV: long term effects (III) - 96 HCV + patients, allo-hsct, median f-up 15.8 yrs vs. 158 HCV neg. controls (median f-up yrs) - period CI of cirrhosis and cancer in HSCT HCV+ CI of cirrhosis: HSCT vs. non-hsct pts At 20 years, the CI of cirrhosis was 24% and of HCC was 5% Median time to cirrhosis was 18 years (HSCT) vs. 40 yrs (non-hsct) Peffault de la Tour et al. Blood 2004

26 HCV: long term effects (IV) Summary of the retrospective studies on the long-term f-up of HCV + pts post-hsct Peffault de la Tour et al. J Hepatol 2008

27 HCV: treatment (V) 85/195 patients treated for HCV post-hsct Median time from HSCT: 9.3 yrs Sustained Response Rate: IFN 31% (10/32) IFN + Riba 57% (16/28) Peg-IFN + Riba 67% (6/9) SRR according genotype: genotype 1, 34% (11/32) genotype 2 and 3, 64% (7/11) Adverse effects: In 51 of 85 pts no SAE were reported, only mild flu-like symptoms 5 had leucopenia and/or thrombocitopenia 2 patients received blood transfusions No increase of GVHD activity Ljungman P et al. Bone Marrow Transplant 2012

28 Conclusions Viral hepatitis is a less frequent infective complication in HSCT patients, but not null Mind at geographic provenience of your patient in planning work-up and conditioning regimen In related HSCT, HCV or HBV positivity of the donor seems to not affect final outcome Active HBV or HCV hepatitis are a risk for VOD/liver failure (liver biopsy!) Strict patient monitoring and antiviral prophylaxis (for HBV) are useful tool to reduce morbidity and mortality by viral hepatitis

29 HEV Hepatitis agent, fecal-oral route of trasmission, endemic in limited-resource countries 4 genotypes: 1, 2 responsible for waterborne large outbreaks 3, 4 sporadic zoonotic cases in industrailized countries Prevalence of 1-3% in SOT, progression to chronic HEV in 47-83% of cases, fibrosis 67%, cirrhosis 10% Prevalence of pre-hsct HEV IgG positivity of 13% Prevalence in HSCT of 0-2.4% progression to chronic HEV in 63% Treatment: oral ribavirin ( mg/die), reduction of IS