Antiviral Management for Liver Transplant Patients. Nanjing Medical University Jiangsu Province Hospital

Transcription

1 Antiviral Management f Liver Transplant Patients Nanjing Medical University Jiangsu Province Hospital Jun Li

2 Viral Hepatitis and Liver Transplant Liver transplantation (LT) is the only effective solution f patients with end-stage liver disease. Viral hepatitis B and C are the most common causes of cirrhosis and hepatocellular carcinoma and the most frequent indications f liver transplantation. post-transplant prophylaxis with HBIG and antiviral drugs, drastically reduced hepatitis B virus (HBV)recurrence, resulting in excellent long-term outcomes. recurrence of hepatitis C is the main cause of graft loss in most transplant programs. New antiviral therapies have been introduced in the market

3 % 19.0% 59.5% 2.0% 52.5% 9.3% 6.9% 8.2% % 8.2% Virus Paracetamol Other drugs 24.2% 32.3% 33.0% 20.1% 12.7% 10.8% 22.4% 18.7% 14.1% 11.8% Other known Unknown Evolu'on of ae'ology of acute liver failure as indica'on f liver transplanta'on, accding to different 'me periods. Journal of Hepatology 2012 vol. 57 j

4 Common Indica+ons f liver replacement: Acute liver failure Chronic liver disease; any cirrhosis which may be due to: Alcoholic liver disease Non-alcoholic fany liver disease Chronic viral hepa''s B, C, D Gene'c liver disease haemochromatosis Wilson's disease Glycogen stage disease types 3 and 4 Tyrosinaemia type 1 a-1 an'trypsin deficiency Autoimmune liver diseases: primary biliary cirrhosis, primary sclerosing cholangi's, chronic ac've liver disease overlap syndromes Metabolic liver disease with life-threatening extra-hepa'c complica'ons Crigler-Najjar syndrome Urea cycle defects Hypercholesterolaemia Organic acidaemias Primary hyperoxaluria Glycogen stage disease type 1 Inherited disders of complement causing atypical haemoly'c uraemic syndrome J. Neuberger / Journal of Autoimmunity 66 (2016) 51e59

5 Other Congenital hepa'c fibrosis Caroli's syndrome, Cys'c Fibrosis, Alagille's syndrome other congenital hereditary liver diseases Biliary atresia Secondary sclerosing cholangi's Progressive familial intrahepa'c cholestasis (all types) Budd-Chiari syndrome Grac versus host disease Liver tumours Hepatocellular carcinoma Unresectable hepatoblastoma (without ac've extrahepa'c disease) Unresectable benign liver tumours with disabling symptoms Variant syndromes Diure'c resistant ascites Chronic intractable hepa'c encephalopathy Intractable pruritus Hepatopulmonary syndrome Familial amyloid polyneuropathy Familial hypercholesterolaemia Polycys'c liver disease Hepa'c epithelioid haemangioendothelioma Sickle cell hepatopathy J. Neuberger / Journal of Autoimmunity 66 (2016) 51e59

6 Liver transplant activity in the UK DBD - donation after brain death DCD - donation after circulaty death J. Neuberger / Journal of Autoimmunity 66 (2016) 51e59

7 A Cumulative survival patients (log-rank p = ) 0.2 Years of liver transplantation Years after liver transplantation Number of exposed patients Years Total B Cumulative survival patients (log-rank p = ) Years of liver transplantation Years after liver transplantation Number of exposed patients Years Total Pa'ent (A) and grac (B) survival acer liver transplanta'on f acute liver failure accding to different years of transplanta'on. Journal of Hepatology 2012 vol. 57 j

8 A Don age >60 years 32% B Don age >60 years 44% Male recipient 33% Male recipient 47% Don age >60 years Male recipient 43% Don age >60 years Male recipient 57% Incompatible ABO match 44% Incompatible ABO match 61% Don age >60 years Incompatible ABO match 55% Don age >60 years Incompatible ABO match 70% Male recipient Incompatible ABO match 55% Male recipient Incompatible ABO match 73% Don age >60 years Male recipient Incompatible ABO match 65% Don age >60 years Male recipient Incompatible ABO match 80% Hosmer and Lemeshow test = 1.88 (0.96) Area under the ROC = 0.66 B Hosmer and Lemeshow test = 2.74 (0.90) Area under the ROC = 0.63 Risk of 3-month (A) and 12-month (B) mtality grac loss in pa'ents older than 50 years transplanted f ALF accding to the presence of independently associated risk facts.

9 Causes of later premature gra: loss recipient survival (adapted from Wa< and others) Grac loss (25e30%) Technical problems (such as hepa'c artery thrombosis, biliary strictures) Recurrent disease (viral, autoimmune, exra-hepa'c metabolic diease) Immune mediated rejec'on (acute cellular, chronic ductopenic and plasma cell) Pa'ent loss Cardio and cerebrovascular disease (10e15%) De novo, don acquired and don derived cancer (20e25%) Some infec'ons (5e10%) Renal failure (5e7%) J. Neuberger / Journal of Autoimmunity 66 (2016) 51e59

10 Management strategies of HBsAg positive transplant patients pre-transplant prophylactic post-transplant therapeutic post-transplant approach HBV prophylaxis f LT recipients who receive graft from anti- HBc positive dons.

11 Prevention of recurrence after LT HBV decompensated cirrhosis all decompensated patients lifelong treatment with ETV TDF should be introduced, unless contraindicated ETV and TDF are currently considered the treatments of choice in this group of patients, due to safety, tolerability, and efficacy Pre-transplant HBV DNA level, presence of HCC, antiviral treatment and post transplant viral mutation as the maj risk facts associated with recurrence after LT. Combination therapy (NA + HBIg) are considered the treatment of choice f prevention of HBV re-activation Prophylaxis of patients who receive livers from anti-hbc positive dons Risk of de novo HBV infection had increased Occult HBV infection had a prevalence of > 40% in alcohol related liver transplanted recipients.

12 HCV treatment strategies f peri-lt patients

13 Characteris+cs of new DAAs against HCV DAA Mechanism of Ac'on Genotypic Coverage Special Considera'ons Approved Telaprevir NS3/4A protease inhibit 1 Discon'nued in United States Boceprevir NS3/4A protease inhibit 1 To be discon'nued in United States 2015 Simeprevir NS3/4A protease inhibit 1, 4 Mild CYP3A inhibi'on Indirect hyperbilirubinemia Sofosbuvir Nucleo'de NS5B polymerase inhibit Pan-genotypic Ledipasvir NS5A replica'on complex inhibit Pan-genotypic Paritaprevir/ ritonavir Renal clearance NS3/4A protease inhibit 1, 4 CYP3A inhibi'on Indirect hyperbilirubinemia Ombitasvir NS5A replica'on complex inhibit 1, 4 Dasabuvir Non-nucleoside NS5B polymerase inhibit 1, 4

14 Experimental Asunaprevir NS3/4A protease inhibit 1, 4 Weak CYP3A induc'on Grazoprevir NS3/4A protease inhibit Pan-genotypic Daclatasvir NS5A replica'on complex inhibit Pan-genotypic GS-5816 NS5A replica'on complex inhibit Pan-genotypic Elbasvir NS5A replica'on complex inhibit Pan-genotypic Beclabuvir Non-nucleoside NS5B polymerase inhibit 1

15 Virologic responses with varying regimens in patients with decompensated cirrhosis

16 Virologic responses in post-lt pa'ents with varying regimens by degree of liver disease.

17 Main resistance-associated variants f DAAs Agent class Drug M28^ Q30^ L31^ V36^ T54^ Q80K Y93^ R155^ A156T* L159F D168^ I170T S282T C316Y V321I M414^ S556G NS3-4A protease inhibits Telaprevir Boceprevir Simeprevir Paritaprevir NS5B Sofosbuvir nucleotide analog inhibit NS5B nonnucleoside Dasabuvir inhibit NS5A inhibits Daclatasvir Ledipasvir Ombitasvir Journal of Hepatology 2015 vol. 63 j

18 Host Cirrhosis IL-28B non-cc Previous NR P/ Male gender Failure to multiple DAAs Genotype 1a Baseline NS5A RAVs* Q80K** Genotype 3 Shten duration of treatment Po adherence No addition of Virus Treatment regimen Most commonly iden'fied facts in DAA-based treatment failure

19 A Genotype 1 Previous therapy P BOC/ TVP SMV P Genotype 3 Recommended salvage DCV options 12 weeks 24 weeks / LDV DCV SMV* / LDV DCV /LDV P / LDV / LDV DCV SMV* DCV B Genotype 1 Previous therapy /LDV DCV OBV/PTV/r DSV No NS5A RAVs NS5A RAVs NS5A RAVs NS5B RAVs NS3-4A RAVs Potential salvage options Wait f further data and new combinations SMV* / LDV Interferon based regimens P P OBV/PTV/r Interferon free regimens P P OBV/PTV/r OBV/PTV/r DSV DCV DSV GZV/EBV OBV/PTV/r DSV DSV DSV OBV/PTV/r DSV OBV/PTV/r DSV DSV Management op'ons f DAA treatment failures. Current recom- mended salvage op'ons f genotype 1 and genotype 3 treatment-experienced pa'ents. Currently available poten'al salvage op'ons f genotype 1 treatment-experienced pa'ents. *The plus SMV combina'on is not recom- mended f genotype 1a-infected pa'ents with Q80K polymphism. Journal of Hepatology 2015 vol. 63 j

20 Suggested approach to HCV treatment in pre-lt pa'ents. Severe complica'ons from ptal hypertension are generally medically refracty ascites encephalopathy.

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