Hepatitis C: Management of Advanced and Complicated Disease

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2 Hepatitis C: Management of Advanced and Complicated Disease David C. Wolf, MD, FACP, FACG, AGAF, FAASLD Medical Director of Liver Transplantation Westchester Medical Center Professor of Clinical Medicine New York Medical College

3 Hepatitis C: Advanced and Complicated Disease Objectives: Extrahepatic complications of HCV HCV cirrhosis. Incidence Complications Treating the patient with HCV cirrhosis Approach to the HCV patient awaiting organ transplant (kidney, heart).

4 Extrahepatic complications of hepatitis C

5 Extrahepatic complications of hepatitis C Strongly associated Mixed cryoglobulinemia Sjögren (sicca) syndrome Lymphoproliferative disorders Porphyria cutanea tarda Neuropathy Membranoproliferat ive glomerulonephritis Cryoglobulinemic vasculitis Possibly associated Corneal ulcers (Mooren ulcers) Thyroid disease Lichen planus Pulmonary fibrosis Type 2 diabetes Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis) Arthralgias, myalgias, inflammatory polyarthritis Autoimmune thrombocytopenia Adapted from Ali A, Zein NN. Cleve Clin J Med. 2005;72:

6 Extrahepatic complications of hepatitis C A 39 year old man with non-cirrhotic chronic hepatitis C (genotype 1), presents with: Ankle edema àlower and upper leg edema. Rash over lower extremities. No ascites. Creatinine 3.2 mg/dl. Albumin 1.8 g/dl 24 urine protein = 5 grams Alk phos 50, AST 60, ALT 70, T.bili 1.3 mg/dl, INR 1.0 Complement level is low. What is the diagnosis? Is HCV treatment indicated at this time?

7 HCV-induced cryoglobulinemia What is mixed cryoglobulinemia? Systemic vasculitis. Affects small and medium-sized arteries and veins. Cryoglobulins: Immune complexes. Precipitate out of solution. Deposit in endothelial surfaces. Components of cryoglobulin: IgG (HCV IgG) IgM (i.e. Rheumatoid Factor) HCV RNA Complement Cryoglobulins induce inflammation via B-cell mediated mechanism. B-cell lymphoproliferative disorder Charles ED, Dustin LD. Kidney Int 2009;76:818.

8 HCV-induced cryoglobulinemia Prevalence: 10-70% of HCV patients. Incidence: 3% per year. Cryoglobulin testing. Serum is prepared at 37 o C to prevent premature precipitation of immune complexes. Then, stored at 4 o C. Inspected to assess for a precipitate. % of cyroglobulin in serum is calculated. Cryocrit > 2% is positive. Lab abnormalities: Low C4 level. Positive rheumatoid factor. Positive cryocrit.

9 HCV-induced cryoglobulinemia Potential consequences of cryoglobulinemia. Leukocytoclastic vasculitis à palpable purpura. Glomerulonephritis. Neuropathy. GI vasculitis. Treatments: Plasmapheresis. Rituximab. Steroids. HCV DAA.

10 HCV cirrhosis

11 HCV cirrhosis: Natural history

12 Cirrhosis: Well-compensated vs. Decompensated Well-compensated Quality of life Good Poor Major complications Survival No Decompensated Yes 1-year 94% 60% 2-year 90% 47% 10-year 60% 7% Liver failure End stage liver disease D Amico G, 2001.

13 Cirrhosis: Assessing Severity Child-Turcotte-Pugh Score Parameter 1 point 2 points 3 points Ascites Absent Slight Moderate Hepatic Encephalopathy T. Bilirubin (mg/dl) In PBC or PSC Serum Albumin (g/dl) None Grade 1-2 Grade < >3 >10 > 3.5 g/dl g/dl < 2.8 g/dl INR < > 2.3 Child Class A: 5-6 points Child Class B: 7-9 points Child Class C: points Child CG,Turcotte JG. Major Probl Clin Surg 1964;1:1. Pugh RN et al. Br J Sur 1973;60:646.

14 Cirrhosis: Assessing Severity MELD-Na Score MELD = x Log e (creatinine mg/dl) x Log e (bilirubin mg/dl) x Log e (INR) Then multiply the score by 10 MELD-Na = MELD Na [0.025 x MELD x (140-Na)] If MELD Na is > 12, consider transplant evaluation. MELD-Na Score 3-month mortality < 9 1.9% % % % % If MELD Na is > 15, benefits of transplant exceed risks. Average MELD-Na score at time of liver transplant, New York State, 2016 = 34. Wiesner R et al. Gastroenterol 2003;124:91. Merion RM et al. Liver Transpl 2004;10:S69.

15 Cirrhosis: Complications Variceal Bleeding Hepatic Encephalopathy Ascites Hepatorenal Syndrome Liver cancer

16 Why do these complications occur? Portal hypertension Cardiac index (l/min/m 2 ) No Cirrhosis Child Class A Child Class B Child Class C Nitric Oxide Output (nl/min/m 2 )

17 Hypersplenism

18 Varices

19 Varices Normal esophagus Size of varices Chance of bleed per yr. Prevention of bleeding Small Medium Large 5% 15% > 15% Beta blocker Beta blocker Beta blocker + Band ligation

20 Varices: Management Exam every 2-3 years: Esophagogastroduodenoscopy (EGD, upper endoscopy) Capsule endoscopy of esophagus (PillCam ESO) Beta blocker therapy Nadolol (Corgard ) Propranolol (Inderal ) Carvedilol (Coreg ) Endoscopic variceal ligation (EVL, band ligation )

21 Varices: Management Exam every 2-3 years: Esophagogastroduodenoscopy (EGD, upper endoscopy) Capsule endoscopy of esophagus (PillCam ESO) Beta blocker therapy Nadolol (Corgard ) Propranolol (Inderal ) Carvedilol (Coreg ) Endoscopic variceal ligation (EVL, band ligation )

22 Varices: Management Exam every 2-3 years: Esophagogastroduodenoscopy (EGD, upper endoscopy) Capsule endoscopy of esophagus (PillCam ESO) Beta blocker therapy Nadolol (Corgard ) Propranolol (Inderal ) Carvedilol (Coreg ) Endoscopic variceal ligation (EVL, band ligation )

23 Varices: Management Endoscopic variceal ligation (EVL, band ligation ) Benefits: Prevent esophageal variceal bleeding. EGD risks: 1:3000 chance of bleeding or perforation. Band ligation risks: 2% chance of bleeding Chest pain. Dysphagia.

24 Hepatic encephalopathy Liver confusion. Portosystemic encephalopathy Ammonia is generated in intestine. Typically, is delivered to liver. In cirrhosis: â mass of urea cycle enzymes in liver. â delivery of ammonia to liver due to shunting. Impact of ammonia on brain: Decreased neurological signaling.

25 Hepatic encephalopathy GRADE 1 Decreased attention span. Slightly altered mental status. Trivial lack of awareness. Day night reversal. Personality changes. GRADE 2 Mild disorientation to time or place. Inappropriate behavior Drowsiness. Asterixis.

26 Hepatic encephalopathy GRADE 1 Decreased attention span. Slightly altered mental status. Trivial lack of awareness. Day night reversal. Personality changes. GRADE 3 Stupor, incoherence. Confusion. Gross disorientation. 3a: Agitated delirium. 3b: Decreased responsiveness. GRADE 2 Mild disorientation to time or place. Inappropriate behavior Drowsiness. Asterixis. GRADE 4 Minimal responsiveness to pain. Decerebrate posturing. Seizures.

27 HE: Management Patient and family (and physicians) need to be alert for signs and symptoms. â memory â concentration Avoid the precipitants of HE. Dehydration Constipation Infection GI bleeding Avoid medications that can exacerbate HE. Benzodiazepines: Valium, Xanax, Ambien. Opiates: oxycodone/percocet ; hydrocodone/vicodin ; hydromorphone/dilaudid. Treat other conditions that could contribute to mental dysfunction. Depression. Sleep disturbance. Only get to drive if permitted by their physician (and family).

28 HE: Management Treating HE: Neomycin à AVOID. Lactuloseà aim for 3-4 BMs per day. Rifaximin / Xifaxan Zinc. Sodium benzoate. First Aid for HE. Stop diuretics. Hydrate. Take more lactulose. Severe HE (grade 2) à ER!

29 HE: Management Treating HE: Neomycin à AVOID. Lactuloseà aim for 3-4 BMs per day. Rifaximin / Xifaxan Zinc. Sodium benzoate. First Aid for HE. Stop diuretics. Hydrate. Take more lactulose. Severe HE (grade 2) à ER!

30 HE: Management Treating HE: Neomycin à AVOID. Lactuloseà aim for 3-4 BMs per day. Rifaximin / Xifaxan Zinc. Sodium benzoate. First Aid for HE. Stop diuretics. Hydrate. Take more lactulose. Severe HE (grade 2) à ER!

31 Ascites From Greek askos = wine sac. Affects more than one-half of patients with decompensated cirrhosis.

32 Ascites: Management Low salt diet (< 2000 mg per day). Fluid restriction. Only if the serum sodium level is low. Diuretics / water pills Furosemide / Lasix Spironolactone / Aldactone

33 Ascites: Management Low salt diet (< 2000 mg per day). Fluid restriction. Only if the serum sodium level is low. Diuretics / water pills Furosemide / Lasix Spironolactone / Aldactone Large volume paracentesis. For severe ascites.

34 Ascites: Management TIPS Transjugular intrahepatic portosystemic shunt. Decompress the high-pressure sinusoids within the liver. Benefits: Risks: Improves ascites in 50-75% of patients. Prevents variceal rebleeding. Liver dysfunction. á hepatic encephalopathy.

35 Hepatorenal Syndrome á Nitric Oxide Peripheral vasodilation â central blood volume Activation of Renin-angiotensin-aldosterone system. Antidiuretic hormone. Sympathetic nervous system. TREATMENT: Midodrine, octreotide sc, albumin IV. Terlipressin. Hemodialysis. Liver transplant.

36 Liver Cancer

37 Liver Cancer Liver cancer: May occur in the setting of cirrhosis. Can affect 3% of patients with cirrhosis each year. Is now the #5 most common cancer in U.S. men. Is now the #8 most common cancer in U.S. women. Liver cancer is diagnosed by: Radiology. Biopsy. Patients with cirrhosis should undergo surveillance every 6 months. Ultrasound. Computerized tomography (CT scan). Magnetic resonance imaging (MRI scan).

38 Liver Cancer Resection specimen Liver cancer is curable if caught early. Resection cases: cure rate is about 50%. Transplant cases: cure rate is about 80%. Liver cancer is now the #1 indication for liver transplant in the United States.

39 Referral for liver transplant Patient is at risk of life-threatening complications of liver disease over the next few years. Decompensated cirrhosis Poorly controlled complications of portal hypertension. Variceal bleeding. Ascites. Hepatic encephalopathy. Hepatorenal syndrome. Severely impaired liver function. Jaundice. MELD-Na score > 12. Other indications Liver Cancer Recurrent biliary sepsis Hepatic osteodystrophy Unacceptable quality of life: Fatigue. Itching. Malnutrition

40 Treating the patient with HCV cirrhosis

41 The benefits of achieving SVR The interferon era â liverrelated mortality SVR â allcause mortality â incidence of liver cancer From van der Meer AJ et al. JAMA. 2012;308: Backus LI et al. Clin Gastroenterol Hepatol. 2011;9:509. van der Meer AJ et al. JAMA. 2012;308: Morgan RL et al. Ann Intern Med. 2013;158:329. Kimer N et al. BMJ Open. 2012;2.

42 HCV cirrhosis in the DAA era: Whom should we treat? Patient with well-compensated HCV cirrhosis TREAT!!! Patient with decompensated HCV cirrhosis???

43 The DAA era Can we achieve SVR? In well-compensated cirrhosis. In decompensated cirrhosis.

44 Chance of achieving SVR: Well-compensated cirrhosis

45 Chance of achieving SVR: Well-compensated cirrhosis DAA therapy Treatmentnaïve GT1 Treatmentnaïve GT2 Treatmentnaïve GT3 Treatmentnaive GT4 Treatmentnaïve GT5 Treatmentnaïve GT6 Elbasvir/Grazoprevir 97% % Zepatier Glecaprevir/Pibrentasvir 98% 99% 100% 99% 99% 99% Mavyret Sofosbuvir/Ledipasvir 98% % 96% 96% Harvoni Sofosbuvir/Velpatasvir 99% 99% 93% 98% 100% 100% Epclusa Sofosbuvir/Velpatasvir/ % Voxilaprevir Vosevi Accessed November 19, 2017.

46 Chance of achieving SVR: Decompensated cirrhosis

47 Chance of achieving SVR: Decompensated cirrhosis Study Medications Genotypes under treatment ALLY-1 SOLAR-1 and -2 ASTRAL-4 Sofosbuvir Daclatasvir Sofosbuvir Ledipasvir Ribavirin Sofusbuvir Velpatasvir +/- Ribavirin SVR in Child class B SVR in Child class C % 56% 1 and % 72-90% % --- Data from: Poordad F et al. Hepatology 2016;63:1493. Charlton M et al. Gastroenterol 2015;149:649. Manns M et al. Lancet Infect Dis 2016;16:685. Curry MP et al. N Eng J Med 2015;373:2618.

48 The DAA era The benefits of achieving SVR Improve portal hypertension â incidence of liver cancer SVR Afdhal N. EASL 50 th Liver Congress, April 2015, LP13. Ioannou G et al. AALSD Annual Meeting October 21, Kwong A et al. Liver Transpl DOI: /lt Curry MP et al. Gastroenterol 2015;148:100. Carrat F et al. AASLD Annual Meeting Abstract LB-28. Chhatwal J et al. Clin Gastroenterol 2017;15:827. â mortality on liver transplant waiting list â recurrent HCV after liver transplant â all-cause mortality Cost-effective

49 The DAA era Limitations of drug therapy Decreased tolerability Discontinuation due to adverse event SOLAR-1 SOLAR-2 ASTRAL-4 5% 7% 3%

50 The DAA era Limitations of drug therapy Risk of liver decompensation Protease inhibitors: CONTRAINDICATED in Child class B and C

51 The DAA era Limitations of drug therapy Risk of liver decompensation Protease inhibitors: CONTRAINDICATED in Child class B and C CUPIC trial. PegIFN, Ribavirin, telaprevir. PegIFN, Ribavirin, boceprevir. Complication Liver decompensation Percent 8.4% Severe infection 5.5% Death 2.2% Hezode C et al. Gastroenterol 2014;147:132.

52 The DAA era Limitations of drug therapy Risk of liver decompensation Protease inhibitors: CONTRAINDICATED in Child class B and C Cases of liver failure some fatal reported with: Simeprevir. Paritaprevir / ritonavir / ombitasvir / dasabuvir. Contraindicated in Child class B and C Elbasvir / Grazoprevir Glecaprevir / Pibrentasvir Sofosbuvir / Velpatasvir / Voxilaprevir FDA warnings 4/26/15 10/22/15 accounts/usfda/bulletins/ff49fd DrugSafety/ucm htm

53 The DAA era Limitations of drug therapy Concerns regarding increasing risk of recurrent liver cancer

54 The DAA era Limitations of drug therapy Concerns regarding increasing risk of recurrent liver cancer Reig M et al. J Hepatol 2016;65: patients had HCC prior to DAA therapy. Resection (20, 34.5%), Ablation (32, 55.2%), TACE (6, 10.3%) Median time from neg. scan to DAA Rx = 1.7 mo ( ) Tumor recurred in 16 patients (27.6%). Included five resection patients who were at low risk for recurrence. Median time to recurrence after starting DAA therapy = 5.7 months. ANRS collaborative study group. J Hepatol 2016;65: pts with prior Rx for HCC. HCC recurrence in 24 of 189 (12.7%) of DAA-treated patients. 16 of 78 (20.5%) of untreated patients. P = NS. Conti F et al. J Hepatol 2016;65: patients had HCC prior to DAA therapy. Resection in 23 (39%). RFA +/- TACE +/- PEI in 36 (61%). Tumor recurred in 17 patients (28.8%). Median time to recurrence after starting DAA therapy = 14.9 months. Authors anticipated a 20% early HCC recurrence rate.

55 The DAA era Limitations of drug therapy Concerns regarding increasing risk of recurrent liver cancer Example: 47 y.o. woman with HCV cirrhosis. Well-compensated. T.Bili 1.2 mg/dl, INR 1.0, MELD 7. UNOS stage 2 HCC. Three 2.5 cm lesions, treated with microwave ablation. Near 100% chance that her liver harbors residual liver cancer. Listed as a candidate for liver transplant. TREAT before transplant or TREAT after transplant?

56 Decompensated HCV cirrhosis Why shouldn t we treat with a DAA? DAAs improve MELD score in some patients, but not all. Regimen N SVR MELD Improved SOF + DCV + RBV SOF + LDV + RBV SOF + VEL +/- RBV MELD Unchanged 56 83% 45% 21% 34% 94 & 136 MELD Worsened 83-87% 67-71% 13-16% 16-17% % 54% 21% 25% From Bunchorntavakul C, Reddy KR. J Viral Hepatol 2016;23:408.

57 Decompensated HCV cirrhosis Why shouldn t we treat with a DAA? Sometimes, the MELD score improves. However, the patient might not improve. Will DAA treatment make my patient healthier? Will DAA treatment permit my patient to be delisted? Might DAA treatment improve my patient s MELD score only without improving: Symptoms? Risk of dying? Might unsuccessful DAA Rx send my patient into MELD purgatory?

58 Decompensated HCV cirrhosis Pros and cons of treating prior to transplant Decompensated Cirrhosis MELD < 16 MELD MELD > week mortality < 2%. DAA à 49% chance of improving & being delisted. Liver transplant not an option or contraindicated 12-week mortality = 3-9%. DAA à 18% chance of improving & being delisted. 12-week mortality = 10-19%. DAA à 15% chance of improving & being delisted. Treat after transplant Treat now Treat before transplant Belli Belli LS LS et al. et al. J Hepatol J 2016;65:524. Anand AC. AC. J Clin J Clin Exp Exp Hepatol 2017;7:42.

59 Decompensated HCV cirrhosis Why shouldn t we treat with a DAA? TREAT before transplant or TREAT after transplant? Example: 50 y.o. man with HCV cirrhosis. PE: icteric. moderate muscle wasting. moderate ascites. Labs: T.Bili 5 mg/dl, INR 2, Creatinine 1.3 MELD-Na 23 Course complicated by: Variceal bleed 1 year ago. Massive ascites, requiring two large volume paracentesis procedures over the last 6 months. Hepatic encephalopathy, grade 1.

60 Decompensated HCV cirrhosis Pros and cons of treating prior to transplant Pros Treatment is highly successful. SVR = 83-96% in Child class B. There is potential for clinical improvement and delisting. Successful DAA therapy avoids: Use of a donor organ. Risk of liver transplant. Risk of recurrent hepatitis C. Cons Patient remains at risk for complications of cirrhosis. MELD purgatory. Successful DAA therapy à Eliminate the opportunity to utilize an HCV positive organ.

61 Decompensated HCV cirrhosis Summary Patient characteristic MELD score < 15. No history of variceal bleeding, ascites, HE, or liver cancer. MELD score < 15. Positive history of variceal bleeding ascites, HE or liver cancer. MELD score > 20 Treat before transplant ü Treat after transplant ü ü MELD < 15 Minimal ascites Minimal HE ü? MELD score ü?

62 Approach to the HCV patient awaiting kidney or heart transplant

63 HCV-infected patients with ESRD awaiting kidney transplant Can you treat the patient with HCV and ESRD?

64 HCV-infected patients with ESRD awaiting kidney transplant Can you treat the patient with HCV and ESRD? Regimen Elbasvir / Grazoprevir Glecaprevir / Pibrentasvir Sofosbuvir-based regimens SVR Rate 94-99% % Not recommended for GFR < 30 ml/min

65 HCV-infected patients with ESRD awaiting kidney transplant Can you treat the patient with HCV and ESRD? Should you treat the patient with HCV and ESRD? Regimen Elbasvir / Grazoprevir Glecaprevir / Pibrentasvir Sofosbuvir-based regimens SVR Rate 94-99% % Not recommended for GFR < 30 ml/min

66 HCV-infected patients with ESRD awaiting kidney transplant Can you treat the patient with HCV and ESRD? Should you treat the patient with HCV and ESRD? Regimen Elbasvir / Grazoprevir Glecaprevir / Pibrentasvir Sofosbuvir-based regimens SVR Rate 94-99% % Not recommended for GFR < 30 ml/min Average waiting time for a kidney transplant in New York State: 7 years

67 HCV-infected patients with ESRD awaiting kidney transplant Can you treat the patient with HCV and ESRD? Should you treat the patient with HCV and ESRD? Regimen Elbasvir / Grazoprevir Glecaprevir / Pibrentasvir Sofosbuvir-based regimens SVR Rate 94-99% % Not recommended for GFR < 30 ml/min Average waiting time for a kidney transplant in New York State: 7 years Average waiting time for an HCV-positive kidney transplant in New York State: 2 years

68 HCV-infected patients with ESRD awaiting kidney transplant Can you treat the patient with HCV and ESRD? Should you treat the patient with HCV and ESRD? Regimen Elbasvir / Grazoprevir Glecaprevir / Pibrentasvir Sofosbuvir-based regimens SVR Rate 94-99% % Not recommended for GFR < 30 ml/min Average waiting time for a kidney transplant in New York State: 7 years Average waiting time for an HCV-positive kidney transplant in New York State: 2 years Weigh the risks of treating now versus the risk of waiting to treat until after kidney transplant. The author advises: Wait to treat if stage 1-3 fibrosis. Treat now if patient has cirrhosis.

69 SVR rates after kidney and liver transplant Regimen Glecaprevir / Pibrentasvir Sofosbuvir/ Ledipasvir (not for GT 2 or 3) Daclatasvir/ Sofosbuvir/ Ribavirin SVR Rate 99% 100% 100% (n.b. few patients under study) Accessed November 19, 2017.

70 Use of HCV-positive organs in HCV-negative recipients 500 high-quality kidneys from HCV-positive deceased donors are discarded each year. THINKER Trial [Transplanting Hepatitis C Kidneys into Negative Kidney Recipients] 10 HCV-negative recipients are transplanted with kidneys infected with HCV genotype 1. Average wait time (from trial entry) = 58 days. By post-op day #3, all recipients are HCV RNA positive. All patients received elbasvir-grazoprevir. All patients achieved SVR12. Goldberg DS et al. N Eng J Med 2017;376:2394.