Liver Transplantation 2012

Marion Peters MD

University of California

San Francisco

Proportion of deaths due to ESLD in HIV+

Salmon-Ceron, J Hepatol 2005

Indications for Liver Transplantation Development of liver decompensation

Ascites Variceal hemorrhage Hepatic encephalopathy Synthetic dysfunction Hepatocellular carcinoma

HIV patients with decompensated cirrhosis have a median survival of ≈ 1 year

Survival Time from First Liver Decompensation to Death in HCV

Pineda, Hepatology 2005

•Death during study •366/1037 HCV •100/180 HIV/HCV

• Risk factors for death: •HIV •Baseline CPT •MELD >13 •Age

Natural History of ESLD Increasing

liver fibrosis Development

of HCC

Chronic liver disease

Compensated cirrhosis

Decompensated cirrhosis

Death

• Alcohol • Hepatitis C/B

• NASH • Cholestatic

• Autoimmune

• Variceal hemorrhage • Ascites

• Encephalopathy • Jaundice

HCC, hepatocellular carcinoma; NASH, nonalcoholic steacohepatitis Garcia Tsao CCO Hepatitis.com 2008

Child-Pugh-Turcotte Score Points 1 (normal) 2 3 Hepatic encephalopathy

None 1-2 3-4

Ascites None slight mod Bilirubin <2 2-3 >3 Albumin >3.5 2.8-3.5 <2.8 PT <4 secs ↑ 4-6 secs >6 secs

or INR <1.7 1.7-2.3 >2.3

A: 5-6; B: 7-9; C: > 9

MELD: Model for End-Stage Liver Disease

Bilirubin 2 5 5 5 INR 1.1 2.0 2.0 3.0 Creatinine 1.0 1.0 2.0 2.0 MELD 10 20 27 31

Cirrhosis

Prevalence

35%-80%

25%-40%

Die 30%-50% 50%-70%

Survive

Rebleed 70%

Risk of Bleeding

Risk of Bleeding from Esophageal Varices

Variceal Surveillance

All cirrhotics require Esophagogastroduodenoscopy

Garcia-Tsao G, et al. Hepatology. 2007;46:932-938.

No varices

Repeat endoscopy in 3 years (well

compensated); in 1 year if

decompensated

No beta-blocker prophylaxis

Small varices (< 5 mm), Child B/C

Nonselective Beta-blocker prophylaxis

Medium or large varices

Child Class A, no red wales: beta blockers

Child class B/C, red wales: beta blockers or

band ligation

Ascites: Pathogenesis

and Mechanism of

Action of Different

Therapies

Cirrhosis

Intrahepatic resistance

Portal (sinusoidal) hypertension

Splanchnic/systemic vasodilation

Effective arterial blood volume

Activation of neurohumoral systems

Sodium retention

Ascites

Liver transplantation

TIPS

Albumin PVS

Spironolactone + Furosemide*

Paracentesis (LVP)

PVS LVP, large-volume paracentesis; PVS, peritoneovenous shunt. *Furosemide should only be used in conjunction with spironolactone.

Garcia Tsao CCO Hepatitis.com 2008

Treatment of ascites Diuretic-responsive ascites

Sodium restriction Spironolactone (75-100 mg) and furosemide (20-40 mg)

Refractory ascites Large volume paracentesis with 25% albumin (50 cc/L) TIPS- higher OLT free survival, higher PSE TIPS HVP <12 mm Hg Albumin, midodrine and octreotide- vasoconstriction Experimental: clonidine, vasopression 2 R antagonists

Hyponatremia Fluid restriction, vasopression 2R antagonists, midodrine

Hepatorenal syndrome Results from vasodilatation and marked reduction

in effective arterial blood volume leading to renal vasoconstriction

Occurs in patients with refractory ascites and/or hyponatremia.

Type 1 HRS: rapidly progressive renal failure in 2 weeks with a doubling of serum creatinine to a level > 2.5

mg/dL or halving creatinine clearance to < 20 mL/min Prognosis: < 50% survival at 1 month

HRS-contd Type 2 HRS: slowly progressive

increase in serum creatinine level to > 1.5 mg/dL a creatinine clearance of < 40 mL/mi or a urine sodium < 10 mEq/d associated with ascites that is unresponsive to

diuretic medications median survival: ~ 6 months

Spontaneous bacterial peritonitis (SBP)

Most common type of bacterial infection in hospitalized cirrhotic patients

Clinical suspicion: <50%: fever, abdominal pain or tenderness, and

leukocytosis unexplained encephalopathy, jaundice worsening renal failure

Diagnose: tap ascites: WCC>500, PMN > 250 cells/mm3

Place ascites in blood culture bottles

Start treatment immediately before culture results

SBP treatment Cephalosporins Renal dysfunction is main cause of death

prevented by the use of intravenous albumin if serum bilirubin > 4 mg/dL serum creatinine > 1 g/dL or blood urea nitrogen level > 30 mg/dL

Prevent recurrence: ciprofloxacin, TMP/SMX, norfloxacin

Primary prophylaxis: ciprofloxacin weekly if MELD >9

Hepatic Encephalopathy Results from a combination of

Portosystemic shunting failure to metabolize neurotoxic substances Ammonia remains the most important neurotoxic

substance but poorly correlates with stage

Precipitants Infection- especially SBP or UTI HCC Bleeding Electrolyte imbalance Portal vein thrombosis Worsening liver disease

Hepatic Encephalopathy

Treatment aims to reduce production of ammonia from the colon through nonabsorbable disaccharides

lactulose, lactitol, and lactose

nonabsorbable antibiotics neomycin, rifaximin

Protein restriction promotes protein degradation and, if maintained for long periods, worsens nutritional status and decreases muscle mass No longer recommended

OLT in HIV HAART-associated improvements:

decreased mortality decreased incidence of opportunistic infections decreased hospitalization rates

Immunosuppressives may have anti-HIV effects

cyclosporine, MMF, rapamycin Better prophylaxis for opportunistic infections

Data from NIH multicenter study of 125 OLT 150 CRT

Liver Transplantation

MELD Serum sodium Underestimated

chronic encephalopathy hepatic hydrothorax hepatopulmonary syndrome portopulmonary hypertension

1

0.9

0.8

0.7

0.6

0.5 0 1 2 3 4 5

Sur

viva

l %

Era 3 (1997-2002)

Time (years)

P = .14

Other

HBV

1

0.9

0.8

0.7

0.6

0.5 0 1 2 3 4 5

Sur

viva

l %

Era 1 (1987-1991)

Time (years)

P < 0.01

Other

HBV

Kim WR, et al. Liver Transpl. 2004;10:968.

Liver Transplantation and HBV Progress in Past Decades

5-year survival rates ~50% Many centers consider HBV to be

contraindication for LT

5-year survival rates as good or better than for other indications for LT

HBIG LAM

Outcomes in HBV-HIV Coinfected LT Recipients Summary of Prior Studies

Author, Year Country

N HBV DNA undetectable

pre-LT

HBV Recurrence

Patient Survival

Schreibman(1) 2007, US 8 5/8 13% 75%

Norris, 2006, UK 4 1/4 0% 100%

Fung 2004, US 3

NA 0% 100%

Tateo, 2009, France 13 13/13 0% 100%

All patients received prophylaxis of HBIG and antivirals, except (1)

HBV Patient Survival

*No deaths due to recurrent HBV or HIV-related complications

P=0.09

20 HBV 100 %

22 HBV-HIV 86%

Median follow-up 3.5 years Coffin, et al. AJT; 10:1268 - 1275; 2010

HBV Recurrence & Viremia No recurrent HBsAg

No histologic recurrence

53% detectable HBV DNA post-transplant

Mean HBV DNA 108 IU/ml (range 20-790 IU/ml) More frequent in patients with detectable HBV DNA pre-

transplant and those with prior treated acute rejection No persistently detectable HBV DNA

Coffin, et al. AJT; 10:1268 - 1275; 2010

HBV as Indication for LT HBV common in HIV-infected persons 19-fold higher risk of liver-related death in coinfected vs HBV

monoinfected patients 1 Among referred patients Clinically evident LMV-resistance frequent is 67- >90% 2 Survival lower in patients on LMV vs drug combinations

(ADV/TDF + LMV/FTC) at the time of referral

Post-LT, recurrent disease is rapidly progressive without virologic control Higher rates of LAM-r among HIV-HBV infected patients

presenting for LT may increase risk of prophylaxis failure

Thio CL, et al. Lancet. 2002 Terrault NA, et al. Liver Transplant 2007

HCV as Indication for LT HCV is the most common cause of liver-related

mortality in HIV-infected patients

Prior studies in HCV-HIV coinfected transplant recipients indicate:

Higher rates of wait-list mortality Worse post-LT survival More severe recurrent HCV disease Poor response to HCV treatment

Duclos-Vallee JC, Hepatology 2008;47:407–417.

Castells L, Transplantation 2007;83:354–358. Ragni MV, Liver Transpl 2005;11:1425–1430.

Pineda JA, Hepatology 2005;41:779–789.

Patient Survival: HCV

P=0.01 P=0.01

HCV mono-infected n=135 n=67 n=22

HCV-HIV co-infected n=46 n=28 n=14

% P

ATIE

NT S

URVI

VAL

0

20

40

60

80

100

YEAR0.0 0.5 1.0 1.5 2.0 2.5 3.0

HCV-HIV CoinfectedHCV Monoinfected

P = .01

Terrault N, et al. AASLD 2009. Abstract 195.

Graft Survival: HCV

P=0.01 % G

RAFT

SUR

VIVA

L

0

20

40

60

80

100

YEAR0.0 0.5 1.0 1.5 2.0 2.5 3.0

HCV-HIV CoinfectedHCV Monoinfected

HCV mono-infected N=128 N=67 N=21

HCV-HIV co-infected N=43 N=26 N=13

P=0.01

Terrault 2010

Factors Associated with Mortality: Liver Recipients

1. Dual organ TX (HR 4.86; 1.93, 12.2; p=0.0008) 2. Pre-TX BMI <21 (HR 2.74; 1.25, 5.98; p=0.01) 3. Donor age >40 (HR 2.23; 1.07, 4.64; p=0.03)

Marginally HCV (HR 2.47; 0.95, 6.44; p=0.06)

Marginally detectable enrollment viral load (HR 2.07; 0.89, 4.81; p=0.09)

HCV outcomes and implications for patient selection

Patient and graft survival in HCV-HIV co-infected transplant recipients are lower but acceptable

Not due to HIV-related complications

Outcomes may be improved by:

Restricting to BMI >21; no dual kidney transplant Avoiding use of livers from anti-HCV+ donors

Better management of acute rejection

Stock 2011

HIV and Liver Transplantation What Have We Learned?

HBV outcomes excellent and recurrent low level viremia controllable with combination HBIG and antivirals

Recurrent HCV a significant problem, with increased risk of morbidity and mortality some surprising positive outcomes (spontaneous clearance, higher

response to antiviral therapy)

HAART regimens including PI require major adjustments in CNI and sirolimus dosing

Treatment with anti-T-cell depleting agents results in prolonged depletion of CD4 positive cells

HIV and Liver Transplantation What Have We Learned?

Transplantation is an option for HIV-infected patients with endstage liver disease

Need to consider early at first decompensation

No significant HIV clinical, virologic, immunologic disease progression noted in the immunosuppressed patients

No evidence of impaired graft function due to HIV

Rejection rates unexpectedly high in HCV-infected liver transplant recipients

ESLD and HIV Liver disease has become a major cause of death in

people infected with HIV Prevalence of HCV coinfection is high (30%) Prevalence of HBV coinfection ~ 10% Progression to cirrhosis is rapid in coinfected pt ESLD common Monitor ascites and infection (SBP prophylaxis) EGD for varices, imaging for HCC Consider OLT early