Management del paziente in lista d'attesa per trapianto di fegato - Gastrolearning®

Pierluigi ToniuttoMedical Liver Transplant Section

University of Udine

CLINICAL MANAGEMENT OF PATIENTS AWAITING LIVER TRANSPLANTATION

AIM OF THE CARE DURING THE

WAITING PERIOD

• Waiting time for transplantation varies between 3 and 18 months

• The aims of the pre-transplant management are:– Avoid deterioration of liver function

– Maintain the nutritional status of the patient

– Avoid the appearance of contraindications to transplantation- Active infections- Tumour extension (for those listed for HCC)

– Confirm the need for transplantation

– Survey the appearance of contraindication to transplantation

– Improve the results of transplantation

CARE OF PATIENT DURING WAITING TIME

• Required a regular follow-up

• Every 2 to 4 weeks depending on the severity of liver disease

• Routine US doppler, surveillance of oesophageal varices, management of ascites

• This follow-up can be done:– Directly by the transplant center

– By the referring general physician or specialist

– All therapeutic decisions should be made in accordance with the transplant physicians

SUMMARY OF CARE DURING THE WAITING LIST PERIOD

LISTED

GENERAL CARE LIVER SPECIFIC COMPLICATIONS

NUTRITIONAL/PSYCHOSOCIAL

MELD updateImmunizationPPDHCC screeningBMD screenTreatment of primary etiology

Portal hypertensionAscitesHEPruritusRenal complications (HRS) Pulmonary complicationsPrevention of HCC extension

Support depressionDrug screenNutrition


LISTED






FREQUENCY OF VISITS BASED ON MELD SCORE VALUE

*Every six months update for NITp certification

AIMS OF THE PERIODICAL VISITS

PERFORMED DURING THE FOLLOW-UP

• Update the parameters used for MELD scoring

• Assessment of electrolytes, complete blood count, coagulation profile

• Assessment of HE, ascites, edema

• Blood pressure and pulse measurement

• Screening for HCC by ultrasound and CT or MRI

- Viral hepatitis B and C, HH and alcoholic cirrhosis are at elevated risk of HCC development

HCC SCREENING TOOLS DURING THE WAITING TIME

AISF HCC Guidelines; Dig Liv Dis,2013

Hayashi et al. Liver Transplantation; 2004

HCC PRE-TRANSPLANT DIAGNOSIS AND OUTCOMES IN 172 ADULTS

172 adult liver Tx

129 pre-MELD 43 post-MELD

15 pre Tx HCC diagnosis 15 pre Tx HCC diagnosis

3 no HCC in explant 5 no HCC in explant

8/30 (26.6%) false positive diagnosis

TREATMENT OF PRIMARY ETIOLOGY

•Management of HBV infection

•Management of HCV infection




KEY ISSUES OF THERAPY IN PATIENTS WITH HBV RELATED CIRRHOSIS WAITING FOR LT/1

• Oral antiviral treatment when applied as early as possible helps to improve prognosis in decompensated HBV-induced liver cirrhosis, and may even delay or prevent the need for LT.

• Monotherapy with nucleos(t)ide analogs (NUCs) with high barriers to resistance like ETV or TFV are recommended as first line treatment options according to current guidelines.

• The overall safety and tolerability of NUCs is high in decompensated cirrhosis, but adaptation of the dosage according to renal function and renal monitoring is required.

KEY ISSUES OF THERAPY IN PATIENTS WITH HBV RELATED CIRRHOSIS WAITING FOR LT/2

• Lactic acidosis has been described in rare instances especially in patients with a high MELD score treated with ETV.

• Liver function determined by Child-Pugh and MELD score is the best predictor to differentiate patients who may stabilize and individuals who will require liver transplantation despite initiation of antiviral therapy.

• The risk of HCC development remains significant even in those patients with successful antiviral therapy and complete suppression of HBV DNA. Thus, thorough HCC surveillance remains mandatory.

86% Improved14% Not Improved

50% Improved/Stabilized14% Not Improved30% Death*2% No F/U

N = 176 (226)CPT A = 40%, B = 38%, C = 22%

43%Transplanted

21% Removed from

Wait List

36% Still Wait Listed

*All deaths occurred prior to 24 weeks

Schiff et al. Liver Transpl; 2007

OUTCOME OF WAIT-LISTED LAM RESISTANT HBV CIRRHOSIS TREATED WITH ADEFOVIR

EFFECT OF ENTECAVIR ON HBV-RELATED ACUTE-ON-CHRONIC LIVER FAILURE

• Hepatitis B related acute-on-chronic liver failure (HBV-ACLF) has poor prognosis

• Efficacy and safety of ETV in patients with HBV-ACLF evaluated in retrospective study (N=248)

– 124 patients ETV vs. 124 patients control (no nucleos(t)ide analog)

By multivariate logistic regression, high INR, ≥2 complications and high total bilirubin, but not HBV DNA, were independent predictors of liver-related mortality in HBV-ACLF By multivariate logistic regression, high INR, ≥2 complications and high total bilirubin, but not HBV DNA, were independent predictors of liver-related mortality in HBV-ACLF

Multivariate Logistic Regression Analysis of Independent Risk Factors for Mortality in Patients with HBV-ACLF

Odds Ratio95% CI

Lower Upper

High Total Bilirubin (µmol/L) 1.003 1.001 1.005

High INR 2.589 1.501 4.465

≥2 Complications 9.568 4.319 21.197

HBV DNA (log copies/mL) 1.120 0.869 1.445

Ma K, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 742.

ENTECAVIR TREATMENT DECREASES DISEASE PROGRESSION IN HBV-RELATED ACUTE-ON-

CHRONIC LIVER FAILURE

• ETV group achieved improvement of MELD score compared to controls• 1- and 3-month survival rates of ETV group (72.58% and 61.29%), significantly higher

than that in control group (53.23% and 45.97%)

Ma K, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 742.

EFFICACY AT WEEK 48

TDFTDF(N = 45)(N = 45)

TVDTVD(N = 45)(N = 45)

ETVETV(N = 22)(N = 22)

% with HBV DNA < 400 copies/mL 71% 88% 73%

MELD score Median change

Absolute MELD Week 48 (median)

-2.0-2.0

8

-2.0-2.0

8

-2.0-2.0

8

CTP score Mean change

Absolute CTP Week 48 (median)

-1-1

6

-1-1

6

-1-1

5

Median ALT (U/L) 29 33 31

• An ITT noncompleter/switch = failure analysis was used

• Patients who switched from blinded medication to open-label TVD were considered noncompleters in all 3 arms of the study

• Patients who underwent orthotopic liver transplant (OLT) (6 total; 2 TDF, 4 FTC/TDF) are censored from the HBV DNA, serology, biochemical, MELD and CPT analyses

Liaw Y-F, et al., AASLD 2009; Oral #322.

Study 108: TDF vs FTC + TDF vs ETV

ADATTAMENTO POSOLOGICO NUCINTERVALLI TRA I DOSAGGI /RIDUZIONE DOSE E GFR

Farmaco TelbivudTelbivudinaina

EntecavirEntecavir AdefovAdefovirir

TenofovTenofovirir

GFRmL/GFRmL/min/ 1.73 min/ 1.73

mm22 SC SC

Dose 600 mg

Naïve a Lamivudina dose 0,5

mg

“Experienced” a

Lamivudina

Dose 10 mg

Dose 245 mg

> 50> 50 24h ogni 24 hr

1 mg ogni 24 hr 24 h 24 h

30-4930-49 48 h ogni 48 h 0,5 mg

ogni 24 hr48 h 48 h

10-3010-30 72 h ogni 72 hr0,5 mg

ogni 48 hr72 h 72-96h

ESRDESRD 96 hogni 5-7

gg0,5 mg

ogni 72 hr7 giorni 7 giorni

0100200300400500600700800

HBV

HCV

Kim WR, Gastroenterology 2009

year

DECLINE OF LIVER TRANSPLANTATION FOR HBV CIRRHOSIS IN US

The pattern of liver transplantation waiting list registration among patients with hepatitis B suggests that the widespread application of oral antiviral therapy for HBV contributed to the decreased incidence of decompensated liver disease.

Status

Pre-LT

Anhepatic

First week

Weeks 2-12

>Week 12

HBsAg+DNA-

HBsAg+DNA+

Start NUC pre-Op NUC > 4 weeks

DNA- DNA+

20.000 UI HBIG IV

10.000 UI HBIG IV 20.000 UI HBIG IV x 210000 UI/day

10.000 UI HBIG IV to keepHBsAb >200 IU/L

Reduce HBIG doseHBsAb >100 IU/L

HBV PROPHYLAXIS RECOMMENDATIONS

Dikcson et al. Liver Transpl, mod.; 2006

ETV MONOTHERAPY IS EFFECTIVE IN SUPPRESSING HBV AFTER LT

Fung et al. Gastroenterology; 2011.

• 80 HBsAg+ recipients (47 LDLT)

• Only 21 (26%) had HBV-DNA- at LT

• All free of HBIG

• ETV 0.5 mg in all except 9 (1 mg)

• Median follow-up of 26 months

Study design Summary of pre LT antiviral therapy

ETV MONOTHERAPY IS EFFECTIVE IN SUPPRESSING HBV AFTER LT


• Total number of HBsAg positive patients at the end of follow-up: 18 (22.5%)• (8 patients had persistent HBsAg and 10 had HBsAg reappearance) • Only 1 patient had HBV-DNA positivity in the serum (37 IU/ml)

Cumulative rate of HBsAg seroclearance

Cumulative rate of HBsAg relapse


CUMULATIVE RATE OF HBsAg SEROCLEARANCE AFTER LT IN RELATIONSHIP TO HBsAg AND HBV-DNA SERUM LEVELS AT LT




PREVENTION OF GRAFT HCV RECURRENCE BY ANTIVIRAL THERAPY IN CIRRHOTICS

AWAITING LIVER TRANSPLANT

Everson GT. Clin Gastro Hepatol. 2005.

Pat

ient

s (%

)

HCV Free Posttransplant*

EVR0

20

40

60

80

100

10

30

50

70

90

SVR Transplant

Everson

Forns

Thomas

Crippin

*Regardless of achieving SVR pretransplant

Forns et al. J Hepatol 2003; Carrion et al. J Hepatol 2009; Everson et al. Hepatology 2013.

EFFICACY AND SAFETY OF PEG-IFN PLUS RBV IN HCV POSITIVE RECIPIENTS IN THE WAITING LIST

Verna et al. AASLD 2012.

PRELIMINARY DATA OF TRIPLE THERAPY IN HCV POSITIVE RECIPIENTS IN THE WAITING LIST

CUPIC FRENCH COHORT: SVR 12 RESULTSCUPIC FRENCH COHORT: SVR 12 RESULTS

Fontaine et al. EASL 2013

- SAES in 57% (TVR) and 40.4% (BOC)- Death 2,8% (TVR) and 0.9% (BOC)- Infections in 6.5% (TVR) and 4.4% (BOC)- Hepatic decompensation 0.9% (TVR) and 1.8% (BOC)

www.clinicaltrial.gov:

DAA AND PREVENTION OF HCV RECURRENCE

http://www.clinicaltrial.gov/

Crespo et al. Gastroenterology; 2012.

PREVENTION OF HCV RECURRENCE


LISTED






LIVER SPECIFIC COMPLICATIONS

• Gastrointestinal bleeding should be prevented via routine endoscopy (variceal band ligation) with or without beta blockers.

• Routine paracentesis with albumin supplementation is the best way to control refractory ascites and prevent malnutrition.

• Patients with hepatorenal syndrome (HRS) type 1 can be transplanted after control of HRS with pharmacological agents such as terlipressin.

• In some cases of refractory ascites and HRS type 2, TIPS can be attempted.

• Treatment and prevention of recurrent spontaneous bacterial peritonitis is essential.

• Patients with portal thrombosis should be treated with anticoagulation to avoid portal thrombus extension.

PULMONARY COMPLICATIONS INDUCED BY ADVANCED LIVER DISEASES

Hoeper et al. Lancet; 2004; Palma et al. J Hepatol; 2006. Houlihan et al. Aliment. Pharmacol Ther, 2013

HEPATOPULMONARY SYNDROME

•HPS occurs in 4% to 25% of candidates to liver transplantation•Characterized by

− Cirrhosis and or portal hypertension− Hypoxia (alveolar-arterial oxygen gradient >20 mmHg)− Intrapulmonary vascular dilatation

•Pulmonary features include− Digital clubbing− Cyanosis− Dyspnea− Platypnea− Orthodeoxia

Hoeper et al. Lancet; 2004; Palma et al. J Hepatol; 2006.

WORK UP FOR HEPATOPOLMONARY SYNDROME

Sharma et al. Liver Transpl; 2005, mod.

Arterial hypoxemiaPaO2 <70 mmHg

A-a gradient > 20 mmHgNo evidence of pulmonary disease

Echocardiography with saline solution(presence of microbubbles in the left cardiac chamber after 5 heart beats

after the visualization in the right chambers)99TC macroaggregated albumin (shunt index >7%)

Negative Positive

HPS

HEPATOPULMONARY SYNDROME AND LT

Hoeper et al. Lancet; 2004; Palma et al. J Hepatol; 2006.

• Liver transplantation is the only known effective therapy for HPS and most patients have an improvement in oxygenation at 1 year

• A number of centers have described worse outcome in patients with severe HPS (PaO2 ≤50 mmHg)

• Mortality rates of 16% and 30% at 3 months as a whole and in severe HPS

• More recently mortality rates 7% and 14% as a whole and for severe HPS

• No contraindications for LT independently from PaO2 values in the absence of other comorbidities (MELD exception)- List priority for PaO2 <60 mmHg

Houlihan et al. Aliment. Pharmacol Ther, 2013; AISF-CCTF-SITO Proposed Consensus Conference; 2013

PORTO-PULMONARY HYPERTENSION (PoPH)

•PoPH occurs in 2% to 6% of candidates to liver transplantation•More frequent in severe portal hypertension and refractory ascites, HIV+ recipients, female gender, autoimmune disease (S100A4 SNPs and genetic variation in oestrogen signalling)

•Characterized by:- Portal hypertension with or without liver disease - Resting mean pulmonary artery pressure (mPAP) >25

mmHg - Pulmonary vascular resistance (PVR) >240 dynes/s/cm-5

- Pulmonary capillary wedge pressure ≤15 mmHg- Exclusion of secondary causes of pulmonary arterial

hypertension

Arguedas et al. Hepatology; 2003; Houlihan et al. Aliment. Pharmacol Ther, 2013

CLINICAL MANIFESTATIONS OF PoPH

•Initially mild and non specific (fatigue, edema)•Physical signs of PoPH (right ventricular heave, loud pulmonary second heart sound and elevated jugular venous pressure)

•In more advanced disease: dyspnea on exertion, syncope, chest pain, hemoptysis and orthopnea

•Using doppler echocardiography the estimated upper 95% limit for PASP among low risk normal individuals is 37.2 mmHg - 6% of normal subjects over 50 years of age and in 5% of obese

PASP >40 mmHg

•In cirrhotics a threshold estimated PASP of 30 mmHg demonstrated PPV of 59% and NPV of 100% in identifying patients with PoPH

Houlihan et al. Aliment. Pharmacol Ther, 2013

ASSESSMENT AND MANAGEMENT ALGORITHM OF PoPH


PHARMACOLOGICAL INTERVENTION IN PoPH


• Bosentan (dual endothelin-A and endothelin-B receptor antagonist)

- Can be associated with hepatotoxicity – careful monitoring required

- Contraindicated in decompensated cirrhosis

• Sildenafil (phosphodiesterase inhibitor)

• No large controlled trials

PoPH AND LT

• Patients with PoPH and decompensated cirrhosis must be evaluated for listing independently from MELD score if responders to vasoactive therapy

• Listing priority for those with MPAP >35 mmHg pre vasoactive treatment

• Check of therapy response every 3 months by right heart catheterization

• Criteria for response: MPAP <35 mmHg and PVR <400 dynes/s/cm-5 or normal PVR (<240 dynes.s.cm-5) and normal right heart function

• MPAP >50 mmHg despite vasoactive therapy must be considered as absolute contraindication to LT

Houlihan et al. Aliment. Pharmacol Ther, 2013; AISF-CCTF-SITO Proposed Consensus Conference; 2013


LISTED






ALCOHOL DEPENDENCE IN THE CANDIDATE TO LT

• In order to ration organs, most programmes require a 6-month period of abstinence prior to evaluation of alcoholic patients.

• The 6-month period of abstinence is presumed:

- to permit some patients to recover from their liver disease and obviate the need for LT

- to identify subsets of patients likely to maintain abstinence after LT

• Data concerning the utility of the 6-month rule as a predictor of long-term sobriety are controversial

• Drinking habits of transplanted patients need to be routinely screened with tools of proven reliability

• Severe acute alcoholic hepatitis failing to respond medical therapy (Lille score ≥0.45 at day 7) – controversial indication to LT

DECISIONAL ALGHORITM IN PATIENTS WITH HISTORY OF ALCOHOL CONSUMPTION

History of alcoholism

Non compliance-Social problems?

Success of previous treatments?

No Yes

YesNo

Therapy and re-evaluateYes

Not candidate

No

Active psychosis?

YesNo

Psychiatric therapy terminated? No

Not candidate

YesFamiliar support?

NoYes

Social support available?

Reasonable candidate

Yes

Questionable candidate

No

Yowsey S. and Schneekloth T. In: Transplantation of the liver, 2nd edition. Elsevier and Saunders Ed. 2005.

SURVIVAL OF PATIENTS IN RELATIONSHIP TO PRIMARY INDICATION FOR LT IN EUROPE (01/1988-06/2007)

years

surv

ival

(%

) (N. = 14149)(N. = 11843)

(N. = 3969)

(N. = 2914)(N. = 1601)

European Liver Transplant Registry; 2008

%

SURVIVAL IN PATIENTS TRANSPLANTED FOR ALCOHOLIC DISEASE IN RELATIONSHIP TO MAINTAINANCE OF ABSTINENCE

Pfitzmann et al. Liver Transpl; 2007.

0 2 64 108

0

20

40

60

80

Sur

viva

l (%

)

years after LT

100

abstinent after LTresumed drinking after LTslip drinkersabusive drinkers

RISK FACTORS AND CAUSES OF DEATH FOR RECURRENT ALCOHOL CONSUMPTION AFTER LT

Pfitzmann et al. Liver Transpl; 2007.

Jauhar et al. Liver Transpl; 2004. Pfitzmann et al. Liver Transpl; 2007.

ALCOHOL ADDICTION AND LT

• Alcohol abuse is a frequent cause of acute and chronic liver disease in the general population.

• The social and financial costs of alcoholic liver disease treatment are growing

• Long term prognosis after LT for alcoholic liver disease depends on alcohol relapse

• The predictors of relapse must be checked accurately before LT

• Survival is significantly reduced for patients who relapse due to the development of liver cirrhosis and de novo malignancies

CONCLUSIONS

• In liver centers, a detailed evaluation of the recipient is performed to ensure that transplantation is indicated and feasible.

• Regular follow-up of patients on the waiting list is crucial for the success of transplantation and the reduction of mortality among these patients.

• The aggressive care of candidates to LT has permitted to maintain in the waiting list patients with very advanced liver disease. This should be carefully accompanied by a clear policy of selection of patients who will be transplanted

Education

Management del paziente in lista d'attesa per trapianto di fegato - Gastrolearning®