evaluating hiv patient for liver...

Evaluating HIV Patient for Liver Transplantation

Marion G. Peters, MD Professor of Medicine

University of California San Francisco USA

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 more rapid in HIV patients • End stage liver disease (ESLD) common

Proportion of deaths due to ESLD in HIV+

Salmon-Ceron, J Hepatol 2005

Complications of cirrhosis in HIV- and non-HIV-infected patients

• Ascites • Gastroesophageal variceal bleeding • Synthetic dysfunction: jaundice, coagulopathy • Spontaneous bacterial peritonitis (SBP) • Hepatic encephalopathy (HE) • Hepatorenal syndrome (HRS) • Hepatocellular carcinoma (HCC)

Cardenas & Gines, J Hepatol, 2005; Bruix J, J Hepatol, 2001

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 CTP •MELD >13 •Age

ESLD: Magnitude of the Problem in Western Europe and North America

Estimated No. Western North Patients Europe America • HIV-infected patients 540,000 1,125,000

• HCV co-infection 33% 28%

• HBV co-infection 9% 9%

• Liver cirrhosis 18,000 33,000 • OLT candidates 3,060 5,700

Hamers FF. Lancet. 2004; 364:83; GESIDA/FIPSE. EIMC. 2005;23:340.

EuroSida studies, 2003 & 2005; Fung J, Liver Transpl, 2004.

Overall Mortality

Observation Time (days) 6000 4000 2000 0

Cum

ulat

ive

Surv

ival

1,1

,9

,7

,5

,3

Liver-related Mortality

Observation Time (days) 6000 4000 2000 0

Cum

ulat

ive

Surv

ival

1,1

,9

,7

,5

,3

HAART

ART HAART

ART

None

None

HIV immune reconstitution also improves survival from HCV liver disease

Qurishi, Lancet 2003

Management of ESLD Cirrhotics • Upper endoscopy

– Varices or portal gastropathy, non selective beta blockers • Ascites: diuretics, paracentesis, TIPS, SBP

prophylaxis • Evaluate for HCC

– Liver imaging, alpha fetoprotein q 6-12 monthly • If decompensated

– Refer for possible transplant • Do not treat decompensated HCV with IFN

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

MELD is best Predictor of Mortality in 109 HIV+ Patients after the First Hepatic Decompensation

• Variable Survival HR Child-Pugh class - A 26 1 - B 10 2.06 (1.05-4.02) - C 7 2.56 (1.34-4.87)

MELD score - 6-10 34 1 - 11-15 14 2.83 (1.35-5.94) - 16-20 6 3.80 (1.75-8.27) - ≥21 4 5.26 (2.00-13.9) MELD score - 5 units change NA 1.55 (1.25-1.94 Miró JM at al. 10th EACS. Dublin. 2005; Abstract# PS7/1 1999-2004

OLT in HIV: Why Now? • 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 Patients: CD4+ T-cell count > 100 for liver recipients HIV RNA undetectable or if predicted to suppress OIs excluded PML, cryptosporidiosis and visceral KS

Indications for Liver Transplantation

• Liver decompensation – Development of decompensation (ascites,

variceal hemorrhage, Hepatic encephalopathy) in patients with cirrhosis is associated with a 5y survival of <50% (cf HIV 25%)

• Hepatocellular carcinoma- if small, contained – 3 lesions largest <3 cm – 1 lesion <5 cm

Pre OLT – what can you do?

• Pretransplant monitor for – Varices- yearly if decompensated- beta blockers – Ascites- tap for spontaneous bacterial peritonitis – Ultrasound / CT for HCC

– HCV treatment – HBV antivirals to ensure HBV DNA undetectable

HCV Pre OLT – what can you do? • HCV Pretransplant

– Treat select patients to eradicate HCV if MELD <20 – If HCV RNA positive at OLT then 100% post OLT – Peg IFN- problems with low platelets, WBC, infections – RBV- problems with anemia, renal insufficiency – BOC, TPV with PR- lots of side effects – All oral DAAs ideal here

• Donor – Careful donor selection

The Process- Phase I • How Referred: In patient -FHF • Out patient- hepatologist • Evaluation: Phase I

– Nurse coordinator – Hepatologist – Surgeon – Social Worker, support group – Labs: HBV, HCV, HIV, ABO blood group, MELD – Ultrasound, Doppler

OLT- The Process • Patient referred to hepatologist • Do they need a liver?

– MELD: • Is there a contraindication?

– Severe medical disease – Cancer – Psychosocial

• Does the patient want one?

OLT listing • Need for OLT

– MELD: creatinine, bilirubin, INR – Decompensation: albumin, INR, ascites,

encephalopathy, variceal bleed • Contraindication

– Medical- • AIDS defining illness • cardiac, renal, pulmonary disease, • extrahepatic cancer

– Social, psychiatric

Inclusion Criteria for OLT in HIV-infected patients in USA

• Liver criteria: same as for non HIV-infected • Drug abuse: same as for non HIV-infected • HIV criteria: 1) Clinical: untreatable OI’s: PML, crypto, MDR fungal

infection, Lymphoma, non cutaneous KS 2) Immunological: pre-decomp CD4 cell count greater

than 100 cells/mm3 3) Virological: RNA HIV-1 viral load u/d on ART or, if

detectable, post-OLT suppression predicted

OLT- The Process-2

• Phase I evaluation • Present to selection conference • If approved Phase II

– Cardiac, pulmonary, ca, renal • Sickest patient offered first by MELD • For Live donor, recipient must meet standard

criteria

Mortality on OLT Waiting List is Higher in HIV-Pos than HIV-Neg patients with ESLD

City (Country) n Died OLT Madrid (Spain)1

- HIV-pos 16 25% 0% Barcelona (Spain)2

- HIV-pos 13 62% 38% - Non-HIV patients ND 10% 90% Pittsburgh (PA, USA)3

- HIV-pos 58 36% 26% - Non-HIV patients 1,359 16% 63%

1Maida I, AIDS Research and Human Retroviruses, 2005; 2Rimola A, personal communication; 3Ragni M, Liver Transplantation, 2005

HIV and Liver Disease: OLT • Refer for any decompensation:

– ascites, encephalopathy, UGIB – synthetic dysfunction

• Refer early • Many issues confound ability to reach OLT

– Medical, social, geography, insurance • Need to fulfill listing criteria

– Medical – Psychosocial

• Need multidisciplinary approach

Liver Transplantation • MELD • Serum sodium • Underestimated

– chronic encephalopathy – hepatic hydrothorax – hepatopulmonary syndrome – portopulmonary hypertension

Post OLT – what can you do?

• Immunosuppression (IMS) modulation – steroid and calcineurin inhibitor (CNI)

minimization – Avoid T-cell-depleting treatments, acute rejection – control of metabolic problems- BMI, DM – Start Rx prior to significant damage to the

allograft is strongly recommended.

1

0.9

0.8

0.7

0.6

0.5 0 1 2 3 4 5

Surv

ival

%

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

Surv

ival

%

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 Two 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

HBV 45 41 27 21 HIV-HBV 12 7 5 5

93.1

92.7

Patient and Graft Survival HBV vs HBV-HIV*

90.5

*No deaths due to recurrent HBV

Survival Post-Transplantation (mos) 24 18 12 6 0

1

.8

.6

.4

.2

0

P = 0.54 log-rank test

83.8

Terrault 2007

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

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

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: Clearing HCV prior to OLT Restricting to BMI >21; no dual kidney transplant Avoiding use of livers from anti-HCV+ donors Better management of acute rejection

Stock 2011

HCV/HIV and Liver Transplantation Recurrence is universal and disease progression

appears to be more rapid post-transplantation No effective form of prophylactic therapy Antiviral therapy (peg/interferon plus ribavirin

+DAA) some successes Therapies are suboptimal Limited tolerability (higher rate of treatment

discontinuation) All oral DAA clearing HCV will improve outcomes post

OLT Post OLT DAA PI drug drug interactions with CNI

HIV and Liver Transplantation HBV and HCV are the most common causes of

chronic liver disease in HIV-infected persons Most transplant programs HCV>>HBV

Liver disease progression is accelerated in persons with viral hepatitis and HIV coinfection (compared to HIV un-infected persons)

With use of HAART, the number of liver-related deaths is increasing among HIV-infected persons

New DAA therapies should improve HCV outcomes

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