Evaluating HIV Patient for Liver Transplantation Marion G. Peters, MD Professor of Medicine University of California San Francisco USA
Slide 2 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+ Slide 3 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) Slide 4 Cardenas & Gines, J Hepatol, 2005; Bruix J, J Hepatol, 2001
Slide 5 Survival Time from First Liver Decompensation to Death in HCV Death during study 366/1037 HCV 100/180 HIV/HCV Risk factors for death: HIV Baseline CTP MELD >13 Age Pineda, Hepatology 2005
ESLD: Magnitude of the Problem in Western Europe and North America Estimated No. Western North Patients Europe America Slide 6 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.
HIV immune reconstitution also improves survival from HCV liver disease Slide 7 Cumulative Survival 1,1,9,7,5,3 Overall Mortality HAART ART None 0 2000 4000 Observation Time (days) 6000 Cumulative Survival 1,1,9,7,5,3 0 Liver-related Mortality HAART ART None 2000 4000 6000 Observation Time (days) Qurishi, Lancet 2003
Slide 8 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 Slide 9 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
Slide 10 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
Slide 11 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? Slide 12 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 Slide 13 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? Slide 14 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
Slide 15 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 Slide 16 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 Slide 17 Patient referred to hepatologist Do they need a liver? MELD: Is there a contraindication? Severe medical disease Cancer Psychosocial Does the patient want one?
Slide 18 Need for OLT OLT listing MELD: creatinine, bilirubin, INR Decompensation: albumin, INR, ascites, encephalopathy, variceal bleed Contraindication Medical- AIDS defining illness cardiac, renal, pulmonary disease, extrahepatic cancer Social, psychiatric
Slide 19 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
Slide 20 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% 1 Maida I, AIDS Research and Human Retroviruses, 2005; 2 Rimola A, personal communication; 3 Ragni M, Liver Transplantation, 2005 Slide 21
Slide 22 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
Slide 23 Liver Transplantation MELD Serum sodium Underestimated chronic encephalopathy hepatic hydrothorax hepatopulmonary syndrome portopulmonary hypertension
Post OLT what can you do? Slide 24 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.
Liver Transplantation and HBV Progress in Two Decades Slide 25 Era 1 (1987-1991) 1 HBIG LAM 1 Era 3 (1997-2002) 0.9 0.9 Survival % 0.8 0.7 0.6 HBV Other P < 0.01 Survival % 0.8 0.7 0.6 HBV Other P =.14 0.5 0 1 2 3 4 5 Time (years) 0.5 0 1 2 3 4 5 Time (years) 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 Kim WR, et al. Liver Transpl. 2004;10:968.
Slide 26 Patient and Graft Survival HBV vs HBV-HIV* 1 92.7 90.5.8.6 93.1 83.8 P = 0.54 log-rank test.4.2 0 0 *No deaths due to recurrent HBV HBV 45 41 27 21 HIV-HBV 12 7 5 5 6 12 Survival Post-Transplantation (mos) 18 24 Terrault 2007
Patient Survival: HCV Slide 27 100 % PATIENT SURVIVAL 80 60 40 20 P =.01 P=0.01 HCV-HIV Coinfected HCV Monoinfected P=0.01 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 YEAR HCV mono-infected n=135 n=67 n=22 HCV-HIV co-infected n=46 n=28 n=14 Terrault N, et al. AASLD 2009. Abstract 195.
Slide 28 Graft Survival: HCV 100 % GRAFT SURVIVAL 80 60 40 20 P=0.01 P=0.01 HCV-HIV Coinfected HCV Monoinfected 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 YEAR Terrault 2010 HCV mono-infected N=128 N=67 N=21 HCV-HIV co-infected N=43 N=26 N=13
HIV and Liver Transplantation What Have We Learned? Slide 29 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
Slide 30 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
Slide 31 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
Slide 32 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