Predictors of Patient and Graft Survival Following

Liver Transplantation for Hepatitis C

MICHAEL CHARLTON, ERIC SEABERG, RUSSELL WIESNER, JAMES EVERHART, ROWEN ZETTERMAN,
JOHN LAKE, KATHERINE DETRE, AND JAY HOOFNAGLE

End-stage liver disease secondary to hepatitis C virus

(HCV) infection is the leading indication for liver transplantation in the United States. Recurrence of HCV infection is
nearly universal. We studied the patients enrolled in the
National Institute of Diabetes and Digestive and Kidney
Diseases Liver Transplantation Database to determine
whether pretransplantation patient or donor variables could
identify a subset of HCV-infected recipients with poor
patient survival. Between April 15, 1990, and June 30,
1994, 166 HCV-infected and 509 HCV-negative patients
underwent liver transplantation at the participating institutions. Median follow-up was 5.0 years for HCV-infected and
5.2 years for HCV-negative recipients. Pretransplantation
donor and recipient characteristics, and patient and graft
survival, were prospectively collected and compared. Cumulative patient survival for HCV-infected recipients was
similar to that of recipients transplanted for chronic non
B-C hepatitis, or alcoholic and metabolic liver disease,
better than that of patients transplanted for malignancy or
hepatitis B (P 5 .02 and P 5 .003, respectively), and
significantly worse than that of patients transplanted for
cholestatic liver disease (P 5 .001). Recipients who had a
pretransplantation HCV-RNA titer of H1 3 106 vEq/mL had
a cumulative 5-year survival of 57% versus 84% for those
with HCV-RNA titers of F1 3 106 vEq/mL (P 5 .0001).
Patient and graft survival did not vary with recipient
gender, HCV genotype, or induction immunosuppression
regimen among the HCV-infected recipients. While longterm patient and graft survival following liver transplantation for end-stage liver disease secondary to HCV are
generally comparable with that of most other indications,
higher pretransplantation HCV-RNA titers are strongly
associated with poor survival among HCV-infected recipients. (HEPATOLOGY 1998;28:823-830.)

Abbreviations: HCV, hepatitis C virus; LTD, Liver Transplantation Database; NIDDK,

National Institutes of Diabetes and Digestive and Kidney Diseases; EIA2, secondgeneration enzyme-linked immunosorbent assay; RIBA, recombinant immunoblot
assay; RT-PCR, reverse-transcriptase polymerase chain reaction; UNOS, United Network for Organ Sharing; PH, proportional hazards; ACR, acute cellular rejection; SRR,
steroid-resistant rejection.
From the National Institute of Diabetes and Digestive and Kidney Diseases Liver
Transplantation Database
Received March 9, 1998; accepted May 28, 1998.
Supported by Public Health Service grant GCRC RR00585.
Address reprint requests to: Michael R. Charlton, M.D., Division of Gastroenterology
and Hepatology, Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN
55905. Fax: (507) 266-1856.
Copyright r 1998 by the American Association for the Study of Liver Diseases.
0270-9139/98/2803-0033$3.00/0

Subsequent to the initial cloning of and the development of

diagnostic tests for the hepatitis C virus (HCV) in 1989,1,2
hepatitis C has emerged as a major cause of liver disease. It is
estimated that there are approximately four million individuals infected with HCV in the United States, where HCV
infection causes 20% of acute and 70% of chronic hepatitis.3,4
While published data give conflicting estimates of the proportion of HCV-infected individuals who go on to develop
cirrhosis, the number of patients with HCV infection requiring liver transplantation has grown steadily. In 1991, when
screening for HCV infection first became widely available,
17.8% of liver transplantations were performed for end-stage
liver disease associated with HCV infection. This proportion
has increased every year following 1991 and is currently over
30%, making end-stage liver disease associated with HCV
infection the leading indication for liver transplantation in
the United States.5 Recurrence of HCV infection in liver
allograft recipients is nearly universal.6,7 In the setting of an
increasing donor organ shortage, these facts have raised
pressing questions about liver transplantation for liver disease associated with HCV infection. In 1990, the Liver
Transplantation Database (LTD) was established by the
National Institutes of Diabetes and Digestive and Kidney
Diseases (NIDDK). Three prominent liver transplantation
centers prospectively contributed serum, tissue, clinical, and
demographic information from patients being evaluated for
liver transplantation, the purpose of which was to pool
collective experience in liver transplantation to answer questions that could not readily be addressed by single centers.
Transplantation for HCV-associated liver disease poses several important such questions. Although patients undergoing
liver transplantation for HCV have been reported to have
comparable overall patient and graft survival to most other
indications, it is not known whether a subset of HCV-infected
recipients exists who are at increased risk for poor patient or
graft survival. To date, no viral, donor, recipient, or therapeutic variables identifying a cohort of HCV-infected recipients
with poor patient and/or graft survival have been defined. We
report the experience of the NIDDK LTD in the identification
of risk factors for adverse outcomes following liver transplantation for HCV.
PATIENTS AND METHODS
Study Patients
The LTD is a 7-year prospective study of patients who underwent
liver transplantation at three medical centers.8 The three participating centers were: Mayo Clinic and Foundation, Rochester, MN; the
University of Nebraska, Omaha, NE; and the University of California, San Francisco, CA. The study was approved by the Institutional

823

824

CHARLTON ET AL.

Review Boards of each of the contributing centers. All patients who

were evaluated for possible liver transplantation and who gave their
informed written consent were enrolled.
A total of 916 patients undergoing liver transplantation at the
three contributing centers were enrolled during the accrual phase of
the study between April 15, 1990, and June 30, 1994. Clinical
follow-up data were collected through June 30, 1995, and final vital
status was determined between February and April 1997. Excluded
from these analyses were 111 pediatric recipients, 41 patients with
fulminant hepatic failure, 26 multiorgan recipients, 23 recipients of
livers from donors with antibody to hepatitis B core antigen, 1
recipient who was anhepatic, 1 who received a living-related donor
organ, and 1 in whom the primary data could not be identified.
Thus, 712 recipients were eligible for this study.
Patients were considered to have hepatitis C if they tested positive
for anti-HCV by second-generation enzyme-linked immunosorbent
assay (EIA2) and were also reactive for anti-HCV by recombinant
immunoblot assay (RIBA) or had HCV RNA present in serum as
detected by reverse-transcriptase polymerase chain reaction (RTPCR). Recipients who were not tested by EIA2 for anti-HCV (n 5
13), whose EIA-2 positivity was not or could not be confirmed by
RIBA or PCR (n 5 21), or who had conflicting EIA2 and PCR results
(n 5 3) were excluded from this analysis. The comparison group
consisted of patients who tested negative by EIA2 for anti-HCV and
had no other (RIBA or PCR) test positive for HCV. The comparison
group was analyzed as a whole and also after being broken down
into groups according to their primary diagnosis before transplantation. These groups were: 1) cholestatic liver diseases (primary
biliary cirrhosis and primary sclerosing cholangitis); 2) chronic
hepatitis not caused by hepatitis B or C; 3) metabolic liver disease
(including Wilsons disease and hemochromatosis); 4) alcoholic
liver disease, 5) malignancy; and 6) end-stage liver disease secondary to chronic hepatitis B infection. For the purposes of this analysis,
patients who were diagnosed with a malignancy (hepatocellular
carcinoma or cholangiocarcinoma) before transplantation were
considered to have a primary diagnosis of malignancy regardless of
the cause of their underlying liver disease, i.e., patients with
hemochromatosis, hepatitis B, or hepatitis C complicated by hepatocellular carcinoma were considered to have a primary diagnosis of
malignancy and analyzed with the malignancy cohort.
Immunosuppression
Induction immunosuppression at the Mayo Clinic consisted of
cyclosporine, prednisone, and azathioprine. The University of
Nebraska used cyclosporine and prednisone. The University of
California at San Francisco used antilymphocyte globulin, followed
by cyclosporine, prednisone, and azathioprine. All centers participated in the FK506 Primary Immunosuppression Trial, resulting in a
subgroup of recipients receiving a tacrolimus-based regimen. In
these analyses, induction immunosuppression was defined as all
immunosuppressive medicines administered during the first 3 days
following liver transplantation surgery.

HEPATOLOGY September 1998

RIBA for HCV

A commercially bought four-antigen recombinant immunoblot
assay was used (RIBA-2, Chiron, Emeryville, CA).
Viral RNA Extraction and Amplification
Aliquots of 100 L of sera were extracted by a guanidine
thiocyanate lysis protocol using reagents supplied in the Amplicor
Hepatitis C Test kit (Roche Diagnostics, Branchburg, NJ) for
amplification of the 58 untranslated region and genotyping reactions. Modifications included the addition of 2 L of Pellet Paint
(Novagen, Madison, WI) to facilitate recovery of nucleic acid pellets
after isopropanol precipitation and the addition of 40 units of
recombinant RNasin in a final 25-L volume with RNase-free water
to stabilize the recovered RNA before RT-PCR.
Reverse transcription was performed as previously described.10
DNA Sequencing
Specimens were subjected to DNA sequencing and gel electrophoresis on an ABI Prism 377 Genetic Analyzer to generate DNA
sequence information. Sequences were compared with published
HCV type reference sequences using the FASTA algorithm (Wisconsin Genetics Computer Group, Madison, WI). Genotypes were
assigned based on percentage match scores to the reference strains.9
Nucleotide primers specific for a 401-bp target sequence within
the NS5 region of HCV were used as described by Simmonds et al.9
HCV-RNA Quantitation (Branched DNA Assay)
HCV RNA, expressed in HCV-RNA viral equivalents per milliliter
(vEq/mL), was quantitated in serum by signal amplification employing branched DNA in a sandwich hybridization assay (Quantiplex
Version 2.0, Chiron Corp.). The lower limit of sensitivity of this
assay is 0.2 3 106 vEq/mL. A test of trend demonstrated that the
percentage of recipients with HCV-RNA titers greater than the
overall median of 340,000 vEq/mL did not change significantly over
time (P 5 .66; mean storage time, 4.5 years).
Statistical Analysis
Baseline recipient characteristics included in these analyses were
age, sex, race, cause(s) of end-stage liver disease, United Network
for Organ Sharing (UNOS) status, modified Child-Pugh score,
pretransplantation renal insufficiency, cold ischemia time, donor
liver quality, and donor age. These characteristics were summarized
for the HCV-infected and HCV-negative cohorts using means,
medians, and percentiles, and the two groups were compared using
x2 and Wilcoxon rank sum tests.11 Patient and graft survival curves
were estimated using the Kaplan-Meier product-limit method12 and
compared using the Wilcoxon test.13 Cox Proportional Hazards
(PH) models14 were used to identify characteristics independently
associated with survival time. Time-dependent covariates were
included in these models to measure the association between
rejection and survival time, and to test the assumption of proportional hazards.13

Specimens
Frozen serum and tissue samples were stored as part of a
comprehensive HCV study for the NIDDK LTD. To minimize
specimen degradation, tissue and serum was stored at 220C and
transported on dry ice to the Mayo Clinic and Foundation Tissue
and Serum bank, where samples were thawed, aliquoted, and stored
at 270C before testing. Ninety-eight percent of the samples were
drawn within 3 days before transplantation; 2% were drawn between
1 day and 3 months before transplantation.
EIA-2 for HCV
A commercially bought assay was used (EIA-2, Chiron, Emeryville, CA).

RESULTS
Cohort Characteristics

The cohort analyzed consisted of 675 recipients, of whom

166 (25%) met inclusion criteria for being infected with HCV,
and 509 (75%) were HCV-negative pretransplantation. Median follow-up was 5.0 years for HCV-infected recipients, and
5.2 years for HCV-negative controls. Overall, follow-up
ranged from 1.6 to 6.8 years.
The baseline characteristics of HCV-infected recipients and
HCV-negative controls are shown in Table 1. Among the
HCV-negative controls, end-stage liver disease most commonly was caused by cholestatic liver disease (40.1%),

HEPATOLOGY Vol. 28, No. 3, 1998

CHARLTON ET AL.

TABLE 1. Pretransplantation Characteristics of HCV-Infected

and HCV-Negative Recipients
HCV-neg

from the HCV-infected cohort. Similar results were observed

for graft survival.

HCV-pos

Baseline Characteristics

All
Gender (P 5 .001)
Male
Race (P 5 .03)
White
Recipient age at first liver transplantation
(P 5 .005)
Mean (SD)
Final UNOS status/patient location
(P 5 .46)
At home
In hospital
In ICU
Pugh score at liver transplantation
(P 5 .04)
,7
7-10
.10
Mean (SD)
Renal insufficiency at liver transplantation
(P 5 .55)
Yes
Cold ischemia time (h) (P 5 .02)
.12.0
Mean (SD)
Donor liver quality (P 5 0.40)
Fair/Poor
Donor age (P 5 .92)
50-up
Mean
Range

509

100.0

166

100.0

256

50.3

121

72.9

420

82.5

124

74.7

50.1 (11.3)

341
123
45

67.0
24.2
8.8

96
19.2
236
47.1
169
33.7
8.6 (2.3)

41

8.1

139
27.8
10.2 (4.0)
40

8.3

130
25.5
35.6 (16.7)
7-73

48.1 (10.1)

116
38
12

69.9
22.9
7.2

15
9.4
84
52.8
60
37.7
8.9 (2.0)

11

6.6

55
34.2
10.8 (3.6)
10

825

6.3

43
26.1
35.4 (21.7)
11-70

NOTE. Renal insufficiency was defined as creatinine .2 mg/dL before

transplantation.

chronic nonB-C hepatitis (22.2%), or alcoholic liver disease

(17.3%). HCV-infected recipients were younger than HCVnegative controls, included a greater proportion of nonwhite
recipients, and were more likely to be male. HCV-infected
recipients had a higher mean Child-Pugh score (mean, 8.9 vs.
8.6; P 5 .04) and longer mean cold ischemia time (mean,
10.8 vs. 10.2 hours; P 5 .02) than HCV-negative controls.
The cohorts were similar with respect to final UNOS status,
proportion of recipients with renal insufficiency (creatinine .2
mg/dL), donor liver quality, and donor age.
Overall Patient and Graft Survival: Hepatitis C Versus
Other Indications

A comparison of cumulative patient survival for HCVinfected recipients with that of the various HCV-negative
cohorts is shown in Fig. 1. Cumulative patient survival for
the HCV-infected recipients was 70% at year 6 posttransplantation. Recipients undergoing transplantation for hepatitis B
infection or malignancies had significantly poorer cumulative
survival (RR 5 2.4 and 2.2; P 5 .003 and P 5 .02,
respectively) than the HCV-infected recipients, while patients
transplanted because of cholestatic liver disease had significantly better cumulative survival (RR 5 0.4; P 5 .001) than
the HCV-infected recipients. Patient survival for recipients
with alcoholic liver disease, metabolic liver disease, or
chronic nonB-C hepatitis was not significantly different

Patient and Graft Survival Among Patients Transplanted

for Hepatitis C
Pretransplantation Variables. Multiple baseline characteristics were analyzed in a PH model for association with survival
among the 166 HCV-infected recipients. Baseline characteristics independently associated with increased mortality among
the HCV-infected recipients included recipient age, race, and
pretransplantation Child-Pugh score (Table 2). Gender, pretransplantation renal insufficiency, cold ischemia time, donor
liver quality, donor age, coexisting alcoholic liver disease,
incidental malignancy, and induction immunosuppression
were not independently associated with mortality. After
adjusting for age, race, and pretransplantation Child-Pugh
score, a pretransplantation HCV-RNA titer of $1 3 106
vEq/mL was significantly associated with poorer patient
survival (RR 5 4.3; P 5 .0001). The distribution of pretransplantation HCV-RNA titers and frequency of HCV genotypes
are shown in Table 3. For patients with a pretransplantation
HCV-RNA titer of ,1.0 3 106 vEq/mL, the 1- and 5-year
cumulative patient survival rates were 94% and 84%, respectively, versus 83% and 57%, respectively, for HCV-infected
patients with a pretransplantation HCV-RNA titer of $1.0 3
106 vEq/mL (P 5 .0001) (Fig. 2). Consistent with the patient
survival analyses, pretransplantation HCV-RNA level was
strongly associated with graft survival (RR 5 3.6; P 5 .0004).
In contrast, neither patient nor graft survival varied significantly with HCV genotype (Fig. 3).
Pretransplantation characteristics of HCV-infected recipients with a pretransplantation HCV viral load of $1.0 3 106
vEq/mL are compared with those of recipients with a pretransplantation HCV viral load of ,1.0 3 106 vEq/mL in Table 4.
The two groups were similar with respect to gender, race, age
at first transplantation, UNOS status, Child-Pugh score,
prevalence of renal insufficiency, cold ischemia time, donor
age, and prevalence of pretransplantation alcoholism. The
percentage of recipients with a pretransplantation HCV viral
load of ,1.0 3 106 vEq/mL receiving a donor liver of
fair/poor quality by surgeons assessment was lower (3%;
n 5 4) than for recipients with a pretransplantation HCV
viral load of $1.0 3 106 vEq/mL (14%; n 5 6) (P 5 .03). The
possible effect of the higher proportion, although a small
number, of recipients with a pretransplantation HCV viral
load of .1.0 3 106 vEq/mL receiving livers of fair/poor
quality was incorporated into the multiple Cox regression
models. Donor liver quality did not account for the observed
survival difference.
HCV-RNA levels at 1 year posttransplantation were measured in 112 of the 166 HCV-infected recipients. The median
HCV RNA at 1 year posttransplantation was 8.3 3 106
vEq/mL in recipients whose pretransplantation HCV-RNA
levels were low (,1.0 3 106). For recipients whose pretransplantation HCV-RNA levels were high (.1.0 3 106), the
median HCV RNA at 1 year posttransplantation was 25.3 3
106 vEq/mL. This difference in median 1-year posttransplantation HCV-RNA levels was significant (P 5 .005). Pretransplantation viral levels were thus predictive of the degree of
posttransplantation viremia at 1 year.
Causes of Mortality and Graft Loss. Recurrent HCV with
ensuing graft failure was the primary or secondary cause of
death in 11 (28%) of the 39 HCV-infected recipients who died

826

CHARLTON ET AL.

HEPATOLOGY September 1998

FIG. 1. Cumulative patient survival following liver transplantation for recipients according to primary diagnosis before transplantation. Chol, cholestatic
liver diseases; nonB-C, chronic nonB-C hepatitis; metab, metabolic liver disease; ALD, alcoholic liver disease; malig, malignancy; HBV, end-stage liver
disease secondary to chronic hepatitis B infection. (r), chol; (R), nonB-C; (n), HCV; 3, metab; *, ALD; d, malig; 1, HBV.

in the follow-up period. Similarly, recurrent hepatitis C was

the reason for retransplantation in 5 (42%) of the 12 who
underwent retransplantation. The 5-year cumulative percentage of patients who either died or required retransplantation
because of recurrent HCV or any other infection was 32%
among HCV-infected recipients with an HCV-RNA titer of
$1 3 106 vEq/mL versus 10% among HCV-infected recipients with an HCV-RNA titer of ,1 3 106 vEq/mL (P 5 .001).
Other causes of death among HCV-infected recipients were
non-HCV infections (n 5 11), malignancy (n 5 4), primary
cardiac or cerebrovascular events (n 5 5), primary nonfunction (n 5 2), gastrointestinal bleeding, perforated duodenal
ulcer, central pontine myelinolysis, pancreatitis, fat emboli
syndrome, cryoglobulinemia, posttransplantation lymphoproliferative disease, and unknown (n 5 1 for each). A compari-

TABLE 2. Pretransplantation Factors Independently Associated

With Increased Cumulative Mortality or Graft Loss Among 166
HCV-Infected Recipients
Patient Survival
Characteristic

HCV RNA $ 1 3
vEq/mL
Recipient nonwhite
Recipient age (per
year)
Recipient Pre-LT
Pugh Score . 10

Graft Survival

RR

95% CI

RR

95% CI

4.3
2.1

2.1-8.5
1.0-4.3

.0001
.04

3.6
2.8

2.0-6.6
1.5-5.1

.0001
.001

1.05

1.02-1.09

.004

1.05

1.02-1.08

.004

2.0

1.0-4.0

.04

106

NOTE. Relative risk (RR) of 1.05 is per recipient year of age.

son of the causes of death and retransplantation according to

pretransplantation HCV-RNA levels is shown in Table 5.
The relationship between rejection treatment and patient
survival was investigated among the 166 HCV-infected recipiTABLE 3. Pre-OLT Viral Load and Genotype of the 166
HCV-Infected Recipients
Pre-OLT HCV-RNA Titers
PCR-negative
,0.20
0.20-0.49
0.50-0.99
1.0-1.99
2.0-17.85
Genotype results
PCR-negative
1a
1b
2b
3a
Other types
1
2a/2c
2
4c/4d
4
Nonclassifiable
Unsequenced

n 5 14 (8%)
n 5 53 (32%)
n 5 29 (17%)
n 5 22 (13%)
n 5 17 (10%)
n 5 31 (19%)
n 5 14 (8%)
n 5 52 (31%)
n 5 54 (33%)
n 5 12 (7%)
n 5 18 (11%)
n 5 16 (10%)
n52
n56
n51
n52
n51
n51
n53

NOTE. All 166 were EIA2-positive; 152 (92%) were PCR-positive pre
liver transplantation, and 14 were PCR-negative; 160 (96%) were RIBApositive preliver transplantation, 4 were RIBA-indeterminate, and 2 were
RIBA-negative. HCV RNA expressed as vEq/mL.

HEPATOLOGY Vol. 28, No. 3, 1998

CHARLTON ET AL.

827

FIG. 2. Cumulative patient survival by pretransplantation HCV-RNA load (in units of 106 vEq/mL, measured by branched DNA hybridization). Higher
cumulative patient mortality in HCV-infected recipients with a pretransplantation HCV-RNA viral load of $1 3 106 vEq/mL, when compared with
HCV-infected recipients with a pretransplantation HCV-RNA load of ,1 3 106 vEq/mL, was significant (P 5 .0001). Results were similar for graft survival.
Pre-LT, preliver transplantation. (r), pre-LT RNA ,0.2; (R), pre-LT RNA 0.2-0.49; (n), pre-LT RNA 0.5-0.99; 3, pre-LT RNA .1.

ents. Compared with patients not treated for rejection, being

treated for acute cellular rejection (ACR) (RR 5 2.9; P 5 .03)
and steroid-resistant rejection (SRR) (RR 5 5.4; P 5 .003)
were independently associated with increased mortality. When
ACR and SRR were added to the multivariate PH model for
patient survival, being of the nonwhite race was no longer
independently associated with patient survival (RR 5 1.9;
P 5 .08). However, race remained independently associated
with poorer graft survival (RR 5 2.6; P 5 .003).
Variations in Outcomes With Induction Immunosuppression. Increased allograft rejection in patients infected with HCV has
been alternately associated with the use of tacrolimus15 and
cyclosporine A.16 In this study, the cumulative 1-year incidence of ACR was similar in patients receiving tacrolimus (1
steroids) and cyclosporine (1 steroids 6 azathioprine) (75%
vs. 68%, respectively; P 5 .94). However, the cumulative
1-year incidence of SRR was 0% for recipients receiving
tacrolimus versus 22% for recipients receiving cyclosporine
(P 5 .04 by exact log rank test). The increased incidence of
SRR among recipients receiving cyclosporine-based induction immunosuppression did not translate into increased
graft loss or mortality. For recipients whose induction immunosuppression regimen included tacrolimus, the 3-year patient and graft survival was 81% and 75%, respectively, versus
79% and 75% for recipients receiving cyclosporine (P 5 .98

for patient and P 5 .95 for graft survival). Similar relationships were seen at 1 and 5 years.
Finally, recipients with a mean daily steroid dose in the first
42 days of 100 mg or greater carried a significantly increased
risk of death (RR 5 2.7; P 5 .04) when compared with
recipients with an average daily dose of 50 mg or less.
DISCUSSION

This study was based on combined results of liver transplantation for hepatitis C from three large centers in the United
States. Analysis of 675 adult transplant recipients, including
166 with chronic hepatitis C, showed that HCV-infected
recipients had survival similar to those with other forms of
end-stage liver disease. In this respect, these results are
similar to previous reports from single centers comparing
patient and graft survival of HCV-infected to noninfected
recipients.17-22 It should be stressed, however, that survival
comparisons between patients with hepatitis C and the
average transplant recipient may not be appropriate. In this
study, recurrent hepatitis C was primarily responsible for 9
deaths and 5 retransplantations in the HCV-infected recipients. Of the HCV-infected recipients, 9% demonstrated evidence of severe recurrent disease with subsequent graft loss
during the follow-up period. Thus, the comparison of survival of HCV-infected recipients with all noninfected recipi-

828

CHARLTON ET AL.

HEPATOLOGY September 1998

FIG. 3. Cumulative graft survival by HCV genotype. None of the genotypes were associated with either a significantly better or worse graft survival than
any of the other genotypes. (d), 1a; (R), 1b; (n), 2b; 3, 3a; *, other.

ents failed to demonstrate that HCV infection adversely

affected outcome of transplantation. More insights into the
problem are provided by analysis of transplant recipients by
diagnostic category. In these analyses, survival of patients
with HCV infection was similar to that of patients with
chronic nonB-C hepatitis and patients with alcoholic liver
disease, but was not as good as for patients with cholestatic
liver diseases. Thus, patient survival after transplantation for
hepatitis C may be excellent, but is probably not as good as it
should be were recurrent HCV infection and hepatitis not to
occur.
Specific analysis of HCV-infected patients demonstrated
several well-known factors that were associated with decreased survival. Thus, recipient age, Child-Pugh score, and
donor liver quality were found to correlate with decreased
survival in HCV-infected patients. Importantly, however, two
additional factors were found to correlate with decreased
survival in the HCV-infected cohort. These factors were
recipient race and pretransplantation HCV-RNA levels.
Race or ethnicity has not been widely considered to be an
important factor in patient or graft survival after liver
transplantation. However, in analyses of the national registry
on liver transplantation conducted by the UNOS, race has
been found to correlate with outcome, both in children and
adult recipients. Thus, among adults, overall 6-year survival
in UNOS was reported to be 64% in whites, 67% in Hispanics,
53% in blacks, and 47% in Asians.5 Multivariate analyses
showed that factors independently associated with outcome
in this large national cohort were age, race, location before
transplantation, and primary liver disease diagnosis. In the
LTD, race was not associated with survival in the overall
cohort, but was associated with survival among patients with
hepatitis C. These findings may have major significance

regarding the factors that predict progression and outcome of

HCV infection and deserve further analysis both in the
transplantation and nontransplantation situation.
By far, the greatest risk for patient mortality and graft loss
among HCV-infected recipients was a high pretransplantation
viral load. Recipients who had an HCV-RNA titer of $1 3 106
vEq/mL had a cumulative 5-year survival of 57%, similar to
that of recipients transplanted for hepatitis B virus and
malignancy. Conversely, recipients who had an HCV-RNA
titer of ,1 3 106 vEq/mL had a cumulative 5-year survival of
84%, a figure similar to that of patients transplanted for
cholestatic liver disease. High pretransplantation HCV-RNA
titers were also associated with poor graft survival. This
finding is consistent with the observation that higher pretransplantation viral loads are associated with adverse outcomes
following liver transplantation for hepatitis B.23,24
The basis of the increased risk of patient mortality and graft
loss associated with higher pretransplantation HCV-RNA
levels is not clear. The two most common causes of death in
HCV-infected recipients were non-HCV infections and allograft failure secondary to HCV recurrence. Higher pretransplantation HCV-RNA titers were associated with a higher
frequency of severe posttransplantation HCV recurrence, as
measured by death or graft loss secondary to HCV. Recipients
with pretransplantation HCV-RNA levels of .1 3 106 vEq/
mL, in whom median 1-year posttransplantation HCV-RNA
levels were three times greater than that of recipients whose
pretransplantation HCV-RNA levels were ,1 3 106 vEq/mL
(25.3 vs. 8.3 vEq/mL; P 5 .005), experienced death or graft
loss secondary to HCV recurrence more than twice as
frequently as recipients whose pretransplantation HCV-RNA
levels were ,1 3 106 vEq/mL (15.0% vs. 6.8%; P 5 .11)
(Table 5). Although graft failure secondary to HCV occurred

HEPATOLOGY Vol. 28, No. 3, 1998

CHARLTON ET AL.

TABLE 4. Baseline Characteristics of HCV-Infected Recipients

by Pre-OLT HCV-RNA Levels
Pretransplantation
HCV RNA ,1 3 106
N

All
Gender (P 5 .25)
Male
Race (P 5 .65)
White
Recipient age at first LT (P 5 .90)
Mean (SD)
Final patient location (P 5 .73)
At home
In hospital
In ICU
Child-Pugh score at LT (P 5 .21)
,7
7-10
.10
Mean (SD)
Renal insufficiency (P 5 .73)
Yes
Cold ischemia time (h) (P 5 .48)
Mean (SD)
Donor liver quality (P 5 .03)
Fair/Poor
Donor age (P 5 .17)
50-up
Mean
HCV genotype (P 5 .44)
1a
1b
2b
3a
Other
% With coexisting alcoholic liver
disease (P 5 .16)

118

Pretransplantation
HCV RNA $ 1 3 106

100

48

100

83

70.3

38

79.2

87

73.7

37

77.1

48.1 (10.1)
83
28
7

48.2 (10.1)

70.3
23.7
5.9

33
10
5

68.7
20.8
10.5

10
8.8
59
51.8
45
39.5
9.1 (2.0)

5
25
15

11.1
55.6
33.3
8.6 (2.0)

8.3

5.9

10.7 (3.4)
4

11.2 (4.1)
3.5

13.6

27
22.9
34.3 (16.0)

16
34.0
38.2 (16.3)

33
42
7
11
11
40

19
12
5
7
5
11

31.7
40.4
6.7
10.6
10.6
33.9

39.6
25.0
10.4
14.6
10.4
22.9

NOTE. Baseline characteristics of HCV-infected recipients who had high

pretransplantation viral loads ($1 3 106 vEq/mL) are compared with those
HCV-infected with lower pretransplantation viral loads (,1 3 106 vEq/mL).
Renal insufficiency was defined as a creatinine greater than 2 mg/dL before
transplantation.
Abbreviation: LT, liver transplantation.

TABLE 5. Cumulative 5-Year Cause-Specific Event Rates

for Death or Retransplantation
Cumulative Overall and
Cause-Specific 5-Year
Event Rates for
Death or Re-OLT

Cause of Death
or Re-OLT

Any cause
Recurrent HCV
Other infection
Noninfectious cause

Pre-OLT
Pre-OLT
HCV RNA HCV RNA Exact P Value
,1.0
$1.0
(log rank test)

19.6%
6.8%
3.7%
10.5%

48.2%
15.0%
19.8%
24.0%

.0005
.11
.003
.07

Univariate Cox
Proportional
Hazards Analysis

RR

95% CI

2.8
2.6
5.1
2.2

1.6-5.2
0.8-8.7
1.5-17.5
0.9-5.2

NOTE. Rates are estimated using the Kaplan-Meier method. The increased
incidence of death or graft failure was more than double in the high pre-OLT
HCV-RNA group for all causes. Unadjusted Cox Proportional Hazards
analysis indicate that the greatest difference between the two groups was the
frequency of deaths secondary to non-HCV infections.

829

more commonly among recipients with pretransplantation

HCV-RNA levels of .1 3 106 vEq/mL, this accounted for less
than half of the excess mortality and graft loss experienced by
these recipients, in whom death and graft loss caused by
non-HCV infections were also more common (19.8% vs.
3.7%; P 5 .003). An increased incidence of serious infections
following liver transplantation for end-stage liver disease
secondary to HCV has been reported previously.25 While a
mechanism for an increased incidence of lethal infections
secondary to a high HCV load is not known, it is possible that
HCV recurrence either mimics or causes allograft rejection,
resulting in greater exposure to immunosuppressive agents,
and thereby increased susceptibility to serious infection
and/or HCV-induced allograft injury. Among recipients transplanted for hepatitis C, being treated for a single episode of
acute cellular rejection was associated with an increased
cumulative risk of death (RR 5 2.7; 1.1-7.0 CI; P 5 .04). This
is in marked contrast to recipients who underwent liver
transplantation for other indications, for whom a single
episode of ACR has no impact on overall patient survival. In
our study, there were trends for both increased frequency of
ACR and greater daily steroid doses in the higher viral load
cohort. It is also possible that a higher pretransplantation
viral load may be indicative of relatively poor host immunity.
Whatever the mechanism, the attenuation in patient and graft
survival in patients with higher HCV-RNA titers is profound.
Previous reports of the impact of HCV genotype on
outcomes in HCV-infected recipients following orthotopic
liver transplantation have been mixed. Several groups found
that infection with HCV genotype 1b imparts an increased
risk for more severe chronic allograft injury.10,18,26-29 Others
have found no such association.17,30,31 Why there should be
such heterogeneity in the results regarding the impact of
genotypes on the risk for more severe chronic allograft injury
is difficult to ascertain. It is likely that differences in case
definitions, genotyping methodology (e.g., whether genotype
is assigned through comparison with the 58 untranslated
region vs. the NS5 region), length of follow-up, and selection
bias are contributing factors. In our study, which includes a
large number of HCV-infected recipients in whom the effect
of genotype was assessed, no correlation between HCV
genotype and patient or graft survival was observed. Even in
the studies that found HCV genotype 1b to be associated with
more severe chronic allograft injury,10,18,26-29 no association
was found with overall graft loss or patient mortality. If HCV
genotype 1b is associated with more severe allograft injury,
this should become manifest by an increased frequency of
graft failure in 1b infected recipients. To date, such an
association has not been demonstrated.
In summary, the course and outcome of HCV infection
after liver transplantation is quite variable. This study suggests that the outcome of recurrent HCV infection can, at
least in part, be predicted by pretransplantation levels of HCV
RNA. These findings may have important clinical implications and may point to a potential means of preventing or
ameliorating recurrent hepatitis C after transplantation. Thus,
major efforts at prevention and treatment of hepatitis C after
transplantation might be directed at those recipients with
high initial levels of HCV RNA. Alternatively, lowering HCV
RNA before transplantation might be a reasonable approach
to ameliorating the subsequent recurrent disease. These and
other implications of the findings of this multicenter study on
liver transplantation require further investigation.

830

CHARLTON ET AL.

HEPATOLOGY September 1998

Acknowledgment: Members who contributed to this study

included the following: from the Department of Epidemiology,
University of Pittsburgh Graduate School of Public Health,
Pittsburgh, PA: Katherine M. Detre, M.D., Dr.P.H. (Principal
Investigator); A. Jake Demetris, M.D. (Co-Investigator); Steven
H. Belle, Ph.D. (Co-Investigator); Yuling L. Wei, M.S. (CoInvestigator); Manuel Lombardero, M.S. (Statistician); Sharon
Lawlor, M.B.A. (Data Manager/Analyst); Heather Eng, B.A.
(Data Analyst); Jacqueline Haber, B.S. (Data Manager Assistant); Shannon FitzGerald, M.S. (Graduate Research Assistant); Gerald L. Swanson, B.S. (Systems Analyst); from the
Departments of Medicine and Surgery, Mayo Clinic Foundation,
Rochester, MN: Ruud A. F. Krom, M.D. (Co-Investigator);
Michael K. Porayko, M.D. (Co-Investigator), and Lori
Schwerman, R.N. (Research Nurse Coordinator); Nancy
Evans (Manuscript Preparation); from the Departments of
Medicine and Surgery, the University of Nebraska Medical
Center, Omaha, NE: Byers W. Shaw, Jr., M.D. (Co-Investigator)
and Karen Taylor, R.N., B.S.N. (Research Nurse Coordinator);
from the Departments of Medicine and Surgery, University of
California, San Francisco, CA: Nancy L. Ascher, M.D., Ph.D.
(Principal Investigator); Cherie Bremer-Kamp, R.N. (Research Nurse Coordinator); and from the Division of Digestive
Diseases and Nutrition, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD: James Everhart, M.D., M.P.H. (Program Director); and Jay H. Hoofnagle, M.D. (Division Director).
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