OUTCOMES

Hepatitis C Infection and Survivals of Liver Transplant Patients in

Canada, 1997–2003
Z. Hong, G. Smart, M. Dawood, K. Kaita, S.-W. Wen, J. Gomes, and J. Wu

ABSTRACT
Introduction. Liver transplantation is an important health and health care issue for
Canadians. Very few studies have estimated the survival results among liver transplant
patients infected with hepatitis C virus (HCV) in Canada.
Methods. We carried out a retrospective cohort study to analyze 1- to 5-year survival
rates among liver transplant patients, using Canadian Organ Replacement Registry data
(1997–2003). Patients less than 19 years old were excluded from the study. The patients
were categorized according to previous HCV infection status. The HCV-positive and
HCV-negative groups were compared in the following characteristics: age group, gender,
ethnicity, blood groups, donor type, pretransplantation medical status. Survival curves
were plotted by Kaplan-Meier method. Stepwise regression model was applied to control
the confounding impact related to gender, age, and HCV infection status.
Results. A total of 1842 liver transplant patients were included in the analysis. One-year
survival rate for all patients was 85.4%. There were 319 HCV-positive recipients in the
exposed group and 813 in the HCV-negative group. The HCV-positive and HCV-negative
groups were comparable in age groups, ethnicity, ABO blood group, pretransplantation
medical status, and donor organ type. The HCV-positive group had the higher male:
female ratio (2.32:1) than the HCV-negative recipients (1.49:1) (Mantel Haenszel (MH)
␹2 ⫽ 10.0311, P ⫽ .0015). There was no significant difference in 1-year survival rate
between HCV-positive and HCV-negative groups, but the differences in the 2-year and
5-year survival rates were significant even after adjusting gender factor by stepwise
regression analysis (MH ␹2 ⫽ 4.4203, P ⫽ .0355).
Conclusion. In Canada, the first-year survival rate is about 85.4%, which is comparable
with other industrialized countries. The exaggerated survival disadvantage for HCV-
positive recipients seems to be middle and long term, not short term.

H EPATITIS C VIRUS (HCV) infection is a major

health care issue in liver and kidney transplantation.
There were 460 liver transplants performed across seven
provinces in Canada in 2005. In the meantime, there were
723 end-stage patients awaiting liver transplantations. By
the end of 2005, 120 patients died awaiting an organ, which
constitutes the most urgent issue to be solved.1
Another important concern is the survival time of patients
who received liver transplants. If the treatment and clinical
service did not keep the transplants well, organ failure would
prevail. Those patients who lost an organ transplant go onto
waiting lists again. This situation exaggerates the disparity
between the number of patients in need of liver replacement
and the numbers of available organs.2
We studied several factors, including recipient age, gen-
der, ethnicity, medical status before liver transplantation,
donor type, and HCV infection status on the survival times
of patients. Liver transplantation for HCV-infected patients
also remains controversial because of the risk of HCV
infection recurrence due to graft reinfection. There is
From the Blood Safety Survellance Division, Centre for Infec-
tious Disease Prevention and Control, Public Health Agency of
Canada, Ottawa, Ontario, Canada.
Address reprint requests to Z. Hong, MD, MPH, DrPH, Public
Health Agency of Canada, Health Canada, Building No. 6,
Tunney’s Pasture, Ottawa K1A OL2, Ontario, Canada. E-mail:
zhiyong_hong@phac-aspc.gc.ca

0041-1345/08/$–see front matter © 2008 by Elsevier Inc. All rights reserved.

doi:10.1016/j.transproceed.2008.03.089 360 Park Avenue South, New York, NY 10010-1710

1466 Transplantation Proceedings, 40, 1466 –1470 (2008)

HCV INFECTION AND SURVIVALS IN CANADA
Table 1. Cox Proportion Hazard Analysis for 1842 Liver Transplant Adult Patients in Canada, 1997–2002
1-year
No. of survival rate
Characteristics patients (%)
Transplantation Year
1997 276 83.06
1998 280 81.69
1999 299 83.91
2000 346 87.76
2001 321 86.56
2002 320 88.88
Total 2062 85.33
*There was a significant difference in 1-year survival rates between 1997 and 2002. CL denotes confidence limits.
marked variability regarding the policy about HCV-positive
potential liver donors and the selection criteria for HCV-
positive recipients to undergo liver transplantation. In the
current literature, the data are controversial regarding
survival rates among liver transplant recipients with HCV
infection.3,4 The aim of this study was to analyze the impact
of gender and hepatitis C infection on outcome in Canada,
with a focused discussion of organ allocation policy for liver
transplantation.
MATERIALS AND METHODS
Study Population
The current study was based on all liver transplant patients
registered by the Canadian Organ Replacement Registry (CORR)
for the period January 1, 1997 to December 31, 2003. CORR is a
database developed by the Canadian Institute for Health Informa-
tion. There have been nine active liver transplant programs oper-
ating at nine hospitals in Canada since 1985. CORR has collected
data at nine hospitals that have dialysis or regional transplant
programs, organ procurement organizations, and kidney dialysis
services offered at independent health facilities. Patient-level trans-
plant data were collected retrospectively from 1997 to 2003, given
the expanded mandate of the register. Follow-up was completed on
all patients until the date of graft loss, patient death, or December
31, 2003. The database has information on more than 95% of liver
patients. More detailed information on transplant patients was
collected starting in 1997, with further data enhancements intro-
duced in 2001. Patients younger than 19 years old were excluded
from the study.
We consulted a classification specialist at the Canadian Institute
for Health Information and checked “International Statistical
Classification of Diseases and Related Health Problems,” 10th
Revision, Canada (ICD-10-CA), Volume 1.31 The correct term
“fulminant hepatitis failure” should include the following situa-
tions: hepatitis A with hepatic coma (B15.0) or hepatitis B with
hepatic coma (B16.0) or unspecified viral hepatitis with hepatic
coma (B19.0).
Hepatitis C Virus Infection Markers
Donor and transplant recipients were grouped according to their
HCV infectious status. Serum was tested for antibodies to HCV by
using an enzyme immunoassay (INNOTEST HCV Antibody IV,
Innogenetics, Ghent, Belgium). Samples with indeterminate results
were retested. All positive and twice-indeterminate samples were
confirmed with a third-generation line immunoassay (INNO-EIA
1467
Hazard
ratio 95% CL* ␹2 value P value
1 Reference — —
1.0926 0.7769–1.5366 0.2594 .6106
0.9500 0.6729–1.3412 0.0848 .7709
0.7667 0.5360–1.0969 2.1217 .1452
0.7938 0.5530–1.1394 1.5741 .2096
0.6615 0.4510–0.9701 4.5462 .0330*
HCV Antibody III, Innogenetics). Patients with a positive test for
anti-HCV antibody were defined as HCV positive; the remaining
patients with any negative test were HCV negative.5
Statistical Analysis
Survival curves for liver transplant patients were plotted using the
Kaplan-Meier method. Log-rank tests were used to analyze the
differences between the survival curves. Cox regression models
were employed to assess the effect on survival of various covariates,
including age group, gender, ethnicity, ABO blood group, donor
type, medical status before transplantation, and HCV infection
status.6 The hazard rate ratio (HR), which was used as the effect
measure, was defined as the ratio of the mortality rate in the group
of patients with a given factor to the rate in those without the
factor. A rate larger than 1 HR indicated a lower survival proba-
bility, where a rate smaller than 1 HR, a higher survival probability.
All statistical tests were two-sided, and P ⫽ .05 was considered
significant. Early analyses indicated interactions between age,
gender, and HCV infection status but only when patients aged 0 to
74 years were included. To better quantify the possible age
differences in the presence of these interactions, the analyses were
restricted to patients aged 19 to 74 years, avoiding the heteroge-
neity seen in the younger population. We also applied a stepwise
regression model to differentiate and further account for any
residual interaction between HCV infection status and gender.
RESULTS
Characteristics of the Study Population
From January 1, 1997 to December 31, 2003, 1842 patients
aged 20 to 85 years underwent liver transplantation in
Canada. At the end of our observation (December 31,
2003), 1572 patients remained alive, with a 1-year survival
rate of 85.4%. The most common indication for liver
transplantation was chronic hepatitis C infection (23.1%).
For cohorts 1997–2002, the 1-year survival rates for all
recipients improved steadily year by year, from 83% in 1997
to 89% in 2002 (MH ␹2 ⫽ 4.5462, P ⫽ .0330; Table 1).
There were 319 HCV-positive recipients in the exposed
group and 813 HCV-negative recipients in the control
group. We compared the characteristics between the HCV-
negative and HCV-positive groups. They were comparable
in age, ethnicity, ABO blood groups, pretransplantation
medical status, and donor organ types (Table 2). There was
a significant difference in the gender ratio between the
groups: The HCV-positive recipients showed a higher male:
1468 HONG, SMART, DAWOOD ET AL

Table 2. Comparability on the Characteristics Between 813 HCV-Negative Patients and 319 HCV-Positive Patients Before
Transplantation
HCV-negative HCV-positive Mantel-Haenszel
Characteristics group group chi-square P value

Age 0.0281 .8669

⬍40 y 123 (15.13%) 13 (4.08%)
40–49 y 174 (21.90%) 123 (38.56%)
50–59 y 306 (37.64%) 113 (35.42%)
ⱖ60 y 210 (25.83%) 70 (21.94%)
Gender 10.0311 .0015*
Male 486 (59.78%) 223 (69.91%)
Female 327 (40.22%) 96 (30.09%)
Race 0.3121 .5764
Caucasien 617 (75.89%) 248 (77.74%)
Asian 61 (7.50%) 13 (4.07%)
Aboriginal 17 (2.09%) 9 (2.82%)
Black 14 (1.72%) 5 (1.57%)
Mid-East/Arabian 7 (0.86%) 6 (1.89%)
Unknown 83 (10.21%) 31 (9.72%)
ABO blood groups 2.3285 .1270
Type O 320 (39.36%) 136 (42.63%)
Type A 352 (43.30%) 122 (38.24%)
Type B 96 (11.81%) 42 (13.17%)
Type AB 45 (5.54%) 18 (5.64%)
Pretransplantation medical status 1.4653 .2261
At home 461 (56.91%) 173 (54.40%)
With tumor 20 (2.47%) 18 (5.66%)
Hospitalized 205 (25.31%) 93 (29.25%)
Hospitalized at ICU 43 (5.31%) 16 (5.03%)
Fulminant at ICU 19 (2.35%) 2 (0.63%)
ICU with intubated and 29 (3.58%) 13 (4.09%)
ventilated
Fulminant at ICU with 30 (3.70%) 2 (0.63%)
intubated and ventilated
Donor organ types 0.8580 .3543
Deceased donor 778 (95.69%) 309 (96.87%)
Parent, offspring, other 24 (2.95%) 6 (1.88%)
relatives
Other 11 (1.36%) 4 (1.25%)
ICU, intensive care unit.
*There was a very significant difference in gender composition between HCV-positive group and HCV-negative group.

female ratio (2.32:1) than the HCV-negative recipients

(1.49:1; MH ␹2 ⫽ 10.0311, P ⫽ .0015).

Survival Estimates
Previous recipient HCV infection posed significant risk for
survival. There was no significant difference in 1-year
survival rates between HCV-positive and HCV-negative
groups, although the 319 recipients with previous HCV
infection showed a lower survival rate (82.76%) than the
813 recipients without HCV infection (85.24%). The dis-
crepancy between the two groups became more significant
after 2 years with survival rates of 58.62% and 65.31%,
respectively (MH ␹2 ⫽ 4.4203, P ⫽ .0355). The gap between Fig 1. Survival curves between HCV-positive recipients (P) and
two groups became larger after a 5-year observation (Fig 1). HCV-negative recipients (N). X-axis represents the survival time
After adjusting to gender ratio using a stepwise regres- (days). Y-axis represents the survival probabilities. HCV-positive
sion model, a significant difference in survival rates still recipients (P) had significant lower survival probabilities than
persisted between the two groups (F value ⫽ 3.84, P ⫽ .05). HCV-negative recipients (N).
HCV INFECTION AND SURVIVALS IN CANADA
DISCUSSION
The burden of HCV infection in liver transplantation is
heavy. Available prevalence data predict that the number of
patients requiring liver transplantations in North America
will rise over the next two decades due to the patients who
have contracted HCV.7,8
The results of HCV assays among the various transplant
centers in Canada were valid and consistent in our study.
The first enzyme immunoassay (EIA) to detect HCV
antibody (anti-HCV) became available in 1990 in Canada,
but it showed relatively poor sensitivity and specificity. In
1992, a second-generation EIA displayed dramatically im-
proved sensitivity and specificity. The third-generation anti-
HCV EIA, in use since mid-1990, has a sensitivity of 95% to
99%, detecting HCV antibodies 6 to 8 weeks after expo-
sure. When the anti-HCV EIA shows an indeterminate
result, a qualitative HCV RNA polymerase chain reaction is
required; the threshold for a positive HCV RNA assay
result is ⬎50 IU/mL.9 There has been strict quality assur-
ance procedures for HCV assays for public health, hospi-
tals, and private laboratories. The Bureau of Medical
Devices (Health Protection Branch, Health Canada) estab-
lished a licensing program for diagnostic kits, requiring all
laboratories performing HCV testing to participate in an
external proficiency testing program. Each province estab-
lished a system to ensure compliance with Health Canada’s
criteria and to review the results of proficiency testing.10
Most transplant centers also use the Centers for Disease
Control Prevention Recommendations for the HCV as-
say.11 Although various transplant centers use different
diagnostic kits, we believe that the diagnostic accuracy is
quite similar, because of the internal and external quality
assurance procedures in Canada.
The 1-year survival rate among 1842 liver transplant
patients in Canada from January 1, 1997 to December 31,
2003 was 85.3%. The survival rate is the outcome of both
the general level of medical practice and nursing care
during hospitalization. The survival rates of liver transplant
patients in Canada were comparable to those reported in
the United States and the United Kingdom, namely 88%
and 84%, respectively,12 demonstrating the competence of
the Canadian public-funded health care system to care for
the most complicated disorders, such as patients requiring
liver transplantation.
During the period of the 5-year cohort study, the survival
rates of liver transplant patients steadily improved year by year
in Canada, as shown by Kemmer et al and Schrem et al.13,14
The improvements in patient survivals reflected innovations of
surgical procedures and discoveries of new drugs, including
antiviral drugs such peginterferon and ribavirin.
It is not surprising that most HCV-positive recipients
were men because they show more risky behaviors than
women, such as injectable drug use, multiple sex partners,
tattooing, and body piecing.
The harmful effects of recipient HCV-positive infection
status on the survival was in the middle and long term, not
1469
short term. Our observations have shown that there is no
significant difference in 1-year survival rates but a signifi-
cant decrease in 2-year and 5-year rates between the
HCV-positive and HCV-negative groups. Our results are
supported by other investigations.15–18
Although there is progress in the treatment of the
patients with HCV infection after liver transplantation, we
cannot ignore the negative influences of HCV infection on
survival rates of liver transplant patients. Emerging data
suggest that HCV patients show lower survival rates after
transplantation than other patients.19 This might affect
transplantation for hepatocellular carcinoma, because most
cases in the United States and Canada are due to hepatitis
C. Hepatitis C infection uniformly recurs in the grafted
organ. Posttransplant hepatitis C shows a highly variable
course from rapid decline with liver failure within the first
year to quiescent disease for more than 5 years. The course
seems to have recently become worse, with approximately
20% and 30% progressing to cirrhosis within 5 years after
transplant, possibly because of the increasing age of de-
ceased donors.20 –22 Older grafted livers may poorly tolerate
HCV infection. The risks of death and allograft failure are
increased in HCV-positive transplant recipients (HR 1.23
and 1.30) compared with HCV-negative recipients.19 The
risk of cirrhosis is as high as 30% within 5 to 10 years after
transplantation.23–26 More recent studies have shown in-
creased rates of death and allograft failure among HCV-
positive compared with HCV-negative recipients.27–29
The natural history of recurrent disease requires further
study; it can be better clarified by long-term prospective
studies using protocol biopsies. There is a need to deter-
mine the best treatment duration and dosage of recurrent
HCV infection with peginterferon and ribaviron. This goal
can be achieved through collaborative work between vari-
ous liver transplant centers worldwide.30
ACKNOWLEDGMENTS
Data for this study were obtained from the CORR, a data holding
of the Canadian Institute for Health Information (CIHI). Infor-
mation available from CORR represents the collaborative efforts
and voluntary contribution of the organ procurement organization,
transplant physicians, surgeons, nurses, and coordinators across
Canada. Public Health Agency of Canada is indebted to this large
number of individuals and The Canadian Transplantation Society
for its success. The CORR Board and Advisory Committee,
composed of volunteers from CORR’s many stakeholder groups,
have provided invaluable guidance to the registry during its evolu-
tion and enhancement. The authors acknowledge the technical
assistance of Dr Naisu Zhu and Dr Lilyanna Trpeski from CIHI.
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