PEREIRA AND SANZ TRANSFUSION COMPLICATIONS
A model of the health and economic impact
of posttransfusion hepatitis C:
application to cost-effectiveness analysis of
further expansion of HCV screening protocols
Arturo Pereira and Cristina Sanz
BACKGROUND: Cost-effectiveness analyses are
needed to decide the value of further expansion of the
screening protocols for HCV in blood donors. However,
such analyses are hampered by imperfect knowledge of
the health and economic repercussions of posttransfu-
sion hepatitis C (PTHC).
STUDY DESIGN AND METHODS: A Monte Carlo simu-
lation of a Markov model representing the outcomes of
patients transfused with HCV-infective blood was used
to estimate the health and economic impact of PTHC
and to calculate the cost-effectiveness ratio of various
HCV screening methods.
RESULTS: Median survival for hypothetical patients with
PTHC and for controls without hepatitis was 11.25 and
11.75 years, respectively. Overall, 12.3 percent of pa-
tients receiving HCV-infective blood will develop chronic
hepatitis, 9.3 percent will progress to liver failure, and
9.25 percent will eventually die of liver disease after a
median time of 20.75 years (range, 6-70). Ninety-one
percent of the infected blood recipients had no reduction
in life expectancy due to PTHC, and the average loss
per patient was 0.754 years. The present value of the
lifetime health costs incurred by patients with PTHC is
$6330 per case. HCV antibody testing increases the pa-
tients’ life expectancy by 20.4 hours per blood collection
tested, and it results in net savings by decreasing the
number of patients that will require treatment for liver
disease in the future. Adding HCV NAT increases the
patients’ life expectancy by 0.08 hours per blood collec-
tion tested, at a cost-effectiveness ratio of $1,829,611
per QALY gained.
CONCLUSION: PTHC has low health benefits because
of the advanced age of many blood recipients. Testing
donors for HCV antibodies results in net savings for the
health care system, despite low health benefits. Adding
HCV NAT would produce little additional gain at a very
high cost.
1182 TRANSFUSION Volume 40, October 2000
T
he risk of acquiring HCV infection through the
transfusion of screened blood has decreased dra-
matically over the last decade, mainly as a result
of the availability and increasing sensitivity of
HCV antibody tests. For instance, in the United States, the
risk declined from 1 per 526 blood units in 19891 to 1 per
103,000 units in 1996.2 Despite this remarkable achieve-
ment, public concern about HCV infection seems to be ris-
ing rather than abating, and the public urges the blood bank
community and regulatory agencies to further increase the
safety of the blood supply.
HCV NAT utilizing PCR techniques, and the recently
described assay for HCV antigen, shortens by several days
the window period of antibody testing and can further re-
duce the risk of transfusion transmission of HCV infec-
tion.3,4 HCV NAT is already required by European regula-
tions for all plasma pools intended to be fractionated in
products for clinical use. In Germany, it also constitutes a
requirement for release of cellular blood components.5
Other European countries and the major US blood collec-
tion agencies are adopting a similar approach. Not surpris-
ingly, expanding the screening protocols for HCV will make
blood transfusion more expensive, whereas the potential
benefits remain uncertain, given the already low risk of HCV
transmission. Cost-effectiveness studies and other decision
ABBREVIATIONS: ASLE = age- and sex-adjusted life expectancy;
PTHC = posttransfusion hepatitis C; QALY = quality-adjusted life
years.
From the Hemotherapy and Hemostasis Service, and the Blood
Bank, Hospital Clínic and Augusto Pi-Sunyer Memorial Institute
for Biomedical Research, Barcelona, Spain.
Address reprint requests to: Arturo Pereira, MD, PhD, Ser-
vice of Hemotherapy, Hospital Clínic, Villarroel 170, 08060
Barcelona, Spain; e-mail: apereira@clinic.ub.es.
Supported in part by Grant FIS 99/0464 from the Ministry
of Health of the Government of Spain and Grant 1999ACES
00033 from the Autonomous Government of Catalonia.
Received for publication September 9, 1999; revision re-
ceived November 29, 1999, and accepted December 9, 1999.
TRANSFUSION 2000;40:1182-1191.

analyses are therefore pertinent, as they can help patients,
physicians, policy makers, and the public in deciding on the
efficacy of these technologies.
However, decision making in regard to further expan-
sion of the screening for HCV in blood donors is severely
constrained by our limited knowledge of the impact that
posttransfusion hepatitis C (PTHC) has on both the health
of patients and the resources for health care. Studies on the
follow-up of patients with PTHC represent the disease as a
slowly progressive one, in which liver failure is a rare and
late complication, and which has a minimal repercussion
on the patients’ life expectancy.6-8 Studies on the more se-
vere outcomes of hepatitis C reveal, however, that it can be
associated with significant morbidity and mortality.9 Unfor-
tunately, none of the above-mentioned studies provide in-
formation that is useful for decision making. Prospective
studies on persons with PTHC usually lack control groups,
exclude patients who die soon after transfusion, and some-
times have short follow-up periods. On the other hand, in
studies on the more severe outcomes of hepatitis C, the size
of the population from which the reported cases were ex-
tracted is not mentioned, and that precludes any risk cal-
culation because of a lack of denominators. Furthermore,
most recent investigations on the evolution of HCV infec-
tion focus on histologic progression, which often does not
correlate with clinical progression or with the need for ther-
apeutic interventions.10-13 Finally, there is a lack of studies
analyzing the lifetime costs of treating patients with PTHC.
Ideally, a study suitable for ascertaining the health and
economic consequences of PTHC would entail the long-
term follow-up of a large and carefully surveyed cohort of
patients and appropriate controls. However, such a study
would be too expensive, and its conclusions would be de-
layed for several decades, by which time the natural history
of HCV infection will have changed because of forthcom-
ing and more effective treatments. As decisions on the ap-
propriateness of new preventive interventions should be
made now, mathematical modeling emerges as the most
suitable tool, albeit an imperfect one, with which to assess
the health and economic repercussions of PTHC.
In the present study, the course of patients with PTHC
and controls without hepatitis has been simulated, focus-
ing on clinical outcomes and associated health care costs.
The main outputs of the simulation were used to estimate
the benefits derived from different HCV screening methods
and to calculate the cost-effectiveness of further expand-
ing the current HCV screening protocols for blood donors.
MATERIALS AND METHODS
Basic model description
A Monte Carlo simulation of a Markov model14 was built to
represent the more relevant health states and outcomes of
patients transfused with HCV-infective blood. Details on
POSTTRANSFUSION HEPATITIS C
how this method allows representation of the patients’
course of disease have been published elsewhere.15 In the
present model, the posttransfusion course of each patient
with HCV infection was compared to what would had been
his or her state of health if he or she had not acquired the
infection, so that each case acted as its own control. Survival
curves were derived from the simulation of 100,000 cases.
For calculating aggregated health repercussions and costs,
10 million cases were simulated for every scenario of the
baseline and sensitivity analysis.
The model was written and compiled in programming
software (PowerBASIC 3.2, PowerBASIC Inc., Carmel, CA).
Outputs were analyzed on a spreadsheet (Excel 5.0, Microsoft
Ibérica, Madrid, Spain) and with a statistical package for
social sciences (SPSS 6.1.3, SPSS Inc., Chicago, IL). Graphi-
cal plots were drawn with analysis software (Prism,
GraphPad Software Inc., San Diego, CA).
Characteristics of blood transfusion recipients
Probability distributions for age and sex of blood recipients
were derived from a population of 9661 patients who re-
ceived transfusion(s) in our institution from July 1996 to
December 1998. The age of these patients ranged from new-
born to 104 years, with first, second, and third quartiles
being 52, 67, and 76 years, respectively; 54 percent of the
patients were males. Age- and sex-adjusted life expectancy
(ASLE) values were obtained from mortality tables for the
population of Catalonia, in northeast Spain.16 These pa-
tients’ characteristics were comparable to those reported
for blood recipients in the United States17 and other west-
ern countries.18
The probability of short-term mortality due to under-
lying diseases was stratified by the age of blood recipients,
according to the study by Vamvakas and Taswell19 (Table 1).
We considered, conservatively, that the impact of underly-
ing diseases on mortality does not extend longer than 2
years after transfusion.
Modeling posttransfusion HCV infection
Health states in the model were defined on the basis of clini-
cal repercussion and need for therapeutic intervention, so
that they do not necessarily correspond to histologic stages.
Accordingly, mild chronic hepatitis was included in the as-
ymptomatic chronic carrier state, and compensated cirrho-
sis, the chronic hepatitis state. This is consistent with recent
investigations that show no difference in perceived quality
of life in patients with chronic hepatitis and those with
compensated cirrhosis.20,21
We considered four possible health states in the pro-
gression of HCV infection. Baseline health is the health sta-
tus of controls without HCV infection and of patients from
whom the virus cleared spontaneously after the acute in-
fection. Asymptomatic chronic carriers are patients with no
symptoms and only occasionally mild elevations of ALT;
Volume 40, October 2000 TRANSFUSION 1183
PEREIRA AND SANZ
TABLE 1. Probabilities, quality of life repercussions, and costs used in the
simulated evolution of PTHC
Baseline estimate
Short-term mortality risk due to underlying diseases
Age <41 (1st/2nd posttransfusion year)
Age 41-65 (1st/2nd posttransfusion year)
Age >65 (1st/2nd posttransfusion year)
Mortality risk after liver transplant
1st year
2nd-3rd years
4th-5th years
Quality of life assigned to health states
Baseline health or asymptomatic chronic carrier
Symptomatic acute hepatitis (only for 3 months)
Chronic hepatitis
Decompensated cirrhosis
Liver transplant
1st quarter
2nd to 4th quarters
2nd and subsequent years
Costs of treating HCV-induced liver diseases
Acute symptomatic hepatitis*
Follow-up asymptomatic chronic carriers (per year)†
Follow-up chronic hepatitis (per year)‡
Interferon treatment
1st quarter§
2nd to 4th quarter (per quarter)
Liver failure (per year)
Liver transplant
1st quarter||
2nd to 4th quarter (per quarter)¶
2nd year¶
Subsequent years (per year)
* Includes two outpatient visits with laboratory, HCV antibody assays, and HCV RNA testing.
† One outpatient visit and laboratory evaluation per year.
‡ Two outpatient visits and laboratory evaluation per year.
§ Includes pretreatment work-up, HCV RNA testing after 3 months of treatment, and drug
cost.
|| Includes preoperative work-up, surgical intervention, and postoperative intensive care.
¶ Includes the prorated cost of a yearly 5 percent probability of retransplantation.
they require only one outpatient visit and laboratory evalu-
ation yearly. Chronic hepatitis patients may have mild
symptoms; their ALT is persistently elevated and/or mod-
erate or severe chronic hepatitis may be found on liver bi-
opsy; medical intervention consists of one interferon
course if there are no contraindications and two outpatient
visits and laboratory evaluations yearly. Liver failure pa-
tients present with clinical complications of decompen-
sated cirrhosis (icterus, ascites, variceal bleeding, encepha-
lopathy) or hepatocellular cancer; intensive outpatient
treatment is necessary, with frequent hospital admissions.
Liver transplantation is scheduled if there are no
contraindications, and it can be performed into the follow-
ing year, if the patient survives that long.
It was assumed that all patients receiving HCV-infec-
tive blood will develop acute hepatitis, that 25 percent will
be symptomatic, and that in 20 percent, the virus will sponta-
neously clear from circulation after the acute infection.22,23 The
ensuing evolution of these latter patients was modeled as
if they had not acquired the HCV infection. Patients from
whom the virus is not cleared were considered to evolve to
1184 TRANSFUSION Volume 40, October 2000
an asymptomatic chronic carrier state,
from which they can progress to chronic
hepatitis. Progression to clinical hepatic
failure was modeled according to Koretz
0.08/0.02 QALY et al.8 That study allowed the authors to
0.22/0.06
estimate that the probability of progres-
0.30/0.20
sion to clinical liver failure was zero un-
0.0525 til the sixth post-transfusion year and
0.0063
0.016 per year during the ensuing follow-
0.0050
up. Because we did not find a study that
1.00 QALY could help in estimating the actuarial
0.70 QALY
risk of transition from the asymtomatic
0.90 QALY
0.50 QALY chronic carrier state to the chronic hepa-
titis state, we extrapolated this risk from
0.50 QALY
the data of Koretz et al.,8 by assuming
0.75 QALY
0.85 QALY that all patients who progress to liver
failure will have to pass through a prior
$1,015
state of chronic hepatitis. The time
$164
$328 elapsed from chronic hepatitis to clini-
cal liver failure was estimated to range
$1,588
from 4 years to 18.2 years, depending on
$1,270
$20,000 the patient’s age at the time the HCV in-
fection is acquired.12
$222,226
The model considers that 70 percent
$21,276
$23,488 of patients less than 60 years old at the
$12,688 time of chronic hepatitis will be treated
with a 12-month course of interferon
therapy (3 million units/3×/week). One-
half of the patients on interferon will stop
treatment after 3 months because of lack
of response, and only 30 percent of those
remaining will achieve a sustained remis-
sion that will stop the disease’s progres-
sion.24 The effect of liver failure on survival was modeled by
adjusting the remaining patients’ ASLE by a relative mortal-
ity factor obtained from the study of Gentilini et al.,25 which
includes the lethality of hepatocellular cancer arising in the
cirrhotic liver. We assumed that only 20 percent of patients less
than 65 years old at the diagnosis of liver failure will be
scheduled to undergo a liver transplant.26 Transplant-re-
lated mortality in the 5 years after the procedure was mod-
eled according to Gane et al.27 Survival after the fifth
posttransplant year was assumed to rely only on each re-
maining patient’s ASLE.
Costs and quality of life repercussions dependent
on health states
Costs of treating HCV-related complications were obtained
from published studies28,29 and are detailed in Table 1. The
Diagnosis-Related Group costs, as tabulated by Bennett et
al.,28 were used to estimate the costs associated with follow-
up of chronic carriers and patients with chronic hepatitis,
with interferon therapy, and with liver transplant. Costs
assigned to treatment of liver failure were derived from the

study by Kimm et al.29 Some of the above cost figures were
adjusted to fit them to our model’s 3-month cycle. Quality
of life repercussions assigned to health states are also shown
in Table 1 and represent the most common estimates that
can decrease life expectancy, as referenced in the pertinent
medical bibliography.28-30 Future costs and impact on qual-
ity-adjusted life years (QALY) were discounted at a 3-per-
cent annual rate.
Costs were assessed from the perspective of a national
health service, and they included only direct health costs.
Indirect costs, such as those related to the loss of produc-
tivity and other social expenses incurred by patients with
PTHC, were not accounted for. Life expectancy was ex-
pressed in QALY, and also in unadjusted and undiscounted
survival years.
The incremental cost for HCV antibody screening was
estimated at $5 per blood collection tested, according to
prior studies.30 There is much uncertainty about the incre-
mental cost of adding HCV NAT to the donor screening pro-
tocols. Factors such as pool size, the number of pools tested
per run, the algorithms used to retest pools that are HCV
positive until the individual HCV-positive donor is identi-
fied and removed before component release, the financial
charges due to acquisition or leasing of expensive equip-
ment, and the wages for technician overtime may greatly
influence the actual cost of NAT. In addition, economies of
scale secondary to centralization of NAT and market com-
petition between firms may further influence costs in the
near future. In the baseline analysis, we estimated the in-
cremental cost of routine HCV NAT as $10 per blood col-
lection tested. However, a wide range, from $5 to $25, was
used in most of our analyses. This spans from the expected
cost of HCV antigen testing (Pereira M, oral communica-
tion, September 1999), to the cost of HCV NAT under the
worst conditions.
Calculation of the cost:benefit ratio for HCV
screening methods
The main outputs of the model and the residual risk of HCV
transmission through screened blood were used to calcu-
late the benefits gained by patients receiving transfusions
of blood tested for HCV by different screening methods. The
rate of HCV transmission via blood not screened for HCV
was estimated as 0.0045 per blood collection, according to
Donahue et al.1 This study was also used to derive the risk
of HCV transmission through blood screened for anti-HBc
and ALT as surrogate markers of hepatitis C (0.0019/blood
collection). For blood donors screened by second- or third-
generation anti-HCV ELISA, we used the 1-of-103,000 rate
calculated by the Retrovirus Epidemiology Donor Study.2 In
the baseline analysis, residual risk after HCV NAT was esti-
mated as 2.7 per million blood collections tested, accord-
ing to Kleinman et al.3 However, because there is some un-
certainty as to the actual magnitude of this risk, a wide
POSTTRANSFUSION HEPATITIS C
range was used in sensitivity analysis, including the “zero
risk” that would derived from a hypothetical, perfect test.
We assumed that each infective blood collection that passes
undetected through blood bank screening will transmit
HCV to 1.656 blood recipients. This figure is the average
number of components that are transfused from each blood
collection, according to data from our blood bank and
transfusion service in 1997.
Marginal cost-effectiveness was calculated per blood
collection tested according to a ratio:
(incremental cost of the HCV screening method – costs
savings derived from treating fewer cases of PTHC in
the future)/QALY gained by the population of blood re-
cipients because of fewer PTHC cases.
RESULTS
Health and economic impact of PTHC
The predicted median survival for patients with PTHC and
for controls without hepatitis was 11.25 and 11.75 years,
respectively, with a 30-year projected survival rate of 18
percent and 19 percent, respectively. As shown in Fig. 1,
early mortality due to underlying diseases was the main
factor in shortening the life expectancy of patients and con-
trols. After exclusion of patients who died early as a result
of their underlying disease(s), median survival for the re-
maining patients and controls increased to 17 and 17.75
years, respectively. The model predicts that 12.3 percent of
patients given HCV-infective blood will develop chronic
hepatitis and 9.3 percent will progress to liver failure. Inter-
feron will be used in 4.9 percent of patients, and 0.5 percent
of patients will undergo liver transplantation. Overall, 9.25
percent of patients in the simulated cohort will eventually
die of HCV-related liver disease(s), which will occur at a
median of 20.75 years (range, 6-70) after transfusion.
100 –
90 –
80 –
70 –
—— theoretical life expectancy
Probability (%)
60 –
50 –
—control survival
40 – —
—— liver
30 – failure
20 – risk
10 – patients
—
with HCV
0–
Years after transfusion
Fig. 1. Projected survival after transfusion-acquired infection,
compared with survival of controls without infection, and the
sex- and age-adjusted theoretical life expectancy. Also shown
is the Kaplan-Meier estimate of the risk of liver failure.
Volume 40, October 2000 TRANSFUSION 1185
PEREIRA AND SANZ

The loss of life expectancy due to PTHC varies consid-
erably among particular patients, being null in 90.7 percent
and longer than 10 years in 3 percent (Fig. 2), with an aver-
age loss of 0.754 years per infected blood recipient. With
regard to QALY, 67.9 percent of patients will suffer no health
impairment due to HCV infection, and the average reduc-
tion per infected blood recipient is 0.468 QALY.
Table 2 shows the predicted lifetime costs of treating
PTHC-related liver diseases. Liver failure is the health state
with the largest requirement for health care resources. Liver
transplant, despite its high unitary cost, represents less than
16 percent of the lifetime costs, which is mainly due to the
small number of patients in whom the procedure will be
performed.
The PTHC-induced loss of life expectancy was very sensi-
tive to the patients’ age. As shown in Fig. 3, the average loss
per patient grew exponentially as the patients became younger.
The lifetime costs associated with treatment of PTHC-related
complications also rose markedly as patient age decreased
(Fig. 4). Reducing the early mortality caused by the patients’
underlying disease(s) also brought an increase in both the
Percentage of patients
PTHC-induced loss of life expectancy and the associated
lifetime costs, but to a much lesser extent (Figs. 3 and 4).
Growth of health care costs above current average
prices can also influence our baseline estimates of the eco-
nomic repercussions of PTHC. Fig. 5 shows that lifetime
costs incurred by patients with PTHC will grow exponen-
tially as the differential inflation rate of medical costs in-
creases, mainly because of the higher costs of treating pa-
tients with liver failure. The long period covered by the
analysis also makes the expected QALY and costs change
with the discount rate used in the analysis. In sensitivity
analysis varying the discount rate from 0 to 10 percent, the
average number of QALY lost per patient decreased from
1.043 to 0.125. Over the same range of discount rates, the
lifetime cost per patient varied from $11,511 to $2,324.
Health and economic gains from HCV screening
protocols in blood donors
Table 3 shows the impact that routine HCV RNA testing of
blood donors would have on the health and economic bur-
den of PTHC, as compared with the gains provided by sur-
rogate markers or HCV antibody testing and those to be
expected from a hypothetical perfect test that completely
eliminated PTHC. As it can be seen, each blood collection

screened by HCV NAT will increase life expectancy by less

than 5 minutes, whereas elimination of PTHC through a
perfect test would prolong the life span of blood recipients
by roughly 7 minutes (around 1 week per every 1 thousand
blood components transfused). The economic savings de-
rived from treating fewer cases of PTHC in the future
amounts to more than $20 per blood collection tested for
HCV antibodies. Further improvements in the prevention
of PTHC could save at best an additional $0.10, which rep-
resents the 0.5 percent of the economic gains provided by
HCV-induced loss of life expectancy (years/patient)
HCV antibody testing.
Fig. 2. Loss of life expectancy of simulated patients with trans-
fusion-acquired HCV infection, as compared with that in con- Cost-effectiveness of HCV NAT
trols without infection. In the baseline scenario, adding HCV NAT to the current
screening protocols would result in a
TABLE 2. Present value of lifetime costs derived from treating PTHC* cost-effectiveness ratio of $1,829,611 per
Average cost Percentage Percentage of QALY gained. In comparison, testing
per patient of total entire group that blood donors for HCV antibodies is a domi-
Health state (in dollars) lifetime costs incurs the cost nant strategy, as it results in a net saving
Acute symptomatic hepatitis 233 3.7 23.3 of $15 per blood collection screened. The
Asymptomatic chronic carrier 1,103 17.2 65.4
Chronic hepatitis cost-effectiveness of NAT is very sensi-
Follow-up 169 2.6 12.3 tive to patient age. As shown in Fig. 6, the
Interferon therapy 118 1.8 4.9 cost-effectiveness ratio grows exponen-
Liver failure
Conventional treatment† 3,810 59.5 9.4 tially as patient age exceeds 60 years.
Liver transplant 680 10.6 0.6 Sensitivity to short-term mortality due to
Follow-up liver transplant 293 4.6 0.6 underlying diseases worked on a much
Total 6,406 100
smaller scale, ranging from $1.448 mil-
* Future costs were discounted at a 3 percent annual rate to obtain their present value and
averaged among all patients who received HCV-infective blood. lion per QALY gained, for patients who
† Refers to medical and surgical treatment of decompensated cirrhosis and hepatocellular survive their underlying diseases, to
cancer, excluding liver transplant. $2.317 million, for those in whom short-

1186 TRANSFUSION Volume 40, October 2000


Short-term mortality due to underlying diseases
(in multiples of the baseline rate)
Loss of life expectancy (years/patient)
Age at transfusion
Fig. 3. Loss of life expectancy of simulated patients with trans-
fusion-acquired HCV infection according to age at the time of
transfusion (•—•) and to short-term rate of mortality due to
their underlying disease(s) ({—{).
Short-term mortality due to underlying diseases
(in multiples of the baseline rate)
,
Lifetime costs ($/patient)
, We have constructed a model of the evolution of PTHC by
, of HCV infection that may influence the model’s accuracy.
Age at transfusion
Fig. 4. Lifetime costs incurred by patients with transfusion-
acquired HCV infection according to age at the time of transfu-
sion („—„) and to the short-term rate of mortality due to
their underlying disease(s) (†—†).
term mortality doubles the baseline estimate (Fig. 6). Sen-
sitivity to the incremental cost of NAT is shown in Fig. 7. As
can be derived from the slope of the function relating both
values, the cost of each QALY gained by blood recipients will
grow by $184.000 per each dollar invested in NAT of blood
donors. Residual risk of PTHC after NAT implementation
influenced the cost-effectiveness ratio, but only to a limited
extent. For instance, the cost-effectiveness ratio of a hypo-
thetical perfect test that eliminated PTHC would be $1.316
million per QALY gained, a figure that is only 28 percent
smaller than the baseline estimate. Cost-effectiveness of
POSTTRANSFUSION HEPATITIS C
Short-term mortality rate due to underlying diseases
(in multiples of the baseline value)
,
Cost-effectiveness (thousands of
,
dollars/QALY gained)
,
Age at transfusion
Fig. 5. Cost-effectiveness of NAT in relation to patients’ age
(•—•) and their short-term rate of mortality due to underlying
disease(s) ({—{). Arrows denote the baseline values.
NAT also had little sensitivity to inflation of the medical
costs of treating liver diseases. At a hypothetical annual
inflation rate of 12.5 percent, the cost-effectiveness of NAT
declined to $1.529 million, a decrease of only 13 percent
from the baseline estimate.
DISCUSSION
piecing together data from several observational studies,
each one focused on a different evolutional period of the
disease course. Care was taken to capture several features
First, progression to chronic liver disease was modeled by
using data from studies that included only patients with
transfusion-acquired HCV infection, as the disease seems
to progress more rapidly when acquired through transfu-
sion than when acquired through other parenteral exposure
or in community-acquired cases.31,33 For the same reason,
only studies based on patients with HCV-related liver dis-
ease were used to simulate the outcomes after liver failure
or liver transplant.25,27 Second, transitions among health
states were modeled by using time-dependent probabili-
ties, rather than frequency estimates at fixed times (vs. 16%
cirrhosis at 15 years), because the former allow a more ac-
curate representation of age as a competing risk for death
before the chronic complications of PTHC could occur.
Third, the model captures the fact that the patient’s age
at the time of transfusion influences the outcomes in op-
posite ways at different times along the disease’s progres-
sion. Thus, while progression from chronic hepatitis to liver
failure is more rapid in older patients than in younger pa-
tients9,12 (which would increase the health repercussions of
PTHC in older patients), older persons die more frequently
Volume 40, October 2000 TRANSFUSION 1187
PEREIRA AND SANZ

thetical patients with PTHC who survive

TABLE 3. Incremental health and economic gains yielded by different HCV
screening methods in blood donors* the short-term effect of their underlying
HCV ELISA
disease(s) was similar to that found by
Surrogate (2nd-3rd HCV RNA Perfect Seeff et al.6 in patients with demon-
markers generation) testing test strated posttransfusion NANB hepatitis.
Residual risk of HCV transmission 1,900 09.71 2.7 0 The mean (± SD) time elapsed from
(per 106 blood collections tested)
Number of infections avoided 4,305 3,130 11.6 16.07
transfusion to either chronic hepatitis or
(per 106 blood collections tested) liver failure in our model was 9.1 (± 6.5)
Number of HCV-induced deaths avoided 0,398 0,289 1.07 1.48 years and 16.3 (± 8.1) years, respectively,
(per 106 blood collections tested)
Gain in life expectancy 28.44 20.68 0.08 0.11
which is comparable to the times found
(hours/blood collection tested) in observational studies.9,38,39 Further-
Gain in quality-adjusted life expectancy 17.65 12.83 0.05 0.07 more, the Kaplan-Meier estimate of the
(hours/blood collection tested)
Savings in the future costs of treating HCV- 27.58 20.05 0.07 0.10
probability of liver failure at 25 years of
related complications ($/blood collection tested) follow-up was 17 percent in our model
* The health and economic gains yielded by each method over those already accomplished (Fig. 1), which is the same rate observed
by the previous one: surrogate markers were compared with no HCV screening, HCV ELISA by Gordon et al.31 in patients with PTHC.
with surrogate markers, and both HCV RNA testing and the perfect test with ELISA.
An outstanding result of our model
was the finding of a small effect of PTHC
on the life expectancy of blood recipients who acquire the
,
infection. This is in accordance with the report by Seeff et
al.,6 who did not find any difference between the survival
Lifetime cost ($/patient)

of patients with posttransfusion NANB hepatitis and of

, controls without hepatitis, after a median follow-up of 18
,
Annual inflation rate (%)
Fig. 6. Predicted effect of medical cost inflation on the lifetime
costs incurred by patients with PTHC. Curves represent the
average lifetime cost per patient (•—•) and its main compo-
nents: conventional treatment for liver failure ({—{), liver
transplant (†—†), and medical follow-up of asymptomatic
carriers (
—
).
of liver-unrelated causes,19 which reduces the aggregated
impact of PTHC in older blood recipients. Nevertheless, the
model has some limitations. For instance, we did not take
into account the possible influence on the disease course
of HCV RNA levels,33,34 viral genotypes,10 or alcoholism,13,35
because published data are scarce or contradictory or were
reported in a way that makes their mathematical modeling
difficult. Concurrent infection with other hepatotropic vi-
ruses36,37 was also omitted, as we are waiting for more evi-
dence on the role of these viruses in worsening the outcome
of HCV infection.
Despite the above limitations, model validation shows
that outputs for which observational data allowing com-
parison are available were within the ranges of outcomes
in real-life patients. Thus, median survival for our hypo-
years. In our model, the small survival advantage of controls
over patients was not apparent until the 30th posttransfu-
sion year, which indicates that decades of follow-up would
be needed to detect this difference in real-life patients. As
expected, the average survival reduction due to PTHC re-
flects quite different situations for particular patients. While
most blood recipients will realize no health advantage from
escaping the infection, a few will live out more of their life
than expected.
The advanced age of many blood recipients is the main
factor in attenuating the health impact of PTHC. For in-
stance, PTHC reduces by more than 6 years the average life
expectancy of neonates, whereas a 70-year-old patient loses
only a few days of life expectancy. Because the most severe
complications of hepatitis C are very delayed, appearing
after a long course that is mostly oligosymptomatic, the
advanced age of many blood recipients and, to a lesser ex-
tent, the severity of their underlying disease(s) are strong,
competing risks for death before PTHC could have a signifi-
cant effect upon the patients’ health.
Besides the limited impact on patients’ health, the
present value of the future costs incurred by patients with
PTHC mounts to $6330 per case, a figure that may increase
exponentially under some assumptions as to the future
trends of medical costs. The per-capita amount of the na-
tional health expenditures in the United States has in-
creased at an average annual rate of 6.8 percent over the last
two decades,40 which is a period in which most of the fu-
ture costs of treating PTHC-related complications will be
settled. Despite the fact that these rates of growth in health
costs are generally envisaged as unsustainable in the future,

1188 TRANSFUSION Volume 40, October 2000


Cost-effectiveness (thousands
of dollars/QALY gained)
Incremental cost per blood collection tested ($)
Fig. 7. Cost-effectiveness of NAT in relation to the incremental
cost per blood collection tested („—„). A hypothetical, perfect
test that would eliminate PTHC completely is also represented
for comparison (▲- - -▲). Arrow denotes the baseline value.
some analysts estimate that the US national health expen-
ditures will nearly double over the next decade.40 In addi-
tion, recent experience with HIV infection shows that costs
of treating severe diseases about which there is a high pub-
lic concern may climb to previously unsuspected levels.41
Therefore, some of our assumptions, which project the
present value of the lifetime costs of PTHC as being more
than $50,000 per patient, may be fully within the range of
plausibility.
It should be noted that most of the health care re-
sources currently used for the treatment of HCV infection
translate poorly into improvements of life expectancy. This
is the case, for instance, with conventional treatment of liver
failure, which accounts for the largest part of the lifetime
medical costs incurred by patients with PTHC. Long-term
prognosis after liver failure relies mainly on the patient’s
residual liver function,42 so that only a liver transplant can
produce a significant increase in life expectancy, while the
expensive conventional therapies are mostly palliative.
Avoidance of these rather inefficient medical costs is the
reason that screening blood donors for HCV antibodies re-
sults in net financial savings for the health care system,
despite the small gains in life expectancy that they produce.
Adding HCV NAT to the routine blood donor screen-
ing protocols would prevent 12 cases of PTHC per million
blood donors tested. This would increase the life expect-
ancy of blood recipients by about 5 minutes per blood col-
lection tested, at a cost-effectiveness ratio of nearly $2 mil-
lion per QALY gained, with the ratio remaining over $1
million in most of the hypothetical scenarios dealt with in
sensitivity analysis. The above figures compare very unfa-
vorably with most of the currently accepted medical inter-
ventions.43 For instance, coronary artery bypass graft sur-
gery produces an average increase of 1.2 years per patient,
at a cost-effectiveness ratio of $26,117.43,44 Even childhood
vaccinations, which are the paradigm of those preventive
POSTTRANSFUSION HEPATITIS C
interventions that should be applied in a large group of
people so that a few can have a significant advantage, pro-
duce an average survival gain of 3 days per child,43 which is
more than 800-fold the expected benefit of NAT in blood
donors.
Factors accounting for the poor efficiency of NAT are
the already low current risk of being infected through HCV
antibody-screened blood, the advanced age of many blood
recipients, and the high incremental cost of NAT. Increas-
ing the yield of HCV NAT has a limited influence on cost-
effectiveness, as, even assuming that a “zero risk” of HCV
transmission could be attained, the cost-effectiveness ra-
tio would remain over $1 million. It is noteworthy that the
above factors will probably evolve in such a way that effi-
ciency of NAT will worsen in the near future. The incidence
of HCV infection in the general population is declining since
its peak in 1989,24 and this will reduce even more the risk
of HCV transmission through antibody-screened blood. In
addition, blood recipients are becoming increasingly older,
which will increase exponentially the cost per QALY gained
by NAT. Therefore, the only feasible way to make HCV NAT
more cost-effective is by reducing its incremental cost. Cen-
tralization of NAT, development of fully automated high-
throughput processors, resorting to equally effective alter-
natives requiring less expensive equipment and no staff
overtime, and/or removal of surrogate marker testing
(where it is still performed) would contribute to decreas-
ing the costs associated with new HCV screening protocols.
The need to reduce the costs per blood collection tested is
further emphasized by the limited ability of NAT to retrieve
even a small share of its implementation cost, as shown by
the insensitivity of its cost-effectiveness ratio to future in-
creases in the costs of treating liver diseases.
In summary, our results show that most of the health
and economic gains that can be obtained from preventing
PTHC have already been realized, leaving little room for
further improvements. Routine HCV NAT of blood donors
would add a very small health benefit at a significant cost.
Until now, cost-effectiveness analyses have had little effect
on decisions about blood safety, which were driven by the
political and emotional consequences of the AIDS epi-
demic.45 However, patients, physicians, policy makers, and
the public should decide whether the small benefits of fur-
ther expanding the current HCV screening protocols are
worth the cost in this era when limited health care resources
should be carefully allocated.
ACKNOWLEDGMENTS
The authors are indebted to Miquel Bruguera, MD, PhD, from
the Service of Hepatology, and to Francisco Cervantes, MD, PhD,
from the Service of Hematology (both in the Hospital Clínic), for
their careful review of the manuscript. They also thank Begoña
Ramírez, administrative director of the Hospital Clínic Blood
Bank, for her assistance in obtaining the blood recipient data.
Volume 40, October 2000 TRANSFUSION 1189
PEREIRA AND SANZ
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