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Risk Factors for Hepatitis C Virus Infection in Hepatitis C
Virus Antibody ELISA-positive Blood Donors Accdrding to
RIBA-2 Status: A Case-control Survey
LAWRENCE
SERFATY,' PHILIPPE GIRAL,' MARIEHELENEELGHOUZZI,3 ANNE MARIEJULLIEN~
ANDRAOULPOUPON~
Unite' d 'He'patogastroentirologie and 'Centre National de Transfusion Sanguine, H6pital Saint-Antoine, 75571 Paris
Cedex 12; and 3Centre National de Transfusion Sanguine, 91943 Les Ulis Cedex, France

Studies of blood donors positive for antibody to However, first- and second-generation anti-HCV ELISA
hepatitis C virus on enzyme-linked immunosorbent tests have poor positive predictive value in this popu-
assay are probably biased by the large number of lation (1-6). As a result, early studies of risk factors for
false-positive results. We evaluated the epidemio- HCV infection among blood donors on the basis of these
logical and biological characteristics of 177 such tests (7,8) were probably biased by the large proportion
donors with regard to the confirmatory second- of false-positive results (9). A better knowledge of the
generation RIBA test (Ortho Diagnostic Systems) and
have compared the results to those from an age- and modes of transmissions of HCV in this low-risk popu-
sex-matched control group of 177 donors negative for lation is essential for improving transfusion policy and
antibody to hepatitis C virus on enzyme-linked immu- thereby reducing the risk of posttransfusional hepatitis.
nosorbent assay. Second-generationrecombinant im- The aim of this study was to identify with a case-
munoblot assay was positive in 38% of cases, indeter- control survey risk factors for HCV infection in a cohort
minate in 6% and negative in 56%. The case-control of donors positive for anti-HCV on ELISA according to
study showed a significantly higher frequency of intra- the confirmatory second-generation recombinant immu-
venous drug abuse (27% vs. O%), blood transfusion (22% noblot assay (RIBA-2; Ortho Diagnostics, Raritan, NJ)
vs. 9%), history of jaundice (21% vs. 7%), elevated ALT test results.
level (49% vs. 4%) and HBc antibody positivity (32% vs.
7%) in second-generation recombinant immunoblot PATIENTS AND METHODS
assay-positive donors. No such differences were found
between the second-generation recombinant immu- Study Population. Between December 1, 1989, and March
noblot assay-negative donors and their controls. The 18,1990,62,322 consecutive blood donors were tested with the
35 second-generationrecombinant immunoblot assay- ClOO ELISA (Ortho Diagnostics) at the Centre National de
positive donors without histories of transfusion or Transfusion Sanguine. A sample of fresh blood from each
intravenous drug abuse had a significantly higher donation was tested once. When the ELISA ratio was greater
frequency of surgery with major blood loss or pro- than 0.9, the sample was retested two more times and was
longed stays in areas of hepatitis B virus endemicity considered positive when the ELISA ratio was greater than 0.9
than did their controls (20% vs. 0% and 49% vs. 26%, at least twice. On this basis, 528 donors (0.85%)were positive
respectively).In conclusion, at least one risk factor for on the ClOO ELISA test ("ELISA-positive").
HCV infection was identified in 82% of the second- All ELISA-positive donors were informed of their test
generation recombinant immunoblot assay-positive results in writing and were invited to participate in epidemi-
donors, 91% of whom could have been identified on the ological and clinical investigations at the liver unit at the
basis of these risk factors, ALT level and presence of HGpital Saint-Antoine. Further letters were sent to donors
HBc antibody. (HEPATOLOGY 1993;17:183-187.) who did not respond. One hundred seventy-seven of the 528
ELISA-positive donors (33.5%) were examined. These 177
donors did not differ significantly from the remaining 35 1
Blood donors are systematically tested for hepatitis C ELISA-positive donors in terms of age (40.4 i 11.3 yr vs.
virus (HCV) antibody anti-HCV with the ELISA. 39 i 10.3yr), sex ratio (1.39vs. 1.41),proportion of first-time
donors (13% vs. 15.3%), ALT level (31.1 2 30.7 IU/L vs.
32.3 % 30.3 IU/L), presence of antibody to HBc (16.4% vs.
15.2%) or ELISA ratio (4.0 5 2.3 vs. 4.1 +- 2.3).
Received June 1, 1992; accepted September 22, 1992. The 177 ELISA-positive donors were tested with the RIBA-2
We thank Ortho Diagnostic Systems France, Roissy Charles de Gaulle, assay (Ortho Diagnostic Systems), which detects antibodies
France, for providing us with the RIBA-2 test.
Address reprint requests to: L. Serfaty, M.D., Unite d'HQpatogastro-
against four recombinant antigens specific for HCV (C100,
enterologie, H6pital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 5.1.1, C22 and C33c) and yeast-expressed human superoxide
Paris Cedex 12, France. dismutase fusion protein. Testing was performed on sera
Copyright 0 1993 by the American Association for the Study of Liver stored at -30" C, in accordance with the manufacturer's
Diseases. recommendations. Nitrocellulose strips containing five an-
0270-9139/93 $1.00 + 0.10 31/1/42891 tigens and two internal IgG controls (1, weakly positive; 2,
183
 15273350, 1993, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.1840170204 by INASP/HINARI - CAMEROON, Wiley Online Library on [05/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
184 SERFATY ET AL. HEPATOLOGY
February 1993

TABLE
1. Epidemiological and biological characteristics of ELISA-positive donors according to the results of
the RIBA-2 test
RIBA-2status
Positive Indeterminate Negative
Characteristics (n = 68) (n = 10) (n = 99) Odds ratio"

Age > 40 yr (96) 41 50 46 -

1.3 1 1.5 -
Sex ratio (MIF)
First-time donors (%I 6 10 18 -
Intravenous drug use (5%) 21b 10 0 39 (5-298)
Transfusion (%) 2 2" 20 9 2 (1-4)
Jaundice history (%) 21' 0 3 9 (2.5-33)
ALT level above normal (%) 4gb 20 I 10 (4.6-24)
Anti-HBc positivity (%) 32' 10 6 7 (2.8-17)
ELISA ratio > 4 (%) 82' 60' 23 13 (6-27)

"Calculated by comparing positive donors with indeterminate or negative donors. Numbers in parentheses represent 95% confidence interval.
hStatistically different from indeterminate or negative donors (p < 0.05).
"Statistically different from negative donors (p < 0.05).

moderately positive) were incubated at room temperature for result were compared with the x2 test or Fisher's exact test
4 hr with 20 p1 of the sample or the controls (positive and when the sample numbers were low. In the case-control
negative), then rinsed and incubated with goat antihuman IgG inquiry, the anti-HCV ELISA-positive donors were compared
conjugated with Raitfort peroxidase. After validating the with their respective anti-HCV ELISA-negative controls using
reaction by reading the two internal and external controls, we MacNemar's test for paired data. A p value of 0.05 or less was
compared the response to each antigen with the staining considered significant, and an odds ratio with a 95%confidence
intensity obtained with the IgG controls 1and 2. The test was interval was calculated for each significant parameter.
considered positive when at least two bands of HCV-specific
antigens had an intensity of 1+ or more, indeterminate when RESULTS
there was only one such band and negative when none of the
four bands had an intensity of 1+ or more. Results of the RIBA-2 Test Among the 177 ELISA-
Control Group. Of the 62,322 donors, 61,794 were negative positive Donors. Sixty-eight (38%) of the 177 ELISA-
on the ClOO ELISA test. One hundred seventy-seven ELISA- positive donors had positive RIBA-2 test results, 10 (6%)
negative donors were randomly selected from the initial cohort had indeterminate results and 99 (56%)were negative
and matched for age and sex with the 177 ELISA-positive (Table 1).Seven of the 10 samples with indeterminate
donors. The control subjects were examined at a later results were positive for (2100, and three were positive
donation.
Epidemiological Investigations. The 177 ELISA-positive
for C22.
donors and their paired controls were interviewed using a Epidemiological and Biological Characteristics of
standardized questionnaire to identify known or potential risk the 177 ELISA-positive Donors According to RIBA-2
factors for HCV infection. History of blood transfusion or Results. The RIBA-2-positive donors were significantly
intravenous drug abuse was considered a known risk factor. different from the RIBA-2-indeterminate or RIBA-2-
Patients with no known risk factors were considered for negative donors in terms of known risk factors, history
potential risk factors (i.e., surgery with major blood loss (heart of jaundice, ALT activity, HBc antibody positivity and
surgery, hysterectomy, hip replacement), medical injections, ELISA ratio (Table 1).
health care employment, dental surgery, acupuncture, tat- Comparison of the 68 ELISA-positive, RIBA-2-
tooing, short ( < 1mo) or prolonged ( > 1 mo) stays in areas of positive Donors and the 99 ELISA-positive, RIBA-2-
HBV endemicity (outside Europe or North America),
household contacts with hepatitis patients, homosexuality, negative Donors with their Respective ELISA-negative
multiple sexual partners ( > 5/yr), history of sexually trans- Controls. Frequency of known risk factors, history of
mitted disease (herpes, urethritis, genital warts) and history of jaundice, elevated ALT level and positivity for HBc
jaundice. antibody were significantly different between the 68
Laboratory Investigations. All 62,322 donors were tested for ELISA-positive, RIBA-2-positive donors and their cor-
serum ALT levels (Biotrol system; Laboratoire Biotrol, Paris, responding ELISA-negative controls (Table 2). In con-
France), HBsAg (Monolisa New HBsAg, Sanofi Diagnostic trast, there was no such difference between the 99
Pasteur, Marnes-la-Coquette, France; confirmed by Ausria ELISA-positive, RIBA-2-negative donors and their cor-
[Abbott Laboratories, North Chicago, ILJ), HBc antibody responding ELISA-negative controls (Table 2).
(Monolisa anti-HBc; Sanofi Diagnostic Pasteur) and human Comparison of Potential Risk Factors for HCV In-
immunodeficiency virus (HIV)-l and HIV-2 antibodies (Well-
come ELISA; confirmed by Western blot). ALT activity was
fection in the ELISA-positive, RIBA-%positive Donors
considered elevated when values were greater than 35 IU/L. with no Histories of Transfusion or Intravenous Drug
The 177 ELISA-positive donors and their paired controls were Abuse and Their ELISA-negative Controls. Of the 68
all negative for HBsAg and for HIV-1 and for HIV-2 antibodies. ELISA-positive, RIBA-2-positive donors, 35 (51%)had
Statistical Analysis. The epidemiological and biological no identifiable known risk factors (transfusion or intra-
characteristics of the donors as a function of the RIBA-2 test venous drug abuse) for HCV infection. Among the
 15273350, 1993, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.1840170204 by INASP/HINARI - CAMEROON, Wiley Online Library on [05/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Vol. 17, NO. 2 , 1993
HEPATOLOGY SERFATY ET AL. 185

TABLE
2. Comparison of epidemiological and biological characteristics of ELISA-positive,RIBA-2-negative donors and
ELISA-positive,RIBA-2-positive donors with their respective ELISA-negativecontrols
RIBA-2-negative Control RIBA-%positive Control
Characteristics (n = 99) (n = 99) (n = 68) (n = 68) Odds ratio"

Transfusion (%) 9 9 22b 9 3.2 (1.05-9.9)

Intravenous drug abuse (%I" 0 0 27' 0 -
Jaundice (%) 3 7 21b 7 3.2 (1.05-9.9)
ALT level above normal (%) 7 4 496 4 16 (3.8-66.6)
HBc antibody positivity (%) 6 8 32' 7 5.5 (1.9-16)
"Numbers in parentheses represent 95% confidence interval.
bp < 0.05.
'None of the intravenous drug abusers had received transfusions.

potential risk factors presented in Table 3, history of TABLE3. Comparison of potential risk factors among
surgery with major blood loss and prolonged stays in ELISA-positive,RIBA-2-positive donors with no histories of
HBV-endemic areas were significantly more frequent transfusion or intravenous drug abuse and their
among the ELISA-positive, RIBA-2-positive donors ELISA-negativecontrols
than among their ELISA-negative controls (respec- RIBA-2-positive Control
tively, 20% vs. 0%;p < 0.05, and 49%vs. 26%, p < 0.05; Risk factors" (n = 35) (n = 35)
odds ratio = 4 (range 1.12 to 14.2) (Table 3). All patients Surgery with major blood loss (%) 20b 0
whose risk factor was a prolonged stay in an area of HBV Acupuncture (%) 20 26
endemicity were white. However, some of these patients Tattooing (%) 0 0
had been born in these areas (Africa, southeast Asia) and Dental surgery (%) 43 40
had stayed there for several years. We noted a tendency Medical injection (%) 0 0
toward a significant difference in terms of health care Health care employment (%) 11 6
employment and household contact with hepatitis Stays in endemic areas
c 1 mo (%) 17 34
patients (respectively, 11%vs. 6% and 11%vs. 3%) > 1mo (%Y 49* 26
(Table 3). Homosexuality (%) 3 0
DISCUSSION Multiple sexual partners (%) 6 3
Sexually transmitted disease (%) 3 3
This study of a population of blood donors shows that Hepatitis in household (%) 11 3
the positive predictive value of the ClOO ELISA test is
very low. Blood transfusion, intravenous drug abuse, "At lemt one potential risk factor in a single donor.
'p < 0.05.
surgery with major blood loss and prolonged stays in
'None of the patients who made prolonged stays in endemic areas
areas of HBV endemicity are risk factors for HCV had a history of surgery with major blood loss.
infection in blood donors and were present in 82% of our
RIBA-2-positive donors.
The RIBA-2 test was positive in 38% of the ClOO
ELISA-positive donors, indeterminate in 6% and neg- ELISA-positive, RIBA-2-negative donors had posttrans-
ative in 56%. The rate of RIBA-2 positivity among the fusional hepatitis and that all were negative for viral
ELISA-positive donors was therefore far lower than in RNA in a polymerase chain reaction-based assay. It
at-risk populations (lo), although the figure appears to therefore appears that a negative RIBA-2 test in an
vary along a north-south gradient. Indeed, Van Der Poel ELISA-positive donor is indicative of false positivity.
et al. (4)obtained a rate of only 12%,and a figure of 94% An indeterminate RIBA-2 test result can have several
has been reported in a population of Egyptian blood meanings. In our study, the frequencies of known risk
donors (11). factors for HCV infection and of liver damage (in terms
The ELISA-positive, RIBA-2-negative donors should of ALT levels) in the donors with indeterminate results
be considered to have false-positive results for a number fell between those of the RIBA-2-positive and RIBA-2-
of reasons. In this study, the frequency of known risk negative donors, probably in part because of the small
factors for HCV infection and of liver damage (reflected number of RIBA-2-indeterminate donors. In the donor-
by elevated ALT activity) was particularly low in the recipient study by Van Der Poel et al. (4), none of the
RIBA-2-negative donors. The epidemiological and bio- donors with intermediate results had posttransfusion
logical characteristics of these donors were significantly hepatitis, and polymerase chain reaction-based testing
different from those of the ELISA-positive, RIBA-2- for viral RNA was negative in all. However, it appears
positive donors but not from those of the ELISA- that the presence of C33 or C22 antibodies is predictive
negative controls. Several donor-recipient studies have of infectivity in donors with indeterminate results (51,
shown that ELISA-positive donor blood is not always suggesting a high degree of heterogeneity among this
associated with posttransfusion hepatitis (12). In one donor population.
such study, Van Der Poel et al. (4) found that none of the With regard to the ELISA-positive, RIBA-2-positive
 15273350, 1993, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.1840170204 by INASP/HINARI - CAMEROON, Wiley Online Library on [05/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
186 SERFATY ET AL. HEPATOLOGY
February 1993

donors, 49% had a known risk factor for HCV infection- detected before 1990). These results may in part explain
namely, history of transfusion in 22% of cases and the relatively high rate of posttransfusion hepatitis in
intravenous drug abuse in 27%. These risk factors were France before 1990. Our data show that although the
significantly more frequent in these patients than in the donors with histories of intravenous drug abuse were
ELISA-negative controls. Many (51%) of the RIBA-2- prohibited from donating before 1990, some were not
positive donors had no known risk factor, but signifi- identified by the screening process. Most of the donors
cantly more patients had histories of surgery with major involved were occasional intravenous drug abusers and,
blood loss and stays in HBV-endemic areas than did therefore, difficult to detect (23).
patients in the ELISA-negative control group. The likely In conclusion, a risk factor for HCV infection was
mode of contamination in the patients with histories of identified in 82% of our RIBA-2-positive donors. ELISA-
surgery with major blood loss is blood transfusion. based screening tests are unable to detect all infectious
However, we distinguished transfusion from surgery donors (24,25),and a risk of posttransfusion hepatitis in
with a major risk of bleeding for two reasons: first, it was the recipient therefore exists (26). This may partly be
not certain that patients who had undergone such explained by the lag time before the production of
surgery had received transfusions, and second, we felt it anti-HCV (24). The detection and exclusion of donors
was more pragmatic to ask the donors both questions. with risk factors for HCV infection, particularly intra-
The frequency of HCV infection can reach 20% in areas venous drug abuse and transfusion, by means of a highly
in which HBV is endemic (11, 13). Stays in endemic efficient interview might help reduce the risk of post-
areas have been suspected as a risk factor in several transfusion hepatitis even further.
studies of patients with non-A, non-B hepatitis (14, 15).
However, most of these patients probably had hepatitis
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Vol. 17, NO. 2, 1993 SERFATY ET AL. 187

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