Blood Donors With Hepatitis C
From the NIH Consensus Development Conference on Management
of Hepatitis C
Title: Blood Donors With Hepatitis C
Author: Harvey J. Alter, M.D.
Cloning of the hepatitis C virus (HCV) (1) and the subsequent
development of sensitive serologic assays and polymerase chain
reaction (PCR) for HCV RNA revealed that this agent was widespread
in the donor population, that it accounted for approximately 90
percent of transfusion-transmitted hepatitis and that infection,
though generally asymptomatic, could in some cases lead to
cirrhosis, hepatocellular carcinoma, and end-stage liver disease.
(2,3) The first-generation test for antibody to HCV (anti-HCV) was
introduced into donor screening in 1990. At that time, 0.5-0.6
percent of donors were repeatedly reactive for this antibody by
enzyme immunoassay (EIA) and approximately 0.3 percent confirmed as
positive by a supplemental strip immunoblot assay (SIA, RIBATM). A
more sensitive second-generation EIA was introduced in 1992(4) and
current data from the American Red Cross show a repeat reactive
rate of 0.23 percent and a confirmed reactive rate of 0.16 percent.
These tests have been extremely beneficial in the prevention of
transfusion-associated hepatitis. An ongoing NIH prospective study
of transfusion recipients shows no cases of hepatitis C among
approximately 650 recipients followed since second generation
screening was implemented.
These screening assays have uncovered a large population of
asymptomatic HCV carriers. It has been estimated that there are
more than I million such carriers in the United States alone.
Further, this virus is globally distributed with anti-HCV rates
among donors throughout the world ranging from 0.3-1.5 percent.
What is the significance of this infection to these asymptomatic
individuals? How were they infected? What is the risk that they
will transmit the infection to others by nonparenteral routes? What
proportion of antibody-positive individuals have active infection?
What proportion have significant liver disease? To address these
issues, we initiated a study, in collaboration with the American
Red Cross, to investigate risk factors, transmission patterns,
viremia rates, and disease manifestations among 248 donors who were
confirmed anti-HCV positives, 102 who were indeterminate on the
SIAsupplemental assay and 131 who were SIA-negative. (5) When
SIA-positives were compared with SIAnegatives, the significant
demographic and historical factors were, respectively, as follows:
lower age (37 vs. 44, p Risk factor analysis revealed several
unexpected findings. When anti-HCV/SIA-positives were compared with
SIA-negatives in a logistic regression model, the significant risk
factors were, respectively: a history of blood transfusion (27
percent vs. 8 percent, p HCV transmission to contacts was measured
in 85 sexual partners, 47 children, and 9 parents of SIA-positive
donors. Although 9 of 85 (11 percent) sexual partners were anti-HCV
positive, 8 had independent parenteral risk factors. Similarly,
although 5 of 47 children ( 11 percent) were anti-HCV positive, in
4, the antibody appeared due to passive transfer from the mother,
and in the other there was an established parenteral risk factor.
Although 2 of 9 parents were anti-HCV positive, both had known
parenteral exposures. Thus in only I of 132 contacts (0.7 percent)
was anti-HCV positivity unexplained by an independent parenteral
risk or by passive transfer of antibody.
HCV RNA by PCR was detected in 86 percent of SIA-positive
donors, 3 percent of SIA-indeterminate donors, and none of the
SIA-negative donors. Of the three SIA-indeterminate donors who were
PCR-positive, two were SIA-positive on a more sensitive
third-generation assay. It is important to note that 14 percent of
confirmed antibody positives were PCR-negative. This remained true
even when the PCR was repeated, and it suggests that approximately
15 percent of HCV-infected individuals recover from their
infection. Prospective studies of transfusion recipients reveal the
same 15 percent recovery rate.
Biochemical evidence of liver disease was found in 56 percent of
SIA-positives on initial evaluation and in 69 percent of those who
were followed over time. The extent of ALT elevation was modest
(median 48 U/L, range 4-556). During followup, 31 percent had
persistently normal ALT and only 15 percent had ALT levels that
exceed two times the upper limit of normal. Elevated ALT strongly
correlated with the presence of HCV RNA. Liver biopsy was performed
in 77 SIA-positive participants; 6 (8 percent) had no histologic
evidence of hepatitis; these 6 had normal ALT and 5 of 6 were HCV
RNA negative. Sixty-six (86 percent) had mild to moderate chronic
hepatitis and 5 (6 percent) had severe lesions, including severe
chronic hepatitis and/or cirrhosis. All with severe lesions were
HCV RNA positive and had ALT levels greater than twice the upper
limit of normal. No participants had characteristic symptoms of
hepatitis and although fatigue was common, its frequency was
similar in infected and uninfected subjects.
Thus, among donors with confirmed antibody to HCV, approximately
85 percent appear to be chronic carriers and 15 percent appear to
have recovered from prior infection. Among the carriers, there were
no distinguishing symptoms. Although the majority had both
biochemical and histologic evidence of chronic viral hepatitis, the
extent of liver injury was generally mild. Only 6 percent had
evidence of severe hepatitis or cirrhosis, despite a duration of
infection that generally exceeded 10 years and frequently exceeded
20 years. Severe histologic lesions correlated with the highest ALT
levels. Standard parenteral sources of infection were identified in
75 percent of HCV-infected individuals. In addition, there was a
very strong association with intranasal cocaine use and this may
represent a covert form of parenteral transmission. There was no
evidence for sexual or familial transmission when specific contacts
of the index cases were tested.
References
1. Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M.
Isolation of a cDNA clone derived from a blood-borne non-A, non-B
viral hepatitis genome. Science 1989;244:359-62.
2. Kuo G, Choo Q-L, Alter HJ, Gitnick GL, Redeker AG, Purcell RH,
Miyamura T, et al. An assay for circulating antibodies to a major
etiologic virus of human non-A, non-B viral hepatitis genome.
Science 1989;244:362-4.
3. Alter HJ. New Kit on the Block: Evaluation of second-generation
assays for detection of antibody to the hepatitis C virus.
Hepatology 1992;15:350-3.
4. Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo
Q-L, Kuo G. Detection of antibody to hepatitis C virus in
prospectively followed transfusion recipients with acute and
chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494-500.
5. Conry-Cantilena C, VanRaden MA, Gibble J, Melpolder J, Shakil
AO, Viladomiu L, Chueng L, DiBisceglie A, Hoofnagle J, Shih JW,
Kaslow R, Ness P, Alter HJ. Routes of infection, viremia, and liver
disease in blood donors found to have hepatitis C virus infection N
Engl J Med l996;334:1691-6
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