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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.

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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