Home Patients Clinicians Links

Diagnostic Testing for Hepatitis C

Robert L. Carithers, Jr., M.D., Anthony Marquardt, and David R. Gretch, M.D., Ph.D.

There have been remarkable advances in diagnostic testing for hepatitis C virus (HCV) over the past decade. This has included progressive improvement in both the sensitivity and specificity of tests for antibodies to HCV (anti-HCV). These tests now provide rapid and inexpensive means of identifying individuals who have been infected with hepatitis C. Qualitative and quantitative tests for HCV RNA provide a molecular basis for determining the presence of viremia. Qualitative tests for HCV RNA have become the gold standard of successful antiviral therapy. Finally, determining the HCV genotype and viral load has become increasingly important in guiding the duration of combination therapy with interferon and ribavirin.1,2 As a result, HCV testing has become the mainstay of both diagnosis and management of patients with hepatitis C.

The goals of this chapter are to review the currently available diagnostic tests for hepatitis C, to emphasize limitations of the various assays, and to suggest the most efficient means of using these tests in clinical practice.


The most commonly used assay for anti-HCV is the enzyme immunoassay (EIA) in which viral antigens are imbedded in the wells of a microtiter plate. Antibodies directed against any of these antigens in patients' sera will adhere to the well. Rapid detection of antibodies is facilitated by adding anti-immunoglobulins containing a colorometric marker (Figure 1). The advantages of this technique include ease of automation, highly reproducible results, and low cost.

Figure 1.   EIA technique for anti-HCV. The first-generation EIA (EIA-1) contained only one HCV antigen. Subsequent tests (EIA-2 and EIA-3) contain additional viral antigens. These additions have improved both the sensitivity and specificity of the test.

Three generations of EIA for anti-HCV have been developed over the past decade. The first EIA (EIA-1), initially used clinically in 1990, contained a single recombinant antigen from the NS4 region of the HCV genome. This assay represented a major breakthrough in screening blood donors for hepatitis C and in clarifying the diagnosis of most patients with non-A, non-B hepatitis. However, it became quickly apparent that this test had a number of serious limitations. There were numerous false-positive reactions, particularly among groups such as blood donors, where the prevalence of hepatitis C is low. In retrospect, only one third to one half of blood donors with a positive EIA-1 test for anti-HCV actually had hepatitis C (Table 1). In addition, there were occasional nonspecific false-positive reactions in patients with various autoimmune disorders. Furthermore, the test was insensitive. As many as 30% of high-risk individuals subsequently found to have hepatitis C had negative reactions to this test (Table 1). Finally, there was a considerable delay between acute HCV infection and the first evidence of anti-HCV (Figure 2). Two complementary approaches were taken to overcome these limitations: development of newer EIA tests with better sensitivity and specificity and supplemental tests to augment EIAs for anti-HCV.

TABLE 1.    Sensitivity and Positive Predictive Value
of EIA for Anti-HCV

  Positive Predictive Value+(%)

Assay Sensitivity*(%) Low Prevalence High Prevalence

EIA-1 70-80 30-50 70-85
EIA-2 92-95 50-61 88-95
EIA-3 97 25 Unknown

* Based on detection of HCV RNA by PCR.
+ Compared with RIBA.
From ref. 3, with permission.

Figure 2.   First detection of HCV RNA and anti-HCV by various assays after acute HCV infection. With each successive EIA, the "window" between the onset of viremia and initial detection of anti-HCV has decreased. Despite these advances, the average window after HCV infection remains over 80 days. (From Ref. 23.)

Many limitations of the first-generation EIA were overcome by the second EIA for anti-HCV (EIA-2). This assay, the clinical standard since 1992, contains antigens from the core and nonstructural three (NS3) and four (NS4) regions of the HCV genome. This test is both more sensitive and specific than the first-generation EIA assay. Use of the second-generation assay further reduced the risk of posttransfusion hepatitis C and false-positive reactions among blood donors (Table 1). Furthermore, it has proved to be quite effective as a screening test in high-risk individuals for chronic hepatitis C. Approximately 92-95% of patients in whom chronic hepatitis C is suspected can be detected using this second-generation EIA (Table 1). Finally, the use of this test shortens the window from blood transfusion to the first detection of anti-HCV to approximately 10 weeks compared with an average of 16 weeks with the first-generation EIA (Figure 2).3 False-positive reactions with the EIA-2 assay are primarily limited to low-risk populations such as blood donors. False-negative tests are seen most commonly among immunosuppressed individuals such as transplant recipients and patients coinfected with HIV.4 EIA-2 continues to be the test routinely used by most clinical laboratories.

A third generation EIA (EIA-3) has been approved for screening blood donors in the United States. This assay contains reconfigured core and NS3 antigens and an additional antigen from the NS5 region of the HCV genome.3 This test offers a slight improvement in sensitivity over the EIA-2 test, particularly in low-risk settings such as a blood bank (Table 1).5 The time from infection to anti-HCV seroconversion is shortened to 7-8 weeks in approximately 30% of patients.(Figure 2).6,7 Although this test is used by some clinical laboratories for routine screening of high risk populations for hepatitis C, the positive predictive value of the EIA-3 assay is not well defined.8 As a result, the benefit of replacing EIA-2 with EIA-3 assays for routine testing in clinical laboratories is unclear.


Because of the high false-positive rate of EIA assays, particularly in low prevalence settings such as blood banks, supplemental tests for anti-HCV were developed. These tests contain the same antigens as the corresponding EIA assay. However, in the commonly used recombinant immunoblot assays (RIBA, Chiron Corporation, Emeryville, CA) individual HCV antigens are displayed on a nitrocellulose strip (Figure 3). As a result, antibodies against specific HCV antigens can be identified. A positive RIBA assay requires at least two reactive bands. Tests with only one reactive band are considered indeterminate. Individuals with only c-100-3 or 5-1-1 positive antigens rarely, if ever, have circulating HCV RNA.3 Therefore, we would argue that single reactive band at c-100-3 or 5-11 should be considered a negative rather than indeterminate RIBA result. RIBA tests are no more sensitive than corresponding EIA tests.9 However, RIBA tests can be used to distinguish false-positive EIA results from prior exposure to HCV. Patients with false-positive EIA tests usually have negative RIBA assays. In contrast, patients previously exposed to hepatitis C typically have positive or indeterminate (C22 or C33) RIBA results.9

Figure 3.   RIBA assays for anti-HCV. Each strip is precoated with specific HCV antigens. HCV antibodies against these antigens in the patient's serum react with the corresponding strip. The strips are then overlaid with anti-human IgG bound to peroxidase. This allows colorimetric detection of the specfic antigens.13 Internal controls include two levels of human IgG (level I, weak positive; level II, moderate positive) and superoxide dismutase (SOD).13 A result is considered positive if two or more HCV bands have an intensity at least as strong as the level I control. A single reactive band is considered indeterminate. In this RIBA assay four positive bands to the HCV antigens in the RIBA 2.0 and RIBA 3.0 assays are illustrated, indicating strongly positive results and high probability of active HCV infection.

The RIBA 2.0 assay, which contains the same antigens as the EIA-2 assay, has been the most commonly used supplemental assay for anti-HCV. In the low prevalence blood bank setting, 40-50% of EIA-2 positive test results are RIBA 2.0 negative, indicating a false-positive result (Table 1).3,10 A RIBA 3.0 assay has been approved for use by blood banks as a supplemental test for EIA-3 positive test results. This test has the advantage over the RIBA-2 assay of fewer indeterminate results and a better correlation with the presence of viremia.11,12 Other supplemental assays are under evaluation.13

RIBAS are standardized and reproducible. However, they are more difficult to perform than EIAs, time consuming, and relatively expensive. Their primary utility has been in excluding false-positive results in blood banks. They have limited if any usefulness among patients clinically suspected of harboring a chronic HCV infection. Fewer than 1% of EIA-2- or EIA-3-positive specimens from such high-risk individuals are RIBA negative.3,14 Furthermore, over 90% of EIA-2-positive specimens from such patients are HCV RNA positive (Table 1).3,14 Thus, it is more efficient to confirm the presence of active infection in these patients using qualitative or quantitative tests for circulating HCV RNA.


Detection of HCV RNA in a patient's blood confirms the presence of active infection. The most sensitive laboratory method of doing so is the reverse transcription polymerase chain reaction (RT-PCR).9,15 Under optimal conditions, the sensitivity of RT-PCR for HCV RNA is 100 molecules/mL of serum or less.

To achieve these conditions, serum or plasma should be separated from whole blood within 4 hours of venipuncture, followed by rapid storage of specimens at -70° C. Failure to follow these procedures can result in false-negative results for circulating HCV RNA.9,16,17

In the laboratory, viral RNA must be isolated and converted into complementary DNA. This is usually accomplished by using oligonucleotide primers specific to the 5' untranslated region of the HCV genome. The DNA product is then amplified using a bacterial DNA polymerase. In some laboratories, this first-round PCR is followed by a second PCR reaction using additional primers. The advantage of this nested-set PCR is the ease of visualizing the amplified DNA products using routine agarose gel electrophoresis.18 The potential disadvantage is an increased risk of sample contamination and false-positive results.18

An alternative approach is to combine a single-stage PCR with a more sensitive DNA detection system. One example is to hybridize the DNA amplification products with a radiolabeled oligonucleotide (Figure 4). This hybridized radioactive product can then be detected using acrylamide gel electrophoresis.18 This method is as sensitive as nested-set PCR but avoids excess sample handling with potential contamination and false-positive results.19

Figure 4.   HCV RNA testing using single-step PCR. RNA is first isolated from the patient's serum. Complementary DNA is produced using oligonucleotide primers specific to the 5' untranslated region of the HCV genome. The DNA product is amplified and then hybridized with a radiolabeled oligonucleotide. The radioactive product can be detected using acrylamide gel electrophoresis.

Whatever technique is used, extreme care and high standards must be maintained to avoid false-positive or -negative results.20 Technologists must be well trained, and all runs require negative controls and multiple low and high copy standards to achieve maximum sensitivity and specificity of test results.9 Initial proficiency tests using blinded specimens indicated abysmally low rates of error-free detection of HCV RNA by PCR in many laboratories.21,22 However, more recent surveys suggest improved performance.9 Development of uniform reference specimens and standardization of virological testing of blood and blood products should continue to improve the accuracy of qualitative testing for HCV RNA.23

In addition to improved quality of the multiple "home brew" PCR assays, progress has been made to develop commercially available tests for detection of HCV RNA. An example of this is the Roche Amplicor test (Roche Molecular Systems, subsidiary of Hoffman-La Roche, Inc., Brandenburg, NJ).24-26 The second-generation Amplicor test has a sensitivity of approximately 100 copies/mL of serum.9 A semiautomated version of this assay (COBAS, Roche Molecular Systems), which has comparable sensitivity and specificity with the manual Amplicor assay, is undergoing extensive clinical investigation.9,27 Some laboratories have reported that the use of whole blood rather than serum improves the sensitivity of qualitative testing for HCV RNA using the Roche Amplicor assay and RT-PCR.28,29 These interesting observations need confirmation. Using the Roche Amplicor assay for HCV RNA in our clinical laboratory, we have found a slight better sensitivity using serum compared to whole blood as a source of HCV RNA (D.R. Gretch, unpublished observations, 2000).


A variety of methods are available for assessing the quantity of circulating HCV RNA in patients with chronic hepatitis C. The most commonly used techniques of determining viral load involve extraction of HCV RNA from serum or plasma, followed by amplification of the target (PCR-based methods) or the signal (branched DNA [bDNA] methods).9

PCR Based Quantitative Assays

The amount of circulating HCV RNA can be determined by a variety of PCR-based assays. Clinical samples can be serially diluted followed by PCR amplification of each dilution, with the quantity of HCV RNA estimated from the last dilution at which the PCR product can be detected. Quantitative competitive PCR is a more elegant approach to determining the quantity of HCV RNA in clinical specimens. Competitor DNA or RNA is constructed that contains sequences at the 5' and 3' ends complementary to the primers used in the PCR. However, these constructs differ from HCV RNA in molecular weight or contain restriction enzyme sites, which allow the competitor and native HCV RNA to be distinguished.9 Although extremely accurate in some laboratories, each method is tedious, expensive, and difficult to replicate from laboratory to laboratory.

The Roche Monitor assay (Amplicor HCV Monitor, Roche Molecular Systems, Nutley, NJ) is the most extensively tested commercial PCR-based assay used for quantitation of HCV RNA. Advantages are standardization and high throughput in the clinical laboratory. The lower limit of sensitivity of this assay is approximately 1000 copies/mL, 10-fold less than qualitative PCR tests for HCV RNA (Figure 5).9,30 A disadvantage reported with the first generation of this assay is underestimation of HCV RNA levels in patients with genotype 2 and 3, compared to those with genotype 1.9,30-33

Figure 5.   Dynamic ranges of the ideal test for quantitating HCV RNA compared with the most commonly used commercial assays. The ideal assay has a dynamic range of 100 to 108 copies of HCV RNA. The bDNA assay (bDNA HCV 2.0, Bayer Diagnostics, Emeryville, CA) has a range of 200,000 to 108 . In comparison, the most commonly used PCR based assay (Roche Amplicor Monitor, Roche Diagnostics, Nutley, NJ) has a reported range of 1,000 to 5 X 106 .


bDNA Assay

An alternative approach to determining viral load in patients with chronic hepatitis C is the bDNA assay (Bayer Diagnostics, Emeryville, CA). In this assay, HCV RNA is captured in a microtiter well by hybridization to synthetic oligonucleotide probes complementary in sequence to the 5'-noncoding region and core of the HCV genome. Additional target probes bind the HCV RNA to bDNA molecules, which are amplified and labeled with a chemiluminescent probe9,15,34 This assay is well standardized, has a high level of precision, and is quite reproducible from laboratory to laboratory. Its major limitation is a relative lack of sensitivity, with a lower limit of approximately 200,000 equivalents of HCV RNA/mL of serum (Figure 5).

Comparison of PCR and bDNA methods

The Roche Monitor and Bayer bDNA assays have been extensively evaluated by a number of investigators. Results from the bDNA assay are quite reproducible, with lower intraassay and kit-to-kit variation than the Monitor assay.9,30,35 The bDNA assay more accurately reflects HCV RNA levels in patients with genotype 2 and 3 infection and has better linearity in patients with high viral loads (Figure 5).9,30,36 In contrast, the Monitor assay has a lower detection limit than the bDNA assay (Figure 5). Although this would suggest much higher sensitivity for the Monitor assay, when the two assays have been directly compared in patients with clinical features of chronic hepatitis C, the sensitivity of each is virtually identical.30,32 For example, in one study of 100 patients with chronic hepatitis C evaluated before treatment, the sensitivity of the Monitor was 98% compared with 97% for the bDNA assay.32 These findings underscore the infrequency in which untreated patients with chronic hepatitis C have HCV RNA values between 1,000 and 200,000 copies/mL, the lower detection limits of these two assays. Another clinically important observation is that values obtained with each of the two assays are not interchangeable because different internal standards are used.9 Results from the bDNA test are generally a log higher than those obtained with the Monitor assay.30-33 Therefore, these tests cannot be used interchangeably to follow patients. Nevertheless, changes in viral load that occur over time can be consistently measured using either assay.33,37


Hepatitis C is a heterogeneous virus with at least six genotypes and numerous subtypes identified from isolates collected throughout the world.38,39 Although considerable controversy surrounds the natural history of disease is patients with different genotypes, there is consensus that the HCV genotype is one of the most important predictors of response to antiviral therapy. A variety of methods have been developed to determine the genotype of a specific HCV infection. These can be broadly separated into two categories: (1) gold standard tests using nucleotide sequencing and (2) phylogenetic analysis of specific HCV genes, and screening tests that detect point mutations within the HCV genome.34

Genotype Analysis by Nucleotide
Sequencing and Phylogenetic Analysis

The most accurate methods of determining the genotype of any isolate of HCV include determining the sequence of specific areas within the HCV genome and comparing the sequence obtained to phylogenetic maps of known genotypes. The envelope (E1) and NS5B genes have been studied most extensively in this regard.39-41 Although these methods offer the most precise means of determining the HCV genotype, they are labor intensive and prohibitively expensive, especially for routine clinical use.

Screening Tests for HCV Genotypes

A number of methods have been developed to rapidly and less expensively determine the genotype of HCV specimens in clinical laboratories. Three of these methods apply innovative uses of PCR for hepatitis C. One technique uses PCR using primers constructed with sequences unique to specific genotypes.42,43 Only HCV specimens that contain these genotype-specific sequences are amplified. Genotype-specific primers for both the core and NS5B regions have been used in this manner.42,43 The core method was optimized for use in Japan and performs less accurately with the most common U. S. genotypes.34

Another approach relies on the knowledge that the nucleotides of most HCV genotypes have unique restriction sites. The HCV genotype can be deduced by digesting amplified PCR products with specific restriction enzymes and determining the differential migration of the resulting nucleic acid fragments using agarose gel electrophoresis.15,44-47 This technique, referred to as restriction fragment length polymorphism (RFLP), has proved to be one of the most accurate screening tests for HCV genotype.

A final creative screening test for HCV genotype uses genotype-specific probes, which are embedded on a nitrocellulose strip. Amplified PCR products from the 5' noncoding region of the HCV genome differentially hybridize to the nitrocellulose strip only when the amplified sequence is complementary to the sequence of an embedded genotype-specific probe. This assay, referred to as the line probe or reverse dot-blot hybridization assay, is now commercially available for HCV genotyping in clinical laboratories (INNO-LiPA, Immunogenetics, Belgium). Reliability and concordance between the RFLP and line probe assays is quite good.48,49 However, these methods of determining HCV genotype remain relatively expensive.

The genotype of HCV infection also can be determined by detecting genotype-specific antibodies. These antibodies are distinguished by reacting patient sera with genotype-specific antigens presented in an immunoblot format. The HCV NS4 region appears to be the best candidate for serotyping assays because this gene encodes specific epitopes that can be used to distinguish HCV genotypes 1 through 3.9,50 Although their concordance with other genotyping methods is quite good, serotyping methods may not be as sensitive as PCR-based methods.48,49,51,52 In addition, serotyping currently cannot be used to differentiate HCV subtypes, such as genotype 1a and 1b.9 However, the low cost and ease of testing of serotyping make them attractive candidates for continued research and development.


The dramatic improvement in HCV testing over the past decade has provided clinicians with a variety of powerful tools for evaluating patients with hepatitis C. However, these tests are expensive (Table 2). Therefore, virological tests for hepatitis C should be used judiciously, based on the specific clinical setting.

TABLE 2.   Current Cost of Various HCV Tests

Assay Price   

Anti-HCV (EIA) $57.15
Anti-HCV (RIBA) $140.00
Qualitative HCV RNA $131.75
Quantitative HCV RNA $197.75
HCV genotype $236.30

From the University of Washington Hepatitis Virology Laboratory.


Diagnosis of Acute Hepatitis C

The diagnosis of acute hepatitis C can be quite difficult. Fewer that half of patients develop jaundice and many have few if any obvious symptoms of hepatitis.53,54 Specific IgM antibodies, which are so useful in the diagnosis of acute hepatitis A and B, have not been found to reliable in the diagnosis of acute hepatitis C. The diagnostic difficulties are compounded by considerable delay between HCV infection and detection of antibodies to the virus in patients' sera.13 This was particularly true for the first-generation EIA test for anti-HCV in which the average lag between infection and seroconversion was 16 weeks.3 This window has been progressively shortened with each generation of EIA testing. For example, the average time from infection to seroconversion is 10 weeks with EIA-2 and is shortened in some patients by an additional 2-3 weeks with the EIA-3 assay.3,6 However, even with the EIA-3 assay, the "window period" between HCV infection and seroconversion is at least 6 to 8 weeks. In contrast, HCV RNA usually can be detected in the patient's serum within 10-14 days after infection (Figure 2). Thus, if there is a strong clinical suspicion of acute hepatitis C, such as recent drug abuse or marked elevation of aminotransferases but anti-HCV cannot be detected, qualitative testing for HCV RNA can be used to confirm the diagnosis.

Diagnosis of Chronic Hepatitis C

It is estimated that 85% of individuals exposed the hepatitis C develop persistent viremia, presumably for life.54-56 However, many patients with chronic HCV infection have minimal symptoms until late in the course of disease. As a consequence, most individuals with chronic hepatitis C are unaware of their condition. The most effective means of screening patients clinically suspected of harboring chronic hepatitis C virus infection is with EIA testing for anti-HCV. In this setting, RIBA confirmation is not necessary because HCV RNA can be detected in more than 90% of anti-HCV-positive sera.8,9 Qualitative HCV RNA testing can be useful to distinguish individuals with prior infection who have cleared the virus from those with persistent HCV infection. However, because some patients with chronic hepatitis C may be only intermittently viremic, repeated qualitative testing for HCV RNA by PCR may be necessary to exclude ongoing infection.

HCV Testing Before, During, and After Treatment

Successful medical treatment of patients with chronic hepatitis C has increased fourfold over the past decade. Interferon remains the mainstay of therapy, but more aggressive treatment schedules and addition of ribavirin have steadily improved the chance of durable responses to treatment.

HCV Testing Before Treatment

The HCV genotype and circulating viral load have emerged as two of the best predictors of response to antiviral therapy for chronic hepatitis C.1,2,57-59 Patients with genotype 1 infection are far less likely to respond to interferon therapy than patients with genotype 2 or 3 infection. High levels of circulating HCV RNA further reduce the chance of achieving a sustained response to either interferon or combination therapy with interferon and ribavirin. The differences can be quite striking. For example, sustained response to 6 months of 3 MU interferon tiw is more than 25 times higher among patients with genotype 2 or 3 and < 2 million copies of HCV RNA than in genotype 1 patients with > 2 million copies of virus per mL of serum (Table 3). Differential response rates to combination therapy with interferon and ribavirin also are quite impressive. Patients with genotype 2 or 3 are six times more likely to achieve a sustained response to 6 months of treatment with combination therapy than patients with genotype 1 infection and > 2 million copies of HCV RNA per mL of serum (Table 3).1,2,57

TABLE 3.   Response to Therapy by Genotype and HCV RNA Level

  Intron A
(24 weeks)
Intron A
(48 weeks)
IFN + Ribavirin
(24 weeks)
IFN + Ribavirin
(48 weeks)

Genotype 1 and HCV RNA > 2 million copies/mL 0.8% 3% 10% 27%
Genotype 1 and HCV RNA < 2 million copies/mL 4% 25% 32% 33%
Genotype 2/3 and HCV RNA > 2 million copies/mL 11% 26% 62% 60%
Genotype 2/3 and HCV RNA < 2 million copies/mL 25% 36% 61% 64%

Adapted from ref. 4, with permission.

Genotype and HCV RNA level are also quite useful in determining the optimum duration of combination therapy with interferon and ribavirin. Sustained response rates are almost three times as high among patients with genotype 1 infection and > 2 million copies of virus who receive 12 months of combination therapy compared with those who receive only 6 months of treatment. In contrast, patients with genotype 2 or 3 infections or those who have < 2 million copies of HCV RNA per mL of serum do not benefit from more than 6 months of treatment with interferon and ribavirin (Table 3).

Thus, assessment of genotype and quantity of circulating HCV RNA provide essential information for counseling and determining the duration of therapy in patients with chronic hepatitis C. In this setting, quantitative measurement of HCV RNA is quite useful, because 90-97% of samples are HCV RNA positive by either PCR or bDNA methods.30,32,36

HCV Testing During and After Treatment

Well-defined and standardized criteria for response to antiviral therapy have been established.60 These include biochemical, virological, and histological responses both at the end of treatment and 6 months after completion of therapy. Virological end points have proven to be more accurate than biochemical measures in predicting sustained clearance of virus.61 For example, patients who have normal aminotransferases but detectable HCV RNA at the end of treatment are more likely to relapse after completion of therapy than patients with abnormal aminotransferases and absence of circulating HCV RNA.61,62

Sustained virological response, defined as continued absence of circulating HCV RNA for at least 6 months after completion of therapy using an assay with detection limits <100 copies/mL of serum, has become the gold standard of successful treatment (Figure 6). Because of their relative insensitivity, quantitative tests for HCV RNA are inadequate measures of end of treatment or sustained virological response in patients with chronic hepatitis C. Long-term studies of sustained virological responders to interferon therapy are quite encouraging. Over the ensuing 5-10 years, circulating HCV RNA has recurred in fewer than 10% of patients in most follow-up studies (Table 4).63-66 A striking exception was reported by Vento et al.67 (Table 4). In most studies, histological injury has continued to improve over time in sustained virological responders to antiviral therapy.63-66

Figure 6.   Sustained response to treatment in a patient with chronic hepatitis C. The patient was treated for 6 months and had monthly assessment of ALT and HCV RNA for an additional 6 months.

TABLE 4.   Long-term Follow-up of Sustained
Virologic Responders

Author Number Follow-up (yr)* SR(%)

Marcellin et al.63 75 4.0 ± 2.0 72 (96%)
Lau et al.64 5 10.4 ± 0.6 5 (100%)
Reichard et al.66 25 5.4 ± 1.6 24 (96%)
Larghi et al.65 23 3.3 23 (100%)
Vento et al.67 29 7 0

* Values are means ± SD.
SR: sustained virologic response (absence of circulating HCV RNA at end of follow-up using qualitative HCV RNA testing).

Patients who achieve a sustained response to interferon monotherapy 3 MU tiw often clear circulating virus quite early in the course of treatment (Figure 6). Very few, if any, patients who have detectable HCV RNA after 3 months of treatment develop a sustained response. For this reason, it has been suggested that therapy should be discontinued in patients who have detectable HCV RNA after 3 months of treatment.68 However, as many as 20% of sustained responders to combination therapy with interferon plus ribavirin first clear circulating HCV RNA between 3 and 6 months after initiating treatment.1,2,57 Thus, a minimum of 6 months of treatment is recommended in patients who receive combination therapy. The rate of viral clearance has not been well established in other more aggressive regimens of interferon or combination therapy.

Measurement of circulating HCV RNA at the end of antiviral treatment can also be quite useful in predicting response to subsequent courses of therapy.69-71 For example, patients with no detectable HCV RNA at the end of a first course of treatment with interferon therapy have sustained response rates greater than 50% to retreatment with more aggressive interferon therapy or treatment with interferon and ribavirin.72-74 In contrast, patients who have detectable HCV RNA at the end of the first course of treatment have sustained response rates to retreatment less than 15%.74,75

Screening for HCV in Blood Banks and
Among Organ Donors

The risk of acquiring hepatitis C from blood products or donor organs has decreased dramatically over the past decade.76 Because of increased sensitivity, each subsequent generation of anti-HCV tests has reduced the possibility that transfused products may harbor HCV.13 The third-generation EIA and RIBA assays have reportedly reduced the number of false-negative, false-positive, and indeterminate results.6,77

The two primary challenges facing blood banks are to eliminate transfused blood products as a source of HCV infection and to determine whether anti-HCV-positive donors actually have HCV infection. One of the major limitations of EIA assays for anti-HCV is the delay from onset of infection to development of detectable antibodies to hepatitis C. Currently available assays can detect antibodies as soon as 40 to 60 days after infection and 30 to 40 days after first appearance of circulating HCV RNA (Figure 2). However, the average delay between infection and first appearance of detectable antibodies remains more than 80 days.23 For this reason, many blood banks are exploring the feasibility of testing all potential donors with qualitative assays for HCV RNA. This approach has the dual advantage of eliminating donors who are in the "window period" of early infection and clarifying the clinical status of donors positive for anti-HCV by EIA.

Use of HCV Testing in Special Situations

The evaluation of patients with potential HCV infection can be confusing in certain clinical settings. This is particularly true in patients with chronic renal failure, immunosuppressed patients, and in infants with HCV. Selective use of HCV tests can be extremely useful in clarifying the clinical status of these patients.

Hemodialysis Units

Approximately 10% of chronic hemodialysis patients in the United States have chronic hepatitis C.78-80 However, the prevalence of infection varies widely from center to center.76,80 Because of the high risk of infection in hemodialysis units, the Center for Disease Control and Prevention recommends routine testing of patients who have not been previously evaluated for the possibility of HCV infection.81

Most chronic renal failure patients with HCV infection have normal serum aminotransferase values.82,83 Thus, screening for hepatitis C in these patients requires sensitive and specific serologic testing.82 The EIA-1 test for anti-HCV had extremely poor sensitivity in this patient population. As many as half of HCV infected patients tested negative using this assay.76,79,82 However, the EIA-2 assay is far more sensitive and specific for detecting HCV infection in hemodialysis patients. Over 90% of EIA-2-positive patients have detectable HCV RNA, and false-positive results are uncommon.82,84 EIA-3 testing does not appear to add substantially to either the sensitivity or specificity of HCV screening in patients with chronic renal failure.84

Organ Transplant Recipients and Other
Immunosuppressed Populations

Chronic HCV infection is quite common in solid organ and bone marrow transplant recipients. Virtually all patients with infection before transplantation have persistent viremia after transplantation.4,85 In fact, viral levels often increase by a log or more within a few weeks after these operations. HCV infection also can be acquired at the time of transplantation from the use of infected donor organs or blood products. This was particularly true before universal anti-HCV screening of blood products and organ donors was initiated in 1992. Cirrhosis secondary to chronic hepatitis C has emerged as a major concern, particularly in renal and marrow transplant recipients.78,86

The diagnosis of chronic hepatitis C in potential transplant recipients is straightforward. EIA-2 or EIA-3 assays for anti-HCV are quite effective in identifying most patients with prior exposure to the virus. Active infection can be differentiated from patients with previous HCV infection by qualitative testing for HCV RNA. However, after transplantation, antibody tests are inadequate for the diagnosis of hepatitis C because of depression of antibody titers and prolonged delay in seroconversion after de novo infection.87-89 The only means of accurately assessing the presence of hepatitis C in transplant recipients is with direct measurement of serum HCV RNA.4,90

The diagnosis of chronic hepatitis C also can be challenging in other immunosuppressed patients, particularly those coinfected with HIV. Some HIV patients with chronic hepatitis C lose anti-HCV antibodies over time.91 For this reason, it is prudent to consider direct measurement of HCV RNA in HIV patients with negative anti-HCV in whom there is a strong clinical suspicion of chronic hepatitis C infection.9

HCV Infection in Children

The two primary modes of infection in children are transfusion of blood products and perinatal transmission. Spontaneous clearance of active HCV infection after blood transfusions appears to be much higher in children than adults. In one recent study, only 55% of children with anti-HCV after blood transfusions had detectable HCV RNA on long term follow-up, far lower than the 85% of patients with persistent HCV infection reported in adults.92 Documenting resolution of HCV infection with qualitative measurements of HCV RNA may be reassuring to both these children and their parents.

The risk of perinatal transmission of hepatitis C from viremic mothers to their infants is approximately 5% to 10%.93,94 Despite the concern about perinatal transmission, it is prudent to delay anti-HCV testing in these infants for 12 to 15 months to allow clearance of maternal antibodies.95 Qualitative HCV RNA testing is the best method to evaluate newborns with elevated aminotransferases and suspected hepatitis C in the perinatal period.


Currently available tests provide powerful tools for the management of patients with chronic hepatitis C. They can be used to inexpensively screen patients for possible HCV infection and to confirm or exclude the presence of active infection. In addition, they have proven extremely useful in the management of patients undergoing antiviral therapy for chronic hepatitis C.


HCV hepatitis C virus
anti-HCV antibodies to HCV
EIA enzyme immunoassay
RIBA recombinant immunoblot assay
RT-PCR reverse transcriptase polymerase chain reaction
bDNA branched DNA
RFLP restriction fragment length polymorphism



  1. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339:1485-1492.
  2. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998; 352:1426-1432.
  3. Gretch DR. Diagnostic tests for hepatitis C. Hepatology 1997; 26 (Suppl 1):43S-47S.
  4. Gretch DR, Bacchi CE, Corey L, dela Rosa C, Lesniewski RR, Kowdley K et al. Persistent hepatitis C virus infection after liver transplantation: clinical and virological features. Hepatology 1995; 22:1-9.
  5. Kao J-H, Lai M-Y, Hwang Y-T, Yang P-M, Chen P-J, Sheu J-C et al. Chronic hepatitis C without anti-hepatitis C antibodies by second-generation assay. A clinicopathologic study and demonstration of the usefulness of a third-generation assay. Dig Dis Sci 1996; 41:161-165.
  6. Uyttendaele S, Claeys H, Mertens W, Verhaert H, Vermylen C. Evaluation of third-generation screening and confirmatory assays for HCV antibodies. Vox Sang 1994; 66:122-129.
  7. Barrera J, Prancis B, Ercilla G, Nelles M, Achord D, Darner J et al. Improved detection of anti-HCV in post-transfusion hepatitis by a third-generation ELISA. Vox Sang 1995; 68:15-18.
  8. Pawlotsky JM, Lonjon I, Hezode C, Raynard B, Darthuy F, Remire J et al. What strategy should be used for diagnosis of hepatitis C virus infection in clinical laboratories? Hepatology 1998; 27:1700-1702.
  9. Morishima C, Gretch DR. Clinical use of hepatitis C virus tests for diagnosis and monitoring during therapy. In: Keefe EB, editor. Treatment of chronic hepatitis C. Philadelphia: W.B. Saunders Company, 1999: 717-740.
  10. Atrah HI, Hutchinson F, Gough D, Ala FA. Hepatitis C seroconversion rate in established blood donors. J Med Virol 1995; 46:329-333.
  11. Pawlotsky JM, Bastie A, Pellet C, Remire J, Darthuy F, Wolfe L et al. Significance of indeterminate third-generation hepatitis C virus recombinant immunoblot assay. J Clin Microbiol 1996; 34:80-83.
  12. Damen M, Zaaijer HL, Cuypers HT, Vrielink H, van der Poel CL, Reesink HW et al. Reliability of the third-generation recombinant immunoblot assay for hepatitis C virus. Transfusion 1995; 35:745-749.
  13. Younossi ZM, McHutchison JG. Serological tests for HCV infection. Viral Hep Rev 1996; 2:161-173.
  14. Pawlotsky JM, Bastie A, Lonjon I, Remire J, Darthuy F, Soussy CJ et al. What technique should be used for routine detection and quantification of HBV DNA in clinical samples? J Virol Methods 1997; 65:245-253.
  15. Fried MW. Clinical application of hepatitis C virus genotyping and quantitation. In: Davis GL, editor. Clinics in Liver Disease. Philadelphia, PA: W.B. Saunders Co, 1997: 631-645.
  16. Busch MP, Wilber JC, Johnson P, Tobler L, Evans CS. Impact of speciman handling and storage on detection of hepatitis C virus RNA. Transfusion 1992; 32:420-425.
  17. Davis GL, Lau JY, Urdea MS, Neuwald PD, Wilber JC, Lindsay K et al. Quantitative detection of hepatitis C virus RNA with a solid-phase signal amplification method: definition of optimal conditions for specimen collection and clinical application in interferon-treated patients. Hepatology 1994; 19:1337-1341.
  18. Polyak SJ, Gretch DR. Molecular diagnostic testing for viral hepatitis: methods and applications. In: Willson RA, editor. Viral Hepatitis. New York: Marcel Dekker, Inc., 1997: 1-33.
  19. Gretch DR, Wilson JJ, Carithers RL, Jr., dela Rosa C, Han JH, Corey L. Detection of hepatitis C virus RNA: comparison of one-stage polymerase chain reaction (PCR) with nested-set PCR. J Clin Microbiol 1993; 31:289-291.
  20. Kwok S, Higuchi R. Avoid false positives with PCR. Nature 1989; 339:237-238.
  21. Zaaijer HL, Cuypers HT, Reesink HW, Winkel IN, Gerken G, Lelie PN. Reliability of polymerase chain reaction for detection of hepatitis C virus. Lancet 1993; 341:722-724.
  22. Damen M, Cuypers HT, Zaaijer HL, Reesink HW, Schaasberg WP, Gerlich WH et al. International collaborative study on the second Eurohep HCV RNA reference panel. J Virol Meth 1996; 58:175-185.
  23. Saldanha J. Standardization, quantification and quality control of assays for HCV RNA. Viral Hep Rev 1999; 5:1-11.
  24. Nolte FS, Thurmond C, Fried MW. Preclinical evaluation of AMPLICOR hepatitis C virus test for detection of hepatitis C virus RNA. J Clin Microbiol 1995; 33:1775-1778.
  25. Young KK, Archer JJ, Yokosuka O, Omata M, Resnick RM. Detection of hepatitis C virus RNA by a combined reverse transcription PCR assay: comparison with nested amplification and antibody testing. J Clin Microbiol 1995; 33:654-657.
  26. Zeuzem S, Ruster B, Roth WK. Clinical evaluation of a new polymerase chain reaction assay (AmplicorTM HCV) for detection of hepatitis C virus. Z Gastroenterol 1994; 32:342-347.
  27. Albadalejo J, Alonso R, Antinozzi R, Bogard M, Bourgault AM, Colucci G et al. Multicenter evaluation of the COBAS AMPLICOR HCV assay, an integrated PCR system for rapid detection of hepatitis C in the diagnostic laboratory. J Clin Microbiol 1998; 36:862-865.
  28. Stapleton JT, Klinzman D, Schmidt WN, Pfaller MA, Wu P, LaBrecque DR et al. Prospective comparison of whole-blood- and plasma-based hepatitis C virus RNA detection systems: improved detection using whole blood as the source of viral RNA. J Clin Microbiol 1999; 37:484-489.
  29. Schmidt WN, Wu P, Brashear D, Klinzman D, Phillips MJP, LaBrecque DR et al. Effect of interferon therapy on hepatitis C virus RNA in whole blood, plasma, and peripheral blood mononuclear cells. Hepatology 1999; 28:1110-1116.
  30. Lunel F, Cresta P, Vitour D, Payan C, Dumont B, Frangeul L et al. Comparative evaluation of hepatitis C virus RNA quantitation by branched DNA, NASBA, and monitor assays. Hepatology 1999; 29:528-535.
  31. Hawkins A, Davidson F, Simmonds P. Comparison of plasma virus loads among individuals infected with hepatitis C virus (HCV) genotypes 1, 2, and 3 by quantiplex HCV RNA assay versions 1 and 2, Roche monitor assay, and an in-house limiting dilution method. J Clin Microbiol 1997; 35:187-192.
  32. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O. Comparison of 3 quantitative HCV RNA assays--accuracy of baseline viral load to predict treatment outcome in chronic hepatitis C. Scand J Infect Dis 1998; 30:441-446.
  33. Tong CY, Hollingsworth RC, Williams H, Irving WL, Gilmore IT. Effect of genotypes of the quantification of hepatitis C virus (HCV) RNA in clinical samples using the Amplicor HCV Monitor test and the Quantiplex HCV RNA 2.0 assay (bDNA). J Med Virol 1998; 55:191-196.
  34. Gretch DR. Use and interpretation of HCV diagnostic tests in the clinical setting. In: Davis GL, editor. Clinic in Liver Disease. Philadelphia: W.B. Saunders, 1997: 543-557.
  35. Gretch DR, dela Rosa C, Carithers RL, Jr., Willson RA, Williams B, Corey L. Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications. Ann Intern Med 1995; 123:321-329.
  36. Pawlotsky JM, Martinot-Peignoux M, Poveda JD, Bastie A, Le B, V, Darthuy F et al. Quantification of hepatitis C virus RNA in serum by branched DNA-based signal amplification assays. J Virol Methods 1999; 79:227-235.
  37. Trabaud MA, Bailly F, Si-Ahmed SN, Chevallier P, Sepetjan M, Colucci G et al. Comparison of HCV RNA assays for the detection and quantification of hepatitis C virus RNA levels in serum of patients with chronic hepatitis C treated with interferon. J Med Virol 1997; 52:105-112.
  38. Bukh J, Miller RH, Purcell RH. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 1995; 15:41-63.
  39. Simmonds P, Holmes EC, Cha TA, Chan SW, McOmish F, Irvine B et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol 1993; 74:2391-2399.
  40. Bukh J, Purcell RH, Miller RH. At least 12 genotypes of hepatitis C virus predicted by sequence analysis of the putative E1 gene of isolates collected worldwide. Proc Natl Acad Sci USA 1993; 90:8234-8238.
  41. Stuyver L, Van Arnhem W, Wyseur A, Hernandez F, Delaporte E, Maertens G. Classification of hepatitis C viruses based on phylogenetic analysis of the envelope 1 and nonstructural 5B regions and identification of 5 additional subtypes. Proc Natl Acad Sci USA 1994; 91:10134-10138.
  42. Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane Y, Sugai Y et al. Typing hepatitis C virus by polymerase chain reaction with type specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol 1992; 73:673-679.
  43. Chayama K, Tsubota A, Arase Y, Saitoh S, Koida I, Ikeda K et al. Genotype subtyping of hepatitis C virus. J Gastroenterol Hepatol 1993; 8:150-156.
  44. Nakao T, Enomoto N, Takada N, Takada A, Date T. Typing of hepatitis C virus genomes by restriction fragment length polymorphism. J Gen Virol 1991; 72:2105-2112.
  45. Simmonds P, McOmish F, Yap PL, Chan SW, Lin CK, Dusheiko G et al. Sequence variability in the 5' non-coding region of hepatitis C virus: identification of a new virus type and restrictions on sequence diversity. J Gen Virol 1993; 74:661-668.
  46. Davidson F, Simmonds P, Ferguson JC, Jarvis LM, Dow BC, Follett EA et al. Survey of major genotypes and subtypes of hepatitis C virus using RFLP of sequences amplified from the 5'-non-coding region. J Gen Virol 1995; 76:1197-1204.
  47. Mahaney K, Tedeschi V, Maertens G, Di Bisceglie AM, Vergalla J, Hoofnagle JH et al. Genotypic analysis of hepatitis C virus in American patients. Hepatology 1994; 20:1405-1411.
  48. Lau JY, Mizokami M, Kolberg JA, Davis GL, Prescott LE, Ohno T et al. Application of six hepatitis C genotyping systems to sera from chronic hepatitis C patients in the United States. J Infect Dis 1995; 171:281-289.
  49. Lau JYN, Davis GL, Prescott LE, Maertens G, Lindsay KL, Qian K et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Ann Intern Med 1996; 124:868-876.
  50. Simmonds P, Rose KA, Graham S, Chan SW, McOmish F, Dow BC et al. Mapping of serotype-specific, immunodominant epitopes in the NS-4 region of hepatitis C virus (HCV): use of type-specific peptides to serologically differentiate infections with HCV types 1, 2, and 3. J Clin Microbiol 1993; 31:1493-1503.
  51. Pawlotsky JM, Prescott L, Simmonds P, Pellet C, Laurent-Puig P, Labonne C et al. Serological determination of hepatitis C virus genotype: comparison with a standardized genotyping assay. J Clin Microbiol 1997; 35:1734-1739.
  52. Prescott LE, Berger A, Pawlotsky JM, Conjeevaram P, Pike I, Simmonds P. Sequence analysis of hepatitis C virus variants producing discrepant results with two different genotyping assays. J Med Virol 1997; 53:237-244.
  53. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997; 26 (Suppl 1):15S-20S.
  54. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic Non-A, Non-B Hepatitis Study Team. N Engl J Med 1992; 327:1899-1905.
  55. Farci P, Alter HJ, Wong D, Miller RH, Shih JW, Jett B et al. A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med 1991; 325:98-104.
  56. Alter HJ. Descartes before the horse: I clone, therefore I am: the hepatitis C virus in current perspective. Ann Intern Med 1991; 115:644-649.
  57. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis 1999; 19 (Suppl 1):57-65.
  58. Davis GL, Lau JY. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997; 26 (Suppl 1):122S-127S.
  59. Barnes E, Webster G, Whalley S, Dusheiko G. Predictors of a favorable response to alpha interferon therapy for hepatitis C. In: Keefe EB, editor. Clinics in Liver Disease. Philadelphia, PA: W.B. Saunders Company, 1999: 775-791.
  60. Lindsay KL. Therapy of hepatitis C: overview. Hepatology 1997; 26 (Suppl 1):71S-77S.
  61. Tong MJ, Blatt LM, McHutchison JG, Co RL, Conrad A. Prediction of response during interferon alfa 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: a comparison. Hepatology 1997; 26:1640-1645.
  62. Chemello L, Cavalleto L, Casarin C, Bonetti P, Bernardinello E, Pontisso P et al. Persistent hepatitis C viremia predicts late relapse after sustained response to interferon-alpha in chronic hepatitis C. Ann Intern Med 1996; 124:1058-1060.
  63. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997; 127:875-881.
  64. Lau D-TY, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998; 28:1121-1127.
  65. Larghi A, Tagger A, Crosignani A, Ribero ML, Bruno S, Portera G et al. Clinical significance of hepatic HCV RNA in patients with chronic hepatitis C demonstrating long-term sustained response to interferon-alpha therapy. J Med Virol 1998; 55:7-11.
  66. Reichard O, Glaumann H, Fryden A, Norkrans G, Wejstal R, Weiland O. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol 1999; 30:783-787.
  67. Vento S, Concia E, Ferraro T. Lack of sustained efficacy of interferon in patients with chronic hepatitis C. N Engl J Med 1996; 334:1479-1480.
  68. National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology 1997; 26 (Suppl 1):2S-10S.
  69. Alberti A, Chemello L, Noventa F, Cavalletto L, De SG. Therapy of hepatitis C: re-treatment with alpha interferon. Hepatology 1997; 26 (Suppl 1):137S-142S.
  70. Chemello L, Cavalletto L, Donada C, Bonetti P, Casarin P, Urban F et al. Efficacy of a second cycle of interferon therapy in patients with chronic hepatitis C. Gastroenterology 1997; 113:1654-1659.
  71. Camma C, Giunta M, Chemello L, Alberti A, Toyoda H, Trepo C et al. Chronic hepatitis C: interferon retreatment of relapsers. A meta- analysis of individual patient data. Hepatology 1999; 30:801-807.
  72. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339:1493-1499.
  73. Davis GL. Combination therapy with interferon alfa and ribavirin as retreatment of interferon relapse in chronic hepatitis C. Semin Liver Dis 1999; 19 (Suppl 1):49-55.
  74. Heathcote EJ, Keeffe EB, Lee SS, Feinman SV, Tong MJ, Reddy KR et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998; 27:1136-1143.
  75. Barbaro G, Di Lorenzo G, Belloni G, Ferrari L, Paiano A, Del Poggio P et al. Interferon alpha-2B and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial. Am J Med 1999; 107:112-118.
  76. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334:1685-1690.
  77. Vrielink H, Zaaijer HL, Reesink HW, van der Poel CL, Cuypers HT, Lelie PN. Sensitivity and specificity of three third-generation anti-hepatitis C virus ELISAs. Vox Sang 1995; 69:14-17.
  78. Terrault NA, Wright TL, Pereira BJG. Hepatitis C infection in the transplant recipient. Infect Dis Clin North Am 1995; 9:943-964.
  79. Roth D. Hepatitis C virus: the nephrologist's view. Am J Kidney Dis 1995; 25:3-16.
  80. Tokars JI, Alter MJ, Favero MS, Moyer LA, Miller E, Bland LA. National surveillance of dialysis associated diseases in the United States, 1993. ASAIO J 1996; 42:219-229.
  81. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998; 47:1-39.
  82. Chan TM, Lok ASF, Cheng IKP, Chan RT. Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays. Hepatology 1993; 17:5-8.
  83. Fabrizi F, Lunghi G, Andrulli S, Pagliari B, Mangano S, Faranna P et al. Influence of hepatitis C virus (HCV) viraemia upon serum aminotransferase activity in chronic dialysis patients. Nephrol Dial Transplant 1997; 12:1394-1398.
  84. Courouc'e AM, Bouchardeau F, Chauveau P, Le MN, Girault A, Zins B et al. Hepatitis C virus (HCV) infection in haemodialysed patients: HCV-RNA and anti-HCV antibodies (third-generation assays). Nephrol Dial Transplant 1995; 10:234-239.
  85. Strasser SI, Myerson D, Spurgeon CL, Sullivan KM, Storer B, Schoch HG et al. Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology 1999; 29:1893-1899.
  86. Strasser SI, Sullivan KM, Myerson D, Spurgeon CL, Storer B, Schoch HG et al. Cirrhosis of the liver in long-term marrow transplant survivors. Blood 1999; 93:3259-3266.
  87. Hsu HH, Wright TL, Tsao SC, Combs C, Donets M, Feinstone SM et al. Antibody response to hepatitis C virus after liver transplantation. Am J Gastroenterol 1994; 89:1169-1174.
  88. Lok AS, Chien D, Choo QL, Chan TM, Chiu EK, Cheng IK et al. Antibody response to core, envelope and nonstructural hepatitis C virus antigens: comparison of immunocompetent and immunosuppressed patients. Hepatology 1993; 18:497-502.
  89. Feray C, Gigou M, Samuel D, Paradis V, Wilber J, David MF et al. The course of hepatitis C virus infection after liver transplantation. Hepatology 1994; 20:1137-1143.
  90. Wright TL, Donegan E, Hsu HH, Ferrell L, Lake JR, Kim M et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterology 1992; 102:317-322.
  91. Chamot E, Hirschel B, Wintsch J, Robert CF, Gabriel V, Deglon JJ et al. Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users. AIDS 1990; 4:1275-1277.
  92. Vogt M, Lang T, Frosner G, Klingler C, Sendl AF, Zeller A et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341:866-870.
  93. Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med 1994; 330:744-750.
  94. Giacchino R, Tasso L, Timitilli A, Castagnola E, Cristina E, Sinelli N et al. Vertical transmission of hepatitis C virus infection: usefulness of viremia detection in HIV-seronegative hepatitis C virus-seropositive mothers. J Pediatr 1998; 132:167-169.
  95. Jonas MM. Hepatitis C infection in children. N Engl J Med 1999; 341:912-913.


©Copyright 2000   University of Washington. All rights reserved