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Comparison of Methodologies for Quantification of Hepatitis C Virus (HCV) RNA in Patients Coinfected with HCV and Human Immunodeficiency Virus

  1. Kenneth E Sherman1,
  2. Susan D Rouster1, and
  3. Paul S Horn2
  1. 1Department of Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Ohio
  2. 2Department of Mathematical Sciences, University of Cincinnati, Ohio
  1. Reprints or correspondence: Dr. Kenneth E. Sherman, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0595 (kenneth.sherman{at}uc.edu)
 
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Abstract

Quantification of hepatitis C virus (HCV) RNA is important in the assessment of HCV-associated liver disease in patients coinfected with HCV and human immunodeficiency virus (HIV). To investigate whether the standard integrity of competing test methodologies might be compromised by higher HCV titers in coinfected patients, 2 technologies (a polymerase chain reaction–based assay [COBAS Amplicor 2.0 assay; Roche Diagnostics] and a branched-chain DNA assay [Versant 3.0; Bayer]) were evaluated by testing paired serum samples from 68 coinfected patients and 137 HCV-monoinfected patients. Although the correlation was highly significant (r = 0.81; P <.001), HCV RNA titers expressed in international units per milliliter could not be standardized; statistically significant differences were observed in all quartiles. Significant variability (P <.0007) was observed in the classification of patients as having a high versus a low virus titer (cutoff, 800,000 IU/mL), which suggests that standardization in international units has low efficacy among coinfected patients. Clinicians should note that test variability precludes direct comparability of HCV RNA titers, particularly in coinfected patients with high titers

Hepatitis C virus (HCV) infection has emerged as a major contributor to liver injury and hepatic decompensation in patients with HIV infection. HCV may be detected indirectly by serological methods (e.g., EIA or recombinant immunoblot assay) or by direct testing for the presence of HCV RNA. Although EIA is recommended as a first-line method for the screening of potentially infected patients, false-positive reactions have been noted. For this reason, many clinicians may choose to use HCV RNA testing as an initial or confirmatory test or for patients whose history of risk exposures suggests increased likelihood of HCV infection. Quantitative HCV RNA assays permit both detection and enumeration, which may have prognostic value in terms of treatment outcomes. Two commercial test technologies are commonly used in the United States, although other kit-based assays and proprietary “home-brew” assays are also available. One of these commercial assays, the branched DNA (bDNA) assay (Versant HCV RNA, version 3.0; Bayer), relies on the use of signal amplification, whereas the other assay uses PCR to amplify target portions of the HCV genome (COBAS Amplicor, version 2.0; Roche Diagnostics)

Patients coinfected with HCV and HIV have been reported to have higher HCV loads than do immunocompetent control patients [1–3]. This observation may be particularly relevant in the coinfected population because test characteristics are optimized around the expected midrange for typical HCV-infected patients who have HCV infection alone. Furthermore, use of a World Health Organization (WHO) international standard for HCV quantitation was recently implemented to reduce intertest variability that made comparison of results between test technologies difficult [4–6]. Therefore, we sought to compare and contrast the relationship of the test technologies in terms of HCV RNA titers, expressed in international units per milliliter and in copies per milliliter, in samples obtained from patients with coinfection. For comparison, test characteristics within a group of patients with HCV infection alone were also evaluated

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Patients and Methods

Patient population Plasma samples from a representative, nationally distributed, HIV-infected cohort were obtained from the Adult AIDS Clinical Trials Group (studies 320 and 343). These studies were trials of highly active antiretroviral therapy for HIV infection. Samples from coinfected patients in this cohort were identified within the context of a substudy of HCV prevalence [7]. All samples were obtained before administration of highly active antiretroviral therapy. Collection of samples occurred after institutional review board approval and appropriate patient consent, including consent to store samples, were obtained at all sites. Samples were collected, separated into aliquots, and frozen at -80°C within 3 h of collection, in accordance with routine virus-collection procedures. When 2 aliquots (1 mL each) were available, paired testing was done with separate aliquots. When only 1 aliquot was available, a single freeze-thaw cycle was required. Coded samples were used for testing, and demographic data were obtained from a central data site, ensuring confidentiality. For the purpose of comparison, a random collection of samples from patients with HCV infection alone was also used. The samples had been collected in accordance with the aforementioned methodology for virus preservation. Again, a maximum of 1 freeze-thaw cycle between tested pairs occurred. These samples included specimens obtained during clinical evaluation for treatment and during treatment with IFN-based therapies. No specific evaluation or treatment protocol was associated with collection of these specimens. Demographic data for this group were not available

HCV RNA testing HCV RNA was evaluated by 2 assays, both of which were performed at the University of Cincinnati College of Medicine and its affiliated clinical laboratory; the assays were done by 2 technicians trained and certified by the assay manufacturers. A bDNA assay (Versant HCV RNA, version 3.0) was run according to its manufacturer's instructions. This updated version of the assay, which uses signal-amplification nucleic acid probe methodology, has been modified to improve sensitivity, compared with previously described versions. In brief, after extraction from serum or plasma, the viral RNA was captured to a microwell by use of a set of 5′ untranslated and core-region capture probes. Subsequent hybridization of preamplifier, amplifier, and alkaline phosphatase–labeled probes resulted in signal amplification, which was quantitated by chemiluminescence. The specimen concentration was determined from a standard curve generated with the use of known concentrations of recombinant single-stranded phage DNA. The data were reported in copies per milliliter and in international units per milliliter. The reporting range of the assay is 2500–40,000,000 copies/mL, or 520–8,320,000 IU/mL

A PCR-based assay (COBAS Amplicor HCV Monitor, version 2.0; Roche Diagnostics) currently in use at many clinical sites was also evaluated. The characteristics of this assay in testing patients with HCV infection alone have been reported [8]. This assay was also performed in accordance with the manufacturer's instructions. HCV RNA from the specimen was extracted by lysis and ethanol precipitation. A quantitation standard of known copy number was added to each specimen to permit accurate quantitation. Reverse transcription and PCR amplification of both HCV target RNA and the internal HCV quantitation standard, followed by colorimetric detection, were done with use of the COBAS Amplicor Analyzer (Roche Diagnostics). Results were reported in copies per milliliter. More recent production lots of the Amplicor 2.0 test kits are standardized against the WHO International Standard for HCV RNA, generating reporting ranges in international units per milliliter, and they include the manufacturer's conversion of data (to copies per milliliter) that is specific to the kit lot. The reporting range of the current version is 600–850,000 IU/mL, with test kit–specific approximate conversion to 1500–2,125,000 copies/mL. Sample specimens that exceeded the upper limit of the reporting range of the Amplicor assay (>850,000 IU/mL) were diluted 1 : 100 in HCV-negative serum

Statistical comparison Test results from each assay were compared within and between groups by use of appropriate parametric and nonparametric methods. Mean virus titers were compared using paired Student's t test and analysis of variance, and median virus titers were compared using a nonparametric rank sum technique (Wilcoxon). Pearson correlation was used to compare matched sample results. Categorical comparisons were made with Fisher's exact test. Selected samples obtained from patients with low and high virus titers were assayed in 4–5 replicates to determine internal variability of the assays at different virus titer ranges. All assay testing related to the replicate portion of the study was done in batches, by assay type, on 2 separate days. Statistical significance was evaluated by a 2-tailed hypothesis with an α value of.05

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Results

Study samples and demographic data Plasma samples obtained from 68 coinfected patients were tested in a paired fashion by use of both virological assays. In addition, 137 patients with HCV infection alone were evaluated for comparison. Demographics for the coinfected sample set revealed that 86% were male, with a mean age of 39.5 years. Fifty percent of patients were white, and 32% were black and non-Hispanic. The majority cited a history of injection drug use or hemophilia, with history of factor concentrate use serving as the primary risk association. The comparison data for samples obtained from patients with HCV alone did not include information that permitted demographic description

Assay comparison for the cohort coinfected with HCV and HIV Among coinfected patients, the mean HCV RNA titer derived from the use of the bDNA assay was 9.02 × 106 copies/mL. By use of the PCR-based assay, the mean virus titer was 12.73 × 106 copies/mL. A paired t test revealed significant differences between the 2 groups (P =.003), as did the nonparametric Wilcoxon signed-rank test (P <.001). Conversion of units to standardized international units per milliliter led to a calculated mean virus titer of 1.875 × 106 IU/mL for the bDNA assay and 6.1 × 106 IU/mL for the PCR assay. This difference was also highly significant according to both parametric and nonparametric testing with the paired t test and the signed-rank test, respectively (P <.001)

For the bDNA assay, determination of the association of copies per milliliter with international units per milliliter revealed 100% correlation, because one is a direct function of the other. For the PCR assay, the correlation between copies per milliliter and international units per milliliter was 0.98. Direct comparison of copy numbers from the bDNA and PCR assays led to a correlation of 0.80. Log10 conversion of copies per milliliter did not significantly alter the correlation (r = 0.83). Of interest, the correlation between test pairs was not significantly improved by use of international units per milliliter (r = 0.82) or log10 international units per milliliter (r = 0.81). Although all correlations were highly significant (P <.001), the scatterplot of these findings revealed that individual patient results were quite variable (figure 1). Moreover, it appeared that although the correlation was high, the actual virus titers reported for the 2 test technologies, expressed in international units per milliliter, were significantly different. To evaluate the relationship of test results among paired samples within discrete ranges, we determined the quartile values for each assay, dividing the sample into 4 equally sized data sets (n = 17). The mean value for each quartile is shown in table 1 for the bDNA and PCR assays

Figure 1
Figure 1

Log-transformed scatterplot showing a comparison of branched DNA (bDNA) and PCR assays performed on samples obtained from patients with hepatitis C virus (HCV) and HIV coinfection (1) and from patients with HCV infection alone (2; n = 205). Data are reported in international units per milliliter, with the ideal regression line shown

Figure 2
Figure 2

Within-test variability of branched DNA (bDNA) and PCR assays for hepatitis C virus (HCV) RNA with use of low-titer (columns 1 and 2) and high-titer (columns 3 and 4) samples. Data are reported in international units per milliliter; the mean value ± SD is shown, and the coefficient of variation for each assay type is given

Table 1
Table 1

Interquartile comparison of branched DNA (bDNA) and PCR assays for hepatitis C virus

An alternative analysis focuses on the middle 50% of the data set (n = 34) to reduce “noise” in the extremes. By use of this alternative analysis, the mean virus titer was 1,038,721 IU/mL for the bDNA assay and 3,869,559 IU/mL for the PCR assay (P <.001)

In clinical practice, a single-value cutoff is often used to define the difference between low and high virus titers. By use of the bDNA assay, the virus titers of 29.4% of our samples were less than 2 × 106 copies/mL. In contrast, by use of the PCR assay, the titers of 26.5% of the samples were less than this critical value. Of samples found to have virus titers less than 2 × 106 copies/mL by the PCR assay, only 11 (61.1%) of 18 also had virus titers of less than 2 × 106 copies/mL by the bDNA assay. Therefore, although similar percentages are less than the “critical” cutoff levels, they do not necessarily represent the same patients. Categorical testing with Fisher's exact test showed significant differences between the assays with regard to classification associated with this cutoff value (P =.0015). The same analysis was done with use of a cutoff of 800,000 IU/mL, which has been associated with poor prognosis of treatment response. Fully 52% of bDNA test sample virus titers were less than this level, whereas PCR results revealed that only 42% of sample titers were less than this value. Again, a significant difference was noted in the number of patients in these categories (P =.0007)

Assay comparison for the HCV-monoinfected cohort To determine whether the discordance observed in HIV-infected patients is relevant to patients with HCV infection alone, paired comparisons were made between virus titers in 168 unique specimens obtained from singly infected patients. Because the manufacturer of the PCR assay (Roche) did not provide a means of conversion of copies per milliliter to international units per milliliter with the early release of the Amplicor 2.0 assay, paired comparison of titers expressed in international units per milliliter was possible for only a subset (n = 137) of samples

The PCR-based assay system detected virus in 4 samples that were below the limit of detection of the bDNA assay (2.4%). The mean virus titer determined by the bDNA assay was 3.07 × 106 copies/mL. In contrast, the mean virus titer determined by PCR was 1.37 × 106 copies/mL (P <.001). Conversion of data from copies per milliliter to international units per milliliter yielded mean virus titers of 639,000 IU/mL and 607,000 IU/mL for the bDNA and PCR assays, respectively (P =.84). The overall correlation between the bDNA and PCR assays was 0.18 for virus titers in international units per milliliter (P =.03), but log10 conversion increased this correlation to 0.90 (P <.0001). Quartile analysis, which divided the cohort into 4 groups (low to high) of 34 patients (35 patients were included in the 4th quartile group), was also done. The correlations in each quartile were 0.28 (P =.11), 0.43 (P =.01), 0.09 (P =.62), and -0.15 (P =.40). Thus, the only significant correlation was in the second quartile (with ranges of 39,596–275,121 IU/mL for the bDNA assay and 26,700–2,720,000 IU/mL for the PCR assay)

Assay comparison for pooled cohorts and replicate samples When all tested paired samples were combined (n = 205), the correlation between assays for virus titers presented in international units per milliliter was 0.74 (P <.0001). This increased to 0.86 when log10 paired comparison was done. Overall summary statistics demonstrated a mean titer (±SE) of 1,049,451 ± 118,993 IU/mL (median, 406,191 IU/mL) for the bDNA assay. For the PCR assay, the mean titer (±SE) was 2,432,164 ± 378,860 IU/mL (median, 413,000 IU/mL). A log-transformed scatterplot and ideal regression line are shown in figure 1. Samples with higher virus titers demonstrated a splayed pattern that seems to be associated with the sample derivation (i.e., coinfected vs. monoinfected patients)

Replicate testing was done on 2 samples to determine the within-test variability of each assay. Samples were selected on the basis of an arbitrary classification either as low- or high-titer samples, and 4–5 replicates were assayed per sample. The means, SDs, and coefficients of variation are shown in figure 2. There was a very small coefficient of variation for the bDNA assay when virus titers were relatively low. In terms of variability, the findings of both assays with regard to the higher-titer specimen appeared to be comparable

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Discussion

Viral RNA testing has emerged as a cornerstone of management for patients coinfected with HCV and HIV. Among clinicians who care for patients with HIV infection, current paradigms rely on measurement of HIV load to determine the risk of progression and treatment response [9, 10]. These concepts do not directly translate to testing of HCV load because of the lack of association between HCV load and disease severity [11]. However, HCV RNA levels are thought to represent an important prognostic marker of response to IFN-based therapies, even with the newest generation of pegylated IFN–based regimens [12]. As in prior reports, 2 × 106 copies/mL was defined as an important prognostic cutoff level for response. Because the study by Manns et al. [12] used a proprietary multicycle PCR assay that did not provide corresponding values expressed in international units per milliliter and that was not evaluated in the study described herein, it is difficult to translate the prognostic value to the assays we described. The role of viral HCV RNA measurement in suppression therapy and histological improvement is less clear, but some studies suggest that 1-log decreases are associated with measurable histological benefit [13]. Further studies, including the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (Halt-C) Study sponsored by the National Institutes of Health, are under way to determine the efficacy of viral RNA suppression for the chronic management of patients with hepatitis C who fail to clear virus after initial therapy. Therefore, it is imperative that clinicians and staff of clinical laboratories understand the characteristics and limitations of the tests used. Furthermore, competition in assay pricing has led to intermittent alternation of test technologies by clinical laboratories. It is incumbent on clinician health providers to select a test methodology and to ensure that this method is used throughout an individual patient's course of treatment. This selection will be based on availability, cost, and the test characteristics most congruent with the treatment issue for the individual patients. For example, if a patient who is classified as a “treatment nonresponder” begins receiving a course of maintenance therapy, use of a test with a low coefficient of variation will permit improved discernment of treatment response, particularly in increments of ⩽1 log

Both the bDNA- and PCR-based assays demonstrate that coinfected patients have relatively high virus loads, as has been previously described [1, 14]. In terms of testing, the implications of this finding are related to the characteristics of the 2 assays studied. The PCR assay has a relatively low ceiling within its effective linear range. Therefore, a significant percentage of samples must be diluted before testing to obtain a true assessment of virus load. The larger linear range of the bDNA assay reduces the need for sample dilution. Dilution theoretically represents the addition of a variable that increases the variability of sample results at higher virus loads. However, the data presented herein demonstrate a divergence of correlation at high virus titers, which appears to be more related to the presence or absence of HIV than to the virus titer itself

Examination of the pooled data by use of a log-transformed scale (figure 1) suggests that interassay correlation is relatively intact to ∼5.2 log10 IU/mL for samples obtained from patients with coinfection and from patients with HCV infection alone. At this point, patients with HCV infection alone have an altered relationship, with lower virus titers recorded in PCR testing. Of interest, the relationship goes in the opposite direction when coinfected patients are evaluated. The reason for this is unclear. The findings may represent lot variability in the PCR assay, or they may suggest an added signal response when either HIV or substances commonly used to treat HIV infection are present. To determine whether lot variability and the associated multiplier for conversion from international units (m × IU/mL = copies/mL) were important factors, we stratified the samples into groups by use of the kit-specific correction factor (1.815–2.8). There was a trend for the highest multiplier (m) to be used for the monoinfected group, which suggests that virus titers expressed in international units are lower for this group, compared with the coinfected cohort, on the basis of lot variability. The intertest variation in correlation was not observed for HIV RNA versions of these assays [15]. Previous versions of the bDNA assay have been compared with the PCR assay. The overall correlation among 87 patients was 0.745, and a mathematical conversion to permit copy-number comparability was described [16]

More disturbing than the divergence in correlation is the poor lack of agreement between the reported virus loads when samples were compared in terms of titers expressed in international units per milliliter. The purpose of the WHO standard was to permit direct and reliable comparison of HCV RNA levels, regardless of the assay type. Our data clearly demonstrate the high degree of variation present. The reason for this variability is unclear. Most likely it is related to the methodology used to determine the relationship of the standards to the internal assay standards. The WHO standard was derived from a lyophilized genotype 1 sample that was accepted as the candidate standard and was assigned a titer of 105 IU/mL [4]. From this standard, different methods may be used to relate this value to the existing assay. The implications of this finding are that clinicians must remain cognizant of the assay method used when following patients through a course of therapy and that maintenance of identical test methodologies will optimize the evaluation of individual patient results. Among patients with low virus titers, this effect is relatively minimal, but among patients with high virus loads, significant variability may result in poor reliability when assessing treatment response

Although coinfected patients are unlikely to have low virus titers before treatment, patients with HCV infection alone may not have RNA that can be detected with the bDNA assay because of the difference observed at the lower limits of detection. Inability to detect lower HCV RNA levels may lead to false reports of virus clearance at the completion of a course of therapy and may necessitate use of supplementary assays with greater sensitivity, including qualitative PCR and transcription-mediated amplification. In this regard, recent reports suggest that transcription-mediated amplification may identify a significant subset of patients with detectable virus at the completion of treatment [17]. Therefore, a combination of test methodologies may be necessary to optimize management of patients with HCV infection

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Acknowledgments

We thank Natasa Rajicic for assistance in characterization of the coinfected cohort and Janet Anderson for critical statistical review

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Footnotes

  • Financial support: National Institutes of Health (grants AI-25987, AI-38858, and AI-49508). Test kits were provided by both Roche Diagnostics and Bayer Diagnostics as unrestricted gifts

  • Received November 29, 2001.
  • Revision received March 26, 2002.
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  1. Clin Infect Dis. (2002) 35 (4): 482-487. doi: 10.1086/341976
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