Real-world Utility of HCV Core Antigen as an Alternative to HCV RNA Testing

Implications for Viral Load and Genotype

Kevin G. Pollock; Scott A. McDonald; Rory Gunson; Allan McLeod; April Went; David J. Goldberg; Sharon J. Hutchinson; Stephen T. Barclay

Disclosures

J Viral Hepat. 2020;27(10):996-1002. 

In This Article

Abstract and Introduction

Abstract

Following positive serology, the gold standard confirmatory test of hepatitis C virus (HCV) infection is detection of HCV RNA by PCR. We assessed the utility of HCV core antigen testing to identify active infection among those positive for anti-HCV antibodies, when introduced to routine testing. We identified serum samples that were tested at a single laboratory in Scotland from June 2011to December 2017. Serum samples testing positive for HCV antibodies (HCV Ab positive) followed by reflex HCV core antigen (Ag) testing during the study period were identified. Those patients for whom a PCR test was requested on the baseline sample were also identified. For this group, the sensitivity and specificity of HCV Ag as a diagnostic tool were assessed using HCV PCR as gold standard. In our cohort of 744 patients, we demonstrated a sensitivity of 82.1% (95% CI 77.1%-86.2%) and a specificity of 99.8% (95% CI 98.6%-100%). Genotype 3 was associated with increased odds of a false-negative result (OR = 3.59, 95% CI: 1.32–9.71), and reduced odds of a false negative were associated with older age (odds ratio (OR)=0.92, 95% CI: 0.88–0.97 per year) and viral load (OR = 0.10, 95% CI: 0.05–0.21 per log10 IU/ml). While the implementation of HCV core antigen testing for diagnosis could lead to significant cost savings in national screening programmes, our data suggest that a significant proportion of HCV-infected individuals may be missed. These findings have implications for HCV diagnosis and determination of viral clearance after treatment, particularly in low- and middle-income regions, where genotype 3 is prevalent.

Introduction

Infection with hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, and it has been estimated that approximately 70 million people were chronically infected in 2016.[1] In recent years, direct-acting antiviral (DAA) drugs for chronic HCV infection have been welcomed as an effective intervention in reducing HCV-related liver disease burden.[2,4] However, a major barrier to HCV treatment and elimination[5] is low rates of testing and diagnosis, with large variations across different regions, countries and at-risk populations. Therefore, improved HCV screening is required to identify people with HCV, to allow improved linkage to care and treatment,[6] with a view to meeting the World Health Organisation (WHO) goals of eliminating HCV as a public health concern by 2030.[7]

The gold standard algorithm for diagnosis of HCV infection requires serologic testing for antibodies, and in those who are tested as being antibody-positive, further confirmation of viral replication by HCV RNA testing.[8] HCV core antigen testing, as an alternative to RNA testing, has the potential to reduce diagnostic costs, if it is both sensitive and specific enough without the need for supplementary PCR testing.[9] For cost reasons, HCV core antigen testing has been recommended for use in low- to middle-income countries (LMICs).[6] However, there are limited data on the performance of core antigen testing when introduced as routine testing and how this concomitantly links patients to appropriate clinical management.

The sensitivity of HCV core antigen detection has been demonstrated to be lower than that of HCV RNA detection by PCR-based methods. Most studies have reported a lower limit of detection for HCV core antigen at an equivalent of 3000–10 000 IU/ml of HCV RNA compared with 12–15 IU/ml HCV RNA for detection by PCR.[10–12] Scotland is well placed to evaluate real-world diagnostic performance as has well-established surveillance of HCV covering testing, diagnosis and treatment.[13,14] In addition, HCV diagnostic testing is provided in a small number of National Health Services (NHS) laboratories only, with no commercial laboratories offering HCV testing within Scotland. The West of Scotland Specialist Virology Centre (WSSVC) provides HCV RNA testing to NHS Greater Glasgow and Clyde Health Board (NHS GG&C), where 25% and 35% of Scotland's general and HCV diagnosed populations resides, respectively.[15]

The WSSVC introduced reflex antigen testing as the standard diagnostic test to detect ongoing infection among HCV antibody-positive patients in NHS GG&C in 2011. Antigen-positive patients were diagnosed with active infection, and a report issued recommending referral to treatment services (where a PCR test would be performed as part of pre-treatment assessment).[16] For antigen-negative patients, reports indicated the absence of ongoing infection but recommended a further sample was requested for PCR testing to confirm. Alternatively, a PCR test could be requested on the same sample by contacting the laboratory. We aimed to assess the utility of HCV core antigen testing when introduced into standard practice by comparing the accuracy of antigen compared with PCR when both tests were performed on the same sample. Our principal objective was therefore to estimate the sensitivity and specificity of HCV Ag using HCV RNA status from PCR testing as the gold standard.

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