Shivkumar S, Peeling R, Jafari Y, Joseph L, Pant Pai N. Accuracy of rapid and point-of-care screening tests for hepatitis C, a systematic review and meta-analysis. Ann Intern Med 2012;157:558–566. (Reprinted with permission.)
Background: 170 million persons worldwide are infected with hepatitis C, many of whom are undiagnosed. Although rapid diagnostic tests (RDTs) and point-of-care tests (POCTs) provide a time- and cost-saving alternative to conventional laboratory tests, their global uptake partly depends on their performance. Purpose: To meta-analyze the diagnostic accuracy of POCTs and RDTs to screen for hepatitis C. Data Sources MEDLINE, EMBASE, BIOSIS, and Web of Science (1992 to 2012) and bibliographies of included articles. Study Selection: All studies evaluating the diagnostic accuracy of POCTs and RDTs for hepatitis C in adults (aged 18 years). Data Extraction: Two independent reviewers extracted data and critiqued study quality. Data Synthesis: Of 19 studies reviewed, 18 were meta-analyzed and stratified by specimen type (whole blood, serum, plasma, or oral fluid) or test type (POCT or RDT). Sensitivity was similarly high in POCTs of whole blood (98.9% [95% CI, 94.5% to 99.8%]) and serum or plasma (98.9% [CI, 96.8% to 99.6%]), followed by RDTs of serum or plasma (98.4% [CI, 88.9% to 99.8%]) and POCTs of oral fluid (97.1% [CI, 94.7% to 98.4%]). Specificity was also high in POCTs of whole blood (99.5% [CI, 97.5% to 99.9%]) and serum or plasma (99.7% [CI, 99.3% to 99.9%]), followed by RDTs of serum or plasma (98.6% [CI, 94.9% to 99.6%]) and POCTs of oral fluid (98.2% [CI, 92.2% to 99.6%]). Limitation:Lack of data prevented sensitivity analyses of specific tests. Conclusion: Data suggest that POCTs of blood (serum, plasma, or whole blood) have the highest accuracy, followed by RDTs of serum or plasma and POCTs of oral fluids. Given their accuracy, convenience, and quick turnaround time, RDTs and POCTs may be useful in expanding first-line screening for hepatitis C. Primary Funding Source: Canadian Institutes of Health Research.
The hepatitis C virus (HCV) is an RNA virus that belongs to the family flaviviridae and replicates in the cytoplasm of hepatocytes. The pathogenesis and clinical manifestations of viral infection are a result of the host immune responses directed against viral antigens along with cytotoxic T lymphocytes and cytokines. Natural history studies have informed that of persons with chronic hepatitis C (∼75%-85% of those exposed), ∼20% will progress to cirrhosis over a 20-year period and 5% will die from HCV-related liver disease due to decompensated cirrhosis or hepatocellular carcinoma (HCC) at a rate of 1%-4% per year.
Over 150 million people are infected with HCV worldwide, with an estimated 2.7 to 3.9 million people infected in the United States per National Health and Nutrition Examination Survey (NHANES) data,[3, 4] which may underestimate the true prevalence of chronic HCV infection due to underrepresentation of high-risk populations. Based on available data, chronic HCV is 3-5 times more prevalent than human immunodeficiency virus (HIV) infection in the U.S., and is now associated with a higher rate of all-cause mortality. The Institute of Medicine was recently charged with the task of reviewing evidence on the prevention and control of HCV and identifying underlying factors that impede the prevention and control of the disease identified three major factors: (1) lack of knowledge and awareness about chronic viral hepatitis on the part of healthcare and social-service providers; (2) lack of knowledge and awareness about chronic viral hepatitis among at-risk populations and members of the public; (3) insufficient understanding about the extent and seriousness of this public-health problem with inadequate public resources allocated to prevention, control, and surveillance programs. As a consequence, they concluded that “chronically infected people do not know they are infected” and that “infected people often have inadequate access to testing, social support, and medical management services.” It is projected that 1.76 million people with untreated HCV will develop cirrhosis, with a peak prevalence of 1 million cases occurring from the mid-2020s through the mid-2030s, that ∼400,000 will develop HCC, and that among persons untreated, 1 million will die from HCV-related complications.[6, 7] With emerging data demonstrating that successful treatment of hepatitis C results in significant improvement in health-related quality of life and a decreased risk for decompensated cirrhosis, HCC, the need for liver transplantation, and liver-related mortality, the rationale for identifying and treating infection is clearly evident.
With the advent of direct-acting antiviral agents (DAAs) and the prospect of interferon-free regimens in the near horizon, there is now more hope than ever for patients chronically infected with HCV. Sustained virologic response rates (SVR) of treatment-naïve patients who receive current first-generation protease inhibitor-based triple therapy with telaprevir or boceprevir are 73% and 67%, respectively.[8, 9] Interferon-free treatment trials have progressed far beyond proof of concept to a reality of the near future of SVRs exceeding 90%, including encouraging results in “difficult-to-treat” populations such as prior null responders to peg-interferon and ribavirin, patients with liver cirrhosis, individuals with HCV-HIV coinfection, and those who are interferon ineligible or intolerant.[11-15]
The first step toward achieving an improvement in clinical outcomes for chronic HCV infection is testing and identification of those chronically infected, noting that as many as two-thirds of this cohort remain undiagnosed. The Center for Disease Control and Prevention (CDC) testing guidelines include use of a screening assay followed by confirmatory testing. Current Food and Drug Administration (FDA)-licensed or approved anti-HCV screening test kits utilized in the U.S. include three immunoassays, as outlined in Table 1, all of which use HCV-encoded recombinant antigens. Supplemental/confirmatory tests include a serologic anti-HCV assay, or nucleic acid tests (NATs) for qualitative detection of HCV RNA using reverse transcriptase polymerase chain reaction (RT-PCR) amplification, also outlined in Table 1. RIBA 3.0 uses both HCV-encoded recombinant antigens and synthetic peptides. This testing method, although efficacious, is limited by time requirement and cost.
|Screening test kits|
|enzyme immunoassay (EIA)||Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, IL|
|enzyme immunoassay||ORTHO HCV v. 3.0 ELISA, Ortho-Clinical Diagnostics, Raritan, NJ|
|enhanced chemiluminescence immunoassay (CIA)||VITROS Anti-HCV assay, Ortho-Clinical Diagnostics, Raritan, NJ|
|serologic anti-HCV assay||HCV RNA strip immunoblot assay Chiron RIBA HCV 3.0 SIA, Chiron Corp., Emeryville, CA|
|nucleic acid test (NATs)||AMPLICOR Hepatitis C Virus (HCV) Test, v. 2.0|
|nucleic acid tests||COBAS AMPLICOR Hepatitis C Virus Test, v. 2.0 Roche Molecular Systems, Branchburg, NJ|
Shivkumar et al. propose that convenient, quality-assured antibody-based rapid diagnostic tests (RDTs defined as those requiring sample processing and refrigerators for storage) and point-of-care tests (POCTs defined as tests that were easy to use, were robust at higher temperatures, and had long shelf life >6 months) could facilitate preliminary screening.
In this systematic review, Shivkumar et al. provide the first comprehensive examination of the evidence supporting the diagnostic performance of globally available RDTs and POCTs for HCV screening. They have specifically reported on sensitivity, specificity, likelihood ratios, and diagnostic odds ratios of available RDTs and POCTs that screen for hepatitis C in oral fluid, whole blood, serum, or plasma specimens from data available over a 20-year time period from 1992-2012. All tests evaluated could be performed in less than 30 minutes. They conducted a meta-analysis of 18 studies and compiled data on the characteristics of the study population, including sampling strategies, risk for hepatitis C, sample size, inclusion and exclusion criteria, specimen tested (oral fluid, whole blood, serum, or plasma), whether the test was an RDT or a POCT, reference standard, funding sources, and any reported conflicts of interest. Raw data including number of true positives, true negatives, false positives, and false negatives were extracted. They noted whether RDT/POCT test results were compared to a perfect (CDC algorithm) or imperfect reference standard. Tests were stratified as: (1) POCTs of serum or plasma; (2) POCTs of whole blood or finger-stick blood; (3) RDTs of serum or plasma; and (4) POCTs of oral fluid. They reported that POCTs of blood demonstrated the highest accuracy, followed by RDTs of serum or plasma, and then by POCTs of oral fluids (detailed statistical data as outlined in Table 2). The authors speculate that POCTs of oral fluids showed a slightly higher false-negative rate than POCTs of whole blood or finger-stick blood due to the lower concentration of antibodies or the weaker binding in oral fluid than in blood samples. This study is limited by detection bias due to lack of blinding in included studies, heterogeneity of reference standards, unmeasured effect of coinfection or genotype, and lack of adequate sensitivity analyses that focused on the accuracy of individual tests.
|Test Type||Sensitivity (95%CI)||Specificity (95%CI)||Positive LR (95%CI)||Negative LR (95%CI)||DOR (95%CI)|
|POCT blood-serum or plasma||98.9 (96.8-99.6)||99.7 (99.3-99.9)||342.7 (140.5-836.4)||0.01 (0.004-0.03)||33800.4 (5862.3-194,885.2)|
|POCT blood-whole blood or finger-stick blood||98.9% (94.5%-99.8%)||99.5% (97.5%-99.9%)||208.7 (38.3-1136.6)||0.01 (0.002-0.06)||19,438.6 (858.4-440,169.7)|
|RDTs of serum or plasma||98.4% (88.9%-99.8%)||98.6% (94.9%-99.6%)||68.4 (19.1-246.2)||0.02 (0.002-0.12)||4,135.2 (517.5-330,421.1)|
|POCTs of oral fluids||97.1% (94.7%-98.4%)||98.2% (92.2%-99.6%)||54.8 (11.9-251.4)||0.03 (0.01-0.06)||1,870.9 (263.9-13,263.6)|
On June 25, 2010 the FDA approved the use of OraQuick HCV Rapid (OraSure) Antibody Test with venipuncture (POCT of blood). This test uses an indirect immunoassay method in a lateral flow device to detect antibodies to HCV in whole blood by way of finger stick, serum, or plasma by way of venipuncture, or oral fluid by way of swab. In this device, antigens from the core, NS3, and NS4 regions of the HCV genome are immobilized on a single test line on a nitrocellulose membrane; antibodies reactive with these antigens are visualized by protein-labeled colloidal gold. The time required to perform the assay is between 20 and 40 minutes. Efficacy data of OraSure reveal a sensitivity of 99.3% (98.1%-99.7%) and specificity of 99.5% (98.4%-99.8%). The test costs ∼$17 and requires training prior to use by clinical staff. CDC screening guidelines for HCV were recently updated to include all persons born between the years of 1945-1965 in addition to previously targeted populations including current or prior intravenous drug users, persons who received clotting factor concentrates prior to 1987, or who received blood, blood components, or an organ transplant prior to July 1992, persons who were ever on long-term hemodialysis, persons with persistently abnormal aminotransferase levels, and those with known exposures.
New screening approaches such as POCTs appear to be uniquely positioned to facilitate on-demand screening to high-risk populations within gastroenterology endoscopy centers, drug treatment centers, HIV clinics, community health centers, or hemodialysis centers, particularly in patient cohorts with known poor follow-up or linkage to care. Although POCTs have the potential to increase overall screening, this remains unproven, and additional data are needed to examine their role in facilitating age-based cohort screening in low-risk primary care settings. Further studies are additionally needed to evaluate the downstream effects of POCTs/RDTs on patient-centered outcomes including acceptability and preference, and on clinically meaningful outcomes such as rate of screening and identification, time to confirmatory testing, linkage to care, evaluation by treating physician for HCV, initiation of antiviral therapy, and treatment-related disease outcomes.
AnnMarie Liapakis, M.D.
Joseph K. Lim, M.D.
Yale Liver Center Yale University School of Medicine New Haven, CT