Diagnostic accuracy of tests to detect Hepatitis C antibody: a meta-analysis and review of the literature

Hepatitis C is a liver disease caused by the hepatitis C virus (HCV) that causes acute and chronic infection [1, 2]. An estimated 71 million people had chronic hepatitis C infection worldwide in 2015 [3]. Viral hepatitis caused 1.34 million deaths in 2015, a number comparable to deaths caused by tuberculosis and higher than those caused by HIV [3]. The introduction of direct-acting antivirals (DAAs) has led to a sustained virological response (SVR) in greater than 90% of treated individuals [4, 5]. DAAs are now recommended by the World Health Organization (WHO) [1] and many other HCV treatment guidelines [1]. DAAs will not only improve SVR rates but also may simplify HCV management algorithms and allow smaller health facilities to manage HCV-infected individuals [6]. Despite the availability of effective treatment, most HCV-infected individuals remain undiagnosed and untreated [7]. Left untreated, approximately 15–30% of individuals with chronic HCV infection progress to cirrhosis, leading to end-stage liver disease and hepatocellular carcinoma [1, 2].

In February 2016 the WHO updated the guidelines for the screening, care, and treatment of persons with chronic hepatitis C infection [1]. These guidelines included recommendations on whom to screen for HCV and how to confirm HCV infection, but not which tests are optimal for initial screening. Advances in HCV detection technology create new opportunities for enhancing screening, referral, and treatment. Previous systematic reviews on HCV infection have focused on treatment response [8, 9], clinical complications [10], and epidemiology [11, 12]. Two previous systematic reviews on hepatitis C testing have focused on evaluating point-of-care tests compared to EIAs and other reference tests [13, 14]. We have undertaken a further systematic review and meta-analysis to generate pooled sensitivity and specificity of rapid diagnostic tests used to detect HCV antibody (HCV Ab), and to inform the development of recommendations on serological testing in the 2017 WHO testing guidelines [15].

There is a global need to expand HCV diagnostic testing. In this meta-analysis, we found HCV Ab RDTs, including those using oral fluid, showed a high overall sensitivity and specificity compared to laboratory-based EIAs. This extends the literature by including several new studies that were not included in prior reviews, including a sub-analysis that focused on use of RDTs with oral fluid. In addition, the evidence collected from this review was used to inform recommendations in the 2017 WHO guidelines on testing for hepatitis B and C [15]. The evidence for generally high levels of diagnostic accuracy across most brands from this systematic review and meta-analysis supported a strong recommendation for the use of HCV RDTs in WHO testing guidelines [15].

Our data suggest that RDTs can be used for HCV Ab detection in a wide range of clinical settings. For example, for all the included studies, 17 were conducted among general populations, 20 were among high risk populations, and 17 were among hospitalized patients (two studies included two kinds of populations). High HCV Ab RDTs sensitivity and specificity were observed across multiple different populations (including general population, high risk populations, and hospital patients), which is consistent with previous systematic reviews [13, 14, 63]. The use of an EIA to detect HCV Ab followed by NAT to confirm active infection is standard practice for diagnosis of HCV infection and recommended by the US Centers for Disease Control and Prevention and the WHO [64, 65]. However, despite these recommendations, HCV Ab EIA assays have not been widely used because of the complexity of laboratory-based assays, long turnaround time, high cost and requirements for specialized apparatus and trained technicians [13]. To overcome these barriers, RDTs for HCV Ab screening were developed [66]. They obviate the need for multiple follow-up appointments, shorten wait times, and allow for the simplification and decentralization of testing (Additional file 8). However, it is essential for policymakers, government officials, and health care practitioners engaged in HCV screening, care, and treatment to be aware that the performance of individual RDTs for detection of HCV Ab vary widely. Individual diagnostic accuracy for specific brands should be examined to ensure acceptable performance.

Our data suggest that oral fluid RDTs have high sensitivity and specificity. This is consistent with other literature [67]. Tests that can be used with non-invasive samples allow testing to be decentralized further and can be used in outreach settings [68]. Our data suggest that oral tests have a slightly lower pooled sensitivity (94%, 95%CI: 93%-96%) compared to blood-based tests (98%, 95% CI: 97%-98%) but comparable specificity. Oral HCV Ab RDTs tests may be particularly useful in contexts where venepuncture may be difficult, such as subsets of people who inject drugs which have difficult veins to access.

With the increasing availability of DAAs, countries are seeking testing kits with high sensitivity and specificity, in order to allow them to scale up HCV Ab screening, especially among at-risk populations. The advantages and disadvantages of EIAs and RDTs are well established [15]. Performance, cost, and accessibility need to be considered. Determining which tests to deploy at which level of the health care system and for what settings require policy makers to consider the different attributes of laboratory-based EIA versus blood-based or oral RDTs. Potential trade-offs include slightly lower accuracy for greater uptake and acceptability of testing, provision of test results, and linkage to care. Each country needs to decide on which trade-offs or compromises are acceptable, based not only on disease prevalence and the health care infrastructure but also on technical, socioeconomic, cultural, behavioral considerations. For example, they need to be clear on whether it is acceptable to buy Test X which is 10% less accurate than Test Y but is considerably cheaper so that many more people can be tested. In addition, although oral RDTs are less accurate than blood-based RDTs, it may be that oral RDTs will be more acceptable for outreach testing and accessing at-risk populations and allow the control programs to identify more HCV cases. In a low prevalence setting, even a test with 98% specificity can yield more false positive than true positive results. All these trade-offs can be modeled to give an estimate of the cost-effectiveness and potential impact of different strategies for HCV Ab screening.

Our review also underlines some of the common methodological problems encountered in evaluating diagnostic accuracy. Cross-sectional or case–control designs were used by all 52 included studies, introducing a potential risk of bias. These studies used a broad range of reference standards, which makes the pooled performance data less meaningful. Within the evaluation of diagnostic accuracy, even cross-sectional studies in patients with diagnostic uncertainty and direct comparison of test results with an appropriate reference standard can be considered high quality [69]. The majority of the included studies used convenience sampling. In this review, we excluded panel studies because they are not based on clinical settings and our purpose was to generate data that would be relevant in clinical settings as part of detection of HCV Ab.

Most studies that reported HIV or HBV co-infection only reported the test performance of the kits among all samples, instead of disaggregated diagnostic accuracy. There were insufficient data from two studies to undertake a subanalysis based on HIV co-infection. It may be important for policymakers to know the diagnostic accuracy of HCV Ab tests among individuals with co-infections, particularly HIV co-infection [70], and this requires further research among co-infected individuals.

Our study is subject to several limitations. First, we included studies conducted among the general population, hospital patients, and high risk populations. Diagnostic performance can be influenced by disease prevalence and HCV prevalence is variable among these different populations [71, 72]. Second, we detected substantial heterogeneity that could influence our confidence in the review findings [73], but addressed this problem through a series of sub-group stratified analyses. Third, about 20 brands of RDT kits were used in the included studies, and their performance varies considerably. This limited our ability to summarize the accuracy of different brands, with the exception of comparing OraQuick to other brands. Another concern is publication bias, as studies with poor test performance may be less likely to be published, leading to distorted estimates of accuracy [74]. Fourth, since not all HCV RDTs can be performed from oral fluid/capillary whole blood (some require plasma/serum), and some of them require a cold chain for storage and transport, the direct comparison between EIA and RDTs in this meta-analysis would be less meaningful. Fifth, we should note that not all test kits are still on the market and that versions of the tests included in this meta-analysis may have since changed. Finally, statistical heterogeneity was present. But is common in meta-analyses of diagnostic studies. Additional research is important for understanding why the tests perform more poorly in certain populations or settings.

RDTs, including oral tests, have excellent sensitivity and specificity compared to laboratory-based methods for HCV antibody detection across a wide range of settings. National policymakers should consider the performance, cost and accessibility of RDTs into consideration, when selecting assays for use in their national testing algorithms.