Hepatitis C Core Antigen Testing: Still an Effective Diagnostic Method for Global Elimination of Hepatitis C

(See the Major Article by Bertisch et al on pages 653–9.)

Chronic hepatitis C infection affects 71 million people worldwide and is one of the most common causes of liver failure and transplantation [1, 2]. The management of chronic hepatitis C virus (HCV) has changed dramatically since the advent of direct-acting antivirals (DAAs). The development of DAA therapy resulted in all-oral regimens with high rates of sustained virologic response (SVR). Treatment with DAAs is well tolerated compared to previous regimens with injectable interferons that were poorly tolerated and resulted in SVR rates of less than 50% [3]. Since 2016, the development of pangenotypic DAAs has created a diverse arsenal for providers to treat patients with HCV. These regimens have demonstrated equal SVR rates regardless of race, gender, genotype, cirrhosis, or human immunodeficiency virus coinfection [4–7]. Due to the success of DAAs, the World Health Organization has established a goal for global elimination of viral hepatitis by 2030. This will be achieved, in part, by pharmaceutical companies that outsource manufacturing of generic DAAs to low- and middle-income countries [8]. The costs of these drugs have also been lowered [9], allowing for successful nationwide elimination programs to be implemented. In 2013, manufacturers in Egypt reduced the price of a 12-week course of treatment from an average cost of $84 000 per patient in the United States to $84 per patient in Egypt. Between 2013 and 2016, 1.6 million Egyptians received HCV treatment—more than all the patients treated in the United States and Europe combined during that period [10].

Improved accessibility and lowered costs of DAAs globally have shifted the HCV continuum of care so that the focus is on developing point-of-care, highly sensitive, low-cost HCV testing modalities. A major focus has been on reducing frequent laboratory monitoring (including viral load) during treatment, which surpasses the cost of DAAs in many countries. The HCV core antigen (Ag) test has been shown to be a cost-effective method for confirming HCV infection compared to the use of reverse-transcription polymerase chain reaction (RT-PCR) for HCV RNA. It is estimated that 90% of the positive HCV RNA samples have an RNA >10 000 IU/mL, which falls in the sensitivity range of HCV core Ag assays. The HCV Ag test has also been proposed as a substitute for HCV RNA in determining SVR [11]. However, concerns have been raised regarding the use of HCV core Ag alone since patients with a very low viral load (VLVL), that is, VL <3000 IU/mL, may have a false-negative HCV core Ag test result, and these patients would be missed during screening [12, 13].

In this edition of Clinical Infectious Diseases, Bertish et al report on their retrospective analysis of characteristics of more than 2500 patients in the Swiss Hepatitis C Cohort Study (SCCS). The study is novel in that it evaluated VLVL detected by RT-PCR and its correlation to positive HCV Ag in a cohort of patients who were HCV treatment naive, whereas most analyses have been performed in HCV treatment-experienced patients. The study showed that the prevalence of VLVL in the SCCS was about 5%, consistent with other reports in treatment-experienced patients. Twenty-four of 133 patients with VLVL had liver cirrhosis (18%), and of those 24 patients, plasma samples were available for 13. HCV Ag was reactive in only 4 of these patients (17% of whom had VLVL and cirrhosis), and all 24 patients with cirrhosis and VLVL had either excessive alcohol consumption or immunosuppression.

The results of this study may cause readers to be hesitant to use the HCV Ag test as a screening modality since its sensitivity is lower for VLVL than that of RT-PCR, missing HCV diagnosis in patients with cirrhosis. The implications for false-negative HCV diagnoses in patients with cirrhosis are grave, as HCV cure can decrease the incidence of hepatocellular carcinoma and overall mortality in these patients. However, fibrosis screening in a cohort is important to identify all patients with cirrhosis, not just those with HCV infection. The study demonstrates that VLVL is more likely to be observed in patients with cirrhosis and excessive alcohol use; it would be appropriate for these patients to be screened for HCV using RT-PCR. Of note, immunosuppression is usually associated with HCV replication and high plasma viral loads, so most guidelines recommend that these patients undergo HCV screening with RT-PCR as well [14]. The Bertish et al study emphasizes the need for a population-based pilot study that will further investigate comparative data using HCV Ag and RT-PCR prior to the launch of large-scale screening programs with HCV Ag alone.

As the authors note, assays with improved sensitivity ranges to detect VLVL are in development. For now, the benefits of the HCV Ag assay as a rapid, point-of-care test in population-based screening still outweigh the risk of a small number of false negatives in a subset of patients since the prevalence of VLVL cohorts is <5%. The Bertish et al study highlights the importance of the likelihood of missing a small fraction of patients with VLVL, a risk that may have to be considered when HCV Ag is used for rapid, large-scale screening. This is a strategy that has gained more significance worldwide in attaining the goal of global elimination of HCV by 2030.

Note

Potential conflicts of interest. S. K. reports payments from Merck, Gilead, and Arbutus. P.M. has no potential conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.