The care cascade for hepatitis C virus and prognosis of chronic hepatitis C patients treated with antiviral agents in a tertiary hospital

The current prevalence of chronic hepatitis C in Korea is estimated to be approximately 0.6 to 0.8% [1]. Among Korean patients afflicted with hepatitis C, genotype 1b and 2 are the most common types [1]. Overall sustained virologic response rate at 12 weeks (SVR₁₂) has improved significantly since the treatment regimen of hepatitis C was switched from interferon drugs to direct-acting antivirals (DAAs), and the efficacy of DAA combination therapy has become more potent. Moreover, DAAs that can treat pangenotypes such as glecaprevir/pibrentasvir (G/P) have been introduced [2]. Nevertheless, patients with chronic hepatitis C often experience DAA treatment failure in the real world. Factors associated with the failure of DAAs include the genetic subtype of chronic hepatitis C, hepatitis C virus (HCV) resistance-associated substitution, liver cirrhosis, a history of previous hepatitis C treatment failure, old age, decreased liver function, and decreased renal function [3]. Furthermore, eradication of HCV by antiviral treatment does not mean that the risk of hepatocellular carcinoma (HCC) is completely eliminated. In particular, patients with advanced fibrosis (F3) or cirrhosis (F4) have a substantial residual risk of HCC, and surveillance is required [4].

It is known that HCC can occur after SVR in the liver of advanced fibrosis (F3). Therefore, early diagnosis and treatment of chronic hepatitis C through a surveillance program is important. Recently, one studied published hepatitis C virus care cascade in one Korea tertiary institution [5]. However, except this study, few studies have analyzed the frequency of HCV ribonucleic acid (RNA) testing among patients who are anti-HCV positive at a tertiary hospital and the proportion of patients who receive HCV treatment in real practice. Therefore, this study aimed to analyze the diagnosis process, treatment results, and prognosis of chronic hepatitis C through a complete investigation of anti-HCV positive patients from January 2005 to December 2020 at a tertiary hospital.

The World Health Organization(WHO)’s 2030 global elimination goals for HCV are that 80% of eligible patients are treated, along with a 90% reduction in the incidence of new infections and a 65% reduction in liver-related mortality [5]. However, approximately 400,000 deaths occur annually owing to liver failure and HCC due to chronic HCV infection (currently estimated to be 71 million people worldwide). An estimated 1.75 million people each year are burdened with the disease owing to new HCV infection [6].

With the introduction of DAAs, the goal of hepatitis C elimination has become more attainable [7]. It is paramount to establish an initial screening and treatment program because HCC may occur depending on whether advanced fibrosis (F3) is present at the time of DAA treatment [8]. Efforts in each country to establish screening and treatment for HCV elimination are continuing every year. For example, in April 2015, Georgia, a region with a high prevalence of hepatitis C virus infection, launched the world’s first HCV elimination program to reduce the prevalence of HCV by 90% by 2020 with technical assistance from the Centers for Disease Control and Prevention [9]. Egypt implemented an effective model for HCV screening and treatment delivery in recent years. Between 2014 and 2017, the Egyptian National Committee for Control of Viral Hepatitis provided free DAA-based HCV treatment to more than two million people. As the number of patients with HCV declined in 2018, the Commission introduced a national HCV screening pilot rather than continuing DAAs treatment [10, 11]. On the other hand, in Korea, where the prevalence is low compared to regions with high prevalence, such as Georgia and Egypt, awareness of chronic hepatitis C is low.

Our study had several clinical implications. First, this study assumes significance in that we comprehensively evaluated the number of anti-HCV positive patients who were confirmed and treated at a tertiary medical institution in South Korea. South Korea has not yet implemented a national hepatitis C elimination program. Amongst the anti-HCV positive people included in the current study (3,253), only 1,177 (36.2%) underwent HCV RNA testing for HCV confirmation (Fig. 1). This ratio is considerably lower than that of approximately 67.3% of anti-HCV positive patients in Egypt from October 2018 to September 2019 [5, 12]. Although it is not known exactly why the patient was not tested for HCV RNA, it can be inferred by analyzing the characteristics of the anti-HCV positive patients who were not tested for HCV RNA. There were more cases of preoperative examination than cases of health check-up or symptomatic hepatitis (Supplementary table 1). In the past, it can be assumed that surgery department did not have a proper referral system to the gastrointestinal department, and patients’ awareness of hepatitis C was low. The second reason for less number of people receiving HCV RNA testing is probably due to the lack of understanding of the pathophysiology of chronic hepatitis C and the HCV treatment processes. In most cases, anti-HCV positive results were found incidentally during screening for other purposes such pre-op evaluation or check-up, and not in the acute HCV infection status without any symptom. Patients are likely to be unaware of the need for HCV RNA testing and follow-up for treatment. Among patients with HCV infection confirmed by HCV RNA, the proportion of patients who received treatment was only 57.6%, lower than that in Egypt. This phenomenon might be owing to the cost of chronic hepatitis C treatment itself and a lack of understanding of the hepatitis C treatment process and prognosis.

Second, the cumulative incidence of HCC showed that liver cirrhosis at the time of diagnosis of chronic hepatitis C was more statistically significant than whether SVR₁₂ was reached (Figs. 2, 3 and 4). These results are consistent with the results of previous reports [13‐17]. It is clear that persistent HCV infection is the strongest factor for HCC in that it induces fibrosis progression and cirrhosis because HCV could induce carcinogenesis indirectly through inflammatory responses or directly via its transcripts or proteins [18, 19]. However, some residual HCC risk could persist after HCV eradication, because HCV-related epigenetic changes and monoclonal micronodules that occur before SVR₁₂ are maintained indefinitely even after SVR₁₂ [20]. Second, residual fibrosis may progress to advanced fibrosis or cirrhosis owing to other hepatotoxic injury sources (e.g., alcohol, drug, non-alcoholic steatohepatitis) [8]. Therefore, it is necessary to continue HCC surveillance even after reaching SVR₁₂ in patients with advanced fibrosis or cirrhosis.

Our study has several limitations. First, this study does not specifically suggest which group to perform the HCV antibody test on as a screening test from a cost-effective point of view. Since the treatment of chronic hepatitis C reduces the risk of HCC and cirrhosis, it is evident that a national screening project to raise people’s awareness should be implemented. However, this study has a drawback in that we did not examine whether screening tests should be performed for all people or only certain groups. Second, this study showed that HCC and liver cirrhosis risk existed even in patients who achieved SVR but did not provide more specific risk stratification for HCC. This is thought to be because our study was conducted over a wide period, from the early days of interferon to the latest DAA treatments, and cirrhosis was only evaluated by abdominal ultrasound. Recently, various tools have been developed to predict HCC risk after SVR, from elastography [17] that can specifically measure the degree of fibrosis to deep learning HCC risk prediction models that use age, sex, race, HCV genotype, and 24 laboratory tests [21]. The HCC surveillance strategy of patients who have reached SVR₁₂ requires the introduction of a more specific and easy-to-use model. Third, various clinical characteristics, including their liver function test, the presence of underlying liver disease et al. could not be collected in detail. Fourth, selection bias may occur because only the treated patients were targeted. Fifth, the sample size was small and there may be statistical errors that may occur. For example, the cumulative incidence of HCC and liver cirrhosis does not appear to be statistically related to the presence or absence of SVR in the Fig. 3. This phenomenon is considered to be a statistical error caused by the small number of SVR (-) group with 33 and 22 patients (excluding subjects with liver cirrhosis at baseline), compared to SVR ( +) group. However, the statistical p values of Fig. 3A and B were 0.084 and 0.051, respectively, and it was confirmed that there was the trend difference between SVR( +) and SVR(-) group, as p value corresponded to less than 0.1. Clearly, since our study is the retrospective single-institution study, the study population is smaller than other large center multicenter cohort studies, and there are limitations in terms of data availability. However, we are sure that our study could be helpful in establishing guidelines for the current situation in South Korea, which has no public health interventions.

In conclusion, owing to the introduction of DAA, a high SVR₁₂ of chronic hepatitis C was achieved overall, but the proportion of anti-HCV positive patients who received HCV RNA testing and treatment was not high at our tertiary medical institution. This is related to an overall lack of awareness of the purpose and necessity of the HCV screening test and chronic hepatitis C treatment process. Ultimately, it appears that a national screening project should be implemented. Our study shows that by using a public health approach, the care cascade can be greatly improved, and more patients who are anti-HCV positive can be diagnosed and treated with DAAs. For patients with chronic hepatitis C accompanied by baseline cirrhosis, HCC surveillance after SVR₁₂ is recommended, and an efficient strategy based on more specific risk stratification is required.