Seo, Yun, Li, Lee, Han, and Park
Clin Mol Hepatol 2017; : cmh.2016.0052.
Published online: March 3, 2017
Barriers to treatment of failed or interferon ineligible patients in the era of DAA: single center study
Kwang Il Seo1, Byung Chul Yun1, Weiquan James Li1, 2, Sang Uk Lee1, Byung Hoon Han1, Eun Taek Park1
Received August 11, 2016 Revised January 9, 2017 Accepted January 16, 2017
Copyright © 2017 by The Korean Association for the Study of the Liver
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Interferon-based treatment is not appropriate for a large number of patients with chronic hepatitis C for various medical and social reasons. Newly developed directly acting antivirals (DAAs) have been used to treat chronic hepatitis C without severe adverse effects and have achieved a sustained viral response (SVR) rate of 80-90% with short treatment duration. We were interested to determine whether all patients who failed to respond to or were ineligible for interferon-based therapy could be treated with DAAs.
Medical records of patients with positive serum anti-hepatitis C virus (HCV) or HCV RNA between January 2009 and December 2013 were reviewed. Demographic, clinical, and treatment data were collected for analysis.
A total of 876 patients were positive for both anti-HCV and HCV RNA. Of these, 244 patients were eligible for interferon, although this was associated with relapse in 39 (16%) of patients. In total, 130 patients stopped interferon therapy (67% adverse effects, 28% non-adherent, 4% malignancy, 1% alcohol abuse) and 502 patients were ineligible (66% medical contraindications, 25% non-adherent, 5% socioeconomic problems). Among 671 patients who were ineligible for or failed to respond to interferon therapy, more than 186 (27.7%) could not be treated with DAA due to financial, social, or cancer-related conditions.
Newly developed DAAs are a promising treatment for patients with chronic hepatitis C who are ineligible for or failed to respond to interferon-based therapy. Nevertheless, not all chronic hepatitis C patients can be treated with DAAs due to various reasons.
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The prevalence of blood-borne HCV infection is estimated to be about 3% worldwide. Although DAAs that target nonstructural protein of HCV have potent antiviral efficacy and few adverse effects, the eradication of HCV is supposed to be difficult because most acute and chronic HCV infection is asymptomatic, and screening programs are limited in most countries. In a prospective, multicenter cohort at five university hospitals from January 2007 to December 2011, 1,173 patients age >18 years who were positive for anti-HCV antibody were enrolled to investigate the epidemiological and clinical characteristics of HCV infection of Korea. The rate of antiviral therapy for HCV was 42.8% of the HCV cohort . At our center, 876 patients were diagnosed in a chronic viremic state, and 374 (42.6%) were treated with interferon-based therapy.
PegIFN-α and ribavirin combination therapy have absolute contraindications including uncontrolled depression; psychosis or epilepsy; pregnancy or couples unwilling to use adequate contraception; severe concurrent medical diseases; and co-morbidities including retinal disease, autoimmune thyroid disease, and decompensated liver disease . After considering the contraindications for interferon-based therapy, a large number of patients diagnosed with chronic hepatitis C could not have treatment. Therefore, the proportion of patients initiating treatment was 31.0% in Swiss cohort study , and 33.0% in Danish cohort study .
According to Falck-Ytter et al. , 72% of chronic hepatitis C patients were not treated. Of these, 37% did not adhere to medical recommendations, 34% were medically or psychologically ineligible, 13% had ongoing alcohol or drug abuse, and 11% refused treatment. Only 28% of chronic hepatitis C patients were treated and 13% had a sustained viral response. Narasimhan et al.  retrospectively reviewed the charts of all HCV patients who underwent liver biopsies. About 60% were not treated with interferon-based therapy because of loss to follow-up or non-compliance (31%), patient preference (22%), etc. In other words, chronic hepatitis C treatment largely depended on patients’ intention to treat, not medical decisions made by doctors. Restrepo et al.  reported that approximately 85% of patients co-infected with HCV and human immunodeficiency virus were not treated. Of these, 40% were noncompliant with medical schedules, 15% were actively abusing drugs or alcohol, and 15% refused antiviral treatment.
In our study, 876 patients were diagnosed with chronic hepatitis C having positive results for both anti-HCV and HCV RNA. Of the 876 patients, 244 were eligible for interferon, but 39 (16%) diagnosed with HCV relapse. 632 patients could not be treated appropriately with interferon-based antiviral therapy (Fig. 1). The reasons for stopping or not receiving interferon-based antiviral treatment include malignancy (30%), co-morbidity (23%), interferon-related reasons (15%) and non-adherence (26%).
The most prevalent malignancy in our cohort was HCC (81%) (Table 2). In the interferon era, HCC was a relative contraindication for antiviral therapy; however, treating chronic hepatitis C with interferon was considered to reduce HCC recurrence and improve survival . The recent introduction of DAA has been expected to reduce the incidence of HCC in HCV-related cirrhotic livers. Unfortunately, DAA-induced clearance of HCV was not able to reduce the occurrence of HCC in patients with HCV-related cirrhotic livers . In spite of DAA treatment, high rate of early HCC recurrence was noted in patients previously treated for HCC [14,15]. Therefore DAA therapy in HCC patients has yet to be determined.
Patients with severe co-morbidities could not be treated with interferon-based therapy because of possible severe adverse effects. About 49% of patients had advanced or decompensated liver cirrhosis that was a contraindication to interferon therapy (Fig. 4). However, an oral DAA regimen could be safe and highly effective in treating patients who are ineligible for interferon-based antiviral therapy due to HCV-related cirrhosis, decompensation. In addition to advanced liver diseases, DAA could be administered safely in patients with symptomatic cardiovascular disease, chronic renal disease, uncontrolled diabetes, extra-hepatic transplantation and psychiatric disorders .
Non-adherence, financial problems and alcohol abuse are also reasons to prevent antiviral therapy. With short treatment duration and all oral regimens, improved compliance is expected in patients using DAA. On the other hand, DAA is so expensive that it would be difficult for a physician to prescribe to all chronic hepatitis C patients. Therefore, a part of compliance and socioeconomic problems would be remained in DAA era.
Therefore, we could suppose that at least 42% of patients who were ineligible or failed to interferon-based antiviral therapy due to co-morbidity (22%), interferon intolerability (14%) and HCV relapse (6%) would be treated with DAAs. However, a large portion of patients who were non-adherent (25%), had alcohol abuse (2%), or had financial concerns (2%) would not be able to get a chance to use the DAA (Fig. 5). Unlike hepatitis B virus-related HCC, patients with HCC occurred with HCV (23%, 156/671) have not been determined to be treated with DAA. This study has some limitations, including a retrospective design and that it was conducted in a single, tertiary hospital. The combined co-morbidity and malignancy rates were higher than in other Korean studies [7,17]. Therefore, the results cannot be accepted generally. In spite of the limitation, this study has a clear message considering limitation of DAA therapy in chronic hepatitis C patients who were ineligible or failed to interferon based antiviral therapy.
In conclusion, only 27.7% of patients diagnosed with chronic hepatitis C in our study were treated with an interferon-based regimen. With the advent of DAAs, at least 42% of patients who were ineligible or failed to interferon and experienced HCV relapse would be able to use DAA. However nonmedical reasons, including noncompliance, financial problems, substance abuse and hepatocelluar carcinoma remain obstacles to treat chronic hepatitis C. Our study suggests that, in spite of DAA development, eradicating HCV would be difficult due to various unexpected reasons.