Background
Chronic hepatitis C virus (HCV) infection is one of the main causes of liver cirrhosis and hepatocellular carcinoma and is a principal cause of liver-related morbidity and mortality worldwide. Previously, the standard treatment for patients with chronic hepatitis C (CHC) included pegylated-interferon alpha (PEG-IFNα) and ribavirin therapy. [
1] Treatment response was not only related to HCV genotype and the host’s interleukin (IL) 28B polymorphism but also related to the tolerability of the drugs. Although Korean patients have favorable single nucleotide polymorphisms near the
IL28B gene, such as rs12979860CC and rs8099917TT allele, [
2] poor tolerability has led to the hesitation to use interferon (IFN)-based treatment.
Recently, direct-acting antivirals (DAAs)—have been developed and substituted IFN-based regimen to treat patients with CHC. These DAAs are substantially more tolerable and effective than PEG-IFNα and ribavirin. [
3‐
6] DAAs are molecules that target specific nonstructural (NS) proteins of the virus and results in disruption of viral replication and infection. There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are NS proteins 3/4A protease inhibitors, NS5B nucleoside polymerase inhibitors, NS5B non-nucleoside polymerase inhibitors, and NS5A inhibitors. [
7] Among the DAAs, combination treatment with daclatasvir (DCV) of NS5A inhibitor and asunaprevir (ASV) of NS3 protease inhibitor was introduced using multiple classes of DAAs with non-overlapping targets. These regimens showed a good treatment outcome in clinical trials of patients with CHC genotype 1b, regardless of IFN-intolerance or lack of response to IFN-based regimens. [
8‐
10] Based on its efficacy and safety compared to that of IFN-based therapy, DCV + ASV combination therapy was the first IFN-free regimen reimbursed by national health insurance in Korea for the treatment of genotype 1b CHC.
However, a NS5A inhibitor, such as daclatasvir, has limited efficacy with baseline resistance-associated variants (RAVs) at NS5A-Y93H and NS5A-L3l. DCV + ASV combination therapy also showed various results depending on the presence of RAVs. According to a previous study, in patients with a sustained virologic response at 24 weeks post-treatment, the virus was eliminated in 98.6% of patients without NS5A polymorphism and in 42.1% of patients with NS5A polymorphism. [
11] Thus, regarding the efficacy of DCV + ASV therapy, the presence of RAVs, especially the presence of NS5A RAVs, can be an important factor. However, impact of RAVs is regimen specific, since reports have shown that SVR rates after DCV combined with a different DAA was not influenced from NS5A RAVs. [
12,
13]
NS5A RAVs prevalence varied from 18% (population-based sequencing) [
6] to 29% (deep sequencing) in Japanese patients. [
14] As the prevalence of HCV genotypes is quite different depending on the region, NS5A RAVs can vary depending on the region or the country in which it is treated, and the results and effects of DCV + ASV therapy are assumed to vary accordingly. Thus, when using DAAs, including NS5A inhibitors, investigating the real-life prevalence of NS5A RAVs in a specific area and its influence is important. The aim of this study was to investigate the real-life prevalence of RAVs against NS5A inhibitors in Korean patients with genotype 1b CHC and the efficiency of the treatment with DCV + ASV in patients with genotype 1b CHC without RAVs.
Discussion
Development of new drugs for HCV infection, one of the world’s major health crises, provides an opportunity to come one step closer to its complete cure. In particular, it provides an opportunity for complete cures for patients who have failed IFN and ribavirin treatment, thus allowing easier treatment because of fewer adverse effects. DAAs mainly act on nonstructural proteins that are formed by the HCV. RAVs are known to drastically reduce the efficiency of these drugs [
6,
17,
18]. Therefore, when prescribing these drugs, such as DCV + ASV, the presence of RAVs needs to be confirmed before starting the treatment and setting the treatment direction. If RAVs vary depending on the regions and countries in which patients live, DAAs’ performance can be expected to differ accordingly. In the previous era of IFN-based treatment, IL28B genetic polymorphisms showed differences between Asian and non-Asian countries, and that treatment performance varied accordingly. [
19‐
22] About 90% of the population of Korea are CC homozygotes, [
2,
23,
24] and response of IFN-based treatment was relatively higher than in Western people. Because IL28B test is not routinely performed before treatment of CHC as guidelines suggested, [
16] IL28B was not evaluated in these patients. Therefore, we could not figure out whether the presence of baseline RAVs differed significantly with respect to IL28B genotype.
Currently availabilities of DAAs differ from country to country. DCV + ASV began to be used in Japan after its approval in 2014, and it has been used in Korea since August 2015 after its insurance application was approved. Therefore, because of its limited use thus far, insufficient investigation has been made into the treatment performance of DCV + ASV and its related NS5A mutations. In this study, the real-life prevalence of NS5A RAVs detected at baseline in 142 Korean patients was investigated and was confirmed to be slightly higher prevalence than was previously reported. [
25‐
27] According to data published in Japan in 2015, the incidence of NS5A mutations in Japan was 18.4%, which was higher than its incidence in non-Asian countries. [
6] Although further studies are needed in the future, in regards to patients with CHC genotype 1b in Asia, frequent NS5A RAVs detected at baseline are considered a substantial limitation in DCV + ASV use, and other DAA regimens need to be considered because impact of RAVs is regimen specific. [
12,
13]
According to our results, the RAV-positive incidence was not different in patients who was naïve or who failed prior IFN-based treatment. Furthermore, in patients with accompanying cirrhosis, the RAV-positive incidence was not statistically different. It is assumed that these patients have been infected with viruses for a long time and have retained viruses with diverse mutations, but again, the exact causes are not known. However, good treatment performance was observed in RAV-negative patients in this study, regardless of presence of cirrhosis or whether prior IFN-based treatments had failed. Patients who reached virologic response during treatment also reached SVR12 without much difficulty.
The number of patients with NS5A RAVs is slightly higher than the previously reported data of 12–18.4%. [
25‐
27] Although further studies are needed in the future, according to our study results, the number of HCV genotype 1b–infected Korean patients without NS5A RAVs, and therefore suitable for treatment with DCV + ASV, might be slightly less than that in other regions or countries where the prevalence of these NS5A RAVs are less.
DAA-based treatment has relatively fewer adverse effects than IFN-based treatment. However, in the case with DCV, patients can have headaches, general weakness, and fatigue. Bradycardia arrhythmias have been observed in patients receiving amiodarone with DCV and sofosbuvir, with or without other drugs that lower heart rate. The mechanism for the bradycardia effect has not been clearly established; recent in vivo studies have demonstrated a sofobuvir amiodarone drug-drug interaction (DDI)-dependent selective nodal dysfunction resulting in bradycardia. [
28] Moreover, ASV can have adverse effects including diarrhea, headache, hyperbilirubinemia, and increased transaminase level. Additionally, cases that were assumed to be immunoallergic hepatitis after DCV + ASV combination therapy have been reported. [
29] According to a large scaled report of DCV + ASV therapy, 2.9% of patients discontinued the therapy as a result of ALT elevation. ALT elevation more than 1.25-fold the upper limit of normal was noted in 37.6% of patients. [
30] Another large scaled study revealed that discontinuation due to liver injury occurred in 28 of 924 patients (3.0%). Other minor cause of discontinuation was fatigue, diarrhea, nausea, appetite loss, pneumonia, rash, platelet decrease and encephalopathy. [
31] In a multi-center study among hemodialysis patients, 4 of 123 patients discontinued DCV + ASV therapy because of elevated serum alanine transaminase levels (
n = 2), rash (
n = 1), and HCC; all of these achieved SVR12. [
32] In this study, three patients stopped treatment because of adverse effects, one of which was marked thrombocytopenia. One patient’s platelet count dropped from normal to very low 2 weeks after beginning treatment. This patient stopped the treatment, and the platelet levels returned to normal after steroid treatment. However, since the medicine can be accompanied by additional complications that can be life-threatening, hematologic disorders need to be carefully monitored during the treatment, though this patient has a history of cured ITP. Another patient had to stop treatment because of weakness and fatigue. Fatigue is often observed as an adverse effect of DCV + ASV therapy, and typically, it is not severe enough to stop treatment. However, the drug can result in general weakness and fatigue too severe for this patients to endure. The other patient discontinued DCV + ASV therapy due to elevated transaminases at week 7 after achieving virologic response at week 4. In this study, since adverse effects occurred within 2 month of the treatment in all cases, more careful observation is needed in the early period of treatment.
Limitations of the study are the limited sample size and dataset from a single center study. Although hepatitis B is endemic in Korea, Hepatitis C is not as prevalent as in Japan or in western countries. Thus, sample size is relatively small comparing other reports form these regions. These clinical data are collected in one tertiary referral hospital. Therefore, patients nationwide are included even though these results can not accurately reflect the patient across the country.