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Development of interferon-free, direct-acting antivirals treatment for Japanese patients with chronic hepatitis C infection and chronic kidney disease

Chronic hepatitis C virus (HCV) infection can progress to liver cirrhosis and hepatocellular carcinoma. Interferon-based treatment was previously the only antiviral therapy for chronic hepatitis C infection; however, development of interferon-free, direct-acting antivirals, in 2014, markedly improved treatment efficacy and safety. Treatment indications were expanded to include elderly adults, patients with advanced liver fibrosis, and patients with chronic hepatitis C infection complicated by chronic kidney disease, for whom antiviral therapy had been difficult or contraindicated. The median age of patients with chronic HCV infection in Japan is 70 years, older than in other countries. Because diminished renal function is common in elderly adults, a safe and effective treatment for chronic hepatitis C complicated by chronic kidney disease has been expected in Japan. In addition, the HCV antibody-positive rate is higher in hemodialysis patients than in non-hemodialysis patients in Japan. Numerous studies have reported that direct-acting antivirals are safe and effective for hepatitis C patients on hemodialysis. This review summarizes treatments available in Japanese clinical practice for patients with chronic HCV infection complicated by chronic kidney disease, including hemodialysis patients.


Introduction
A report published in 2017 noted that about 17 million people are infected with hepatitis C virus (HCV) worldwide and that 400,000 die annually from diseases associated with chronic hepatitis C, such as liver cirrhosis and hepatocellular carcinoma 1 . In Japan, 1.5 to 2 million people are estimated to be infected with HCV 2,3 . The objective of treatment for chronic hepatitis C is to eliminate the virus, prevent progression to liver cirrhosis and hepatocellular carcinoma, and improve prognosis and quality of life. HCV infection was recently reported to be associated with death related to multiple organs other than liver disease; thus, early treatment is recommended 4,5 .
Although interferon-based therapy has been used as antiviral therapy for chronic HCV infection since the 1990s, the rate of sustained virologic response (SVR) after interferon-based treatment is only 40% to 80%, and the high frequency of adverse events reduces therapeutic effectiveness [6][7][8][9][10] . Factors determining the effectiveness of interferon-based therapy include HCV genotype and the presence of amino acid substitutions at position 70/91 of the HCV core region 11 and ISDR mutation of the NS5A region. [12][13] In addition, low vitamin D level was reported to diminish the therapeutic effects of interferon 10 , and a single nucleotide polymorphism near the IL28B gene greatly diminished the effectiveness of interferon-based therapies as a host factor in patients with chronic hepatitis C 8,14 .
To overcome these limitations of interferon-based therapy, interferon-free, direct-acting antivirals (DAAs) were introduced in 2014 in Japan, before their introduction in Western countries. DAAs target the non-structure (NS) protein of the HCV RNA genome, specifically, NS3, NS5A, and NS5B, which are not incorporated in the virion. Currently, a regimen that combines 2 or more NS3 protease inhibitors, an NS5A inhibitor, and an NS5B polymerase inhibitor or NS5B polymerase inhibitor and ribavirin, is approved for therapy.
Daclatasvir/asunaprevir 15  This report reviews the safety and effectiveness of DAA combination therapy for chronic HCV infection complicated by CKD in Japanese clinical practice.

Interferon-based treatment
Because ribavirin is contraindicated for patients with CKD, interferon monotherapy was the only option for such patients until DAAs became available. A multicenter study (REACH study) in Japan reported that interferon monotherapy was not effective for hemodialysis patients. The SVR rate was approximately 30% in genotype 1 patients, who are considered interferonresistant, and the rate of treatment cessation attributable to adverse events was high 25 .
Resistance-associated substitutions (RASs) were noted early on when DAAs were used alone during drug development; thus, several treatment regimens that combine DAAs with interferon and ribavirin were developed. Telaprevir was approved in 2011 as a first-generation DAA, and simeprevir was approved in 2013 as a second-generation DAA. Both were used in a triple-drug regimen requiring concomitant use of pegylated-interferon (PEG-IFN) and ribavirin. The SVR rate of 75% to 80%, even for patients with chronic HCV genotype 1 infection that responded poorly to interferon-based treatment, was a marked improvement over the SVR rate achieved by conventional PEG-IFN/ribavirin combination therapy. However, these regimens are not indicated for patients with chronic HCV infection complicated by CKD.
However, the presence of RASs, especially against daclatasvir, was a notable limitation of this regimen. Iio et al. reported that treatment outcomes were worse in patients with a history of previous treatment with simeprevir and in those with NS5A resistant-associated variant Y93H on the first treatment 38 . Furthermore, transaminase elevation is a frequently reported adverse event 39 . Although daclatasvir/asunaprevir combination therapy has proven highly effective in Japan, this regimen, as of 2020, is not recommended as a first-line treatment, regardless of the presence of CKD, after the development of regimens with high efficacy against RASs, described below 23 .

Sofosbuvir/ledipasvir
In 2015, a second-generation interferon-free DAA regimen, sofosbuvir/ledipasvir, was approved 19 . A Japanese phase 3 clinical trial investigated patients with chronic HCV genotype 1 infection, and the SVR rate was 100%. For genotype 2, a phase 3 study trial that included sofosbuvir/ribavirin combination therapy as a control confirmed the noninferiority of sofosbuvir/ledipasvir to sofosbuvir/ribavirin, which resulted in approval 40

Sofosbuvir/ribavirin
In a Japanese phase 3 study of 153 genotype 2 chronic hepatitis C patients with a median eGFR of 85 mL/min/1.73 m 2 (range, 51-209) the overall SVR rate was 97% 22 . We previously reported treatment outcomes for 270 patients with genotype 2 chronic hepatitis C; the SVR rate was 97% 42 . However, sofosbuvir is contraindicated for patients with an eGFR lower than 30 mL/min/1.73 m 2 , and ribavirin cannot be given to patients with a creatinine clearance lower than 50 mL/min. The therapy was administered to patients with an eGFR of 32 mL/min/1.73 m 2 or higher in the study. In Japan this regimen remains contraindicated for patients with severe renal impairment, as is sofosbuvir/ledipasvir.

Ombitasvir/paritaprevir/ritonavir ± ribavirin
In 2015, a combination tablet containing ombitasvir, paritaprevir, and ritonavir with a booster effect on these drugs was approved for genotype 1 patients 16 .
Because these 3 drugs are mainly metabolized in the liver, they are theoretically administrable to patients with CKD, including those on hemodialysis. To our knowledge, 4 reports have described the use of ombitasvir/paritaprevir/ritonavir in Japanese clinical practice for chronic HCV genotype 1 infection complicated by CKD [43][44][45][46] . Data on the effectiveness of this regimen are shown in Table 2.
The limitations of this regimen include a slight reduction in effectiveness for patients with RASs of the NS5A region (as observed with daclatasvir), a reduction in SVR rate in patients with advanced liver fibrosis 47 , and the fact that many drugs require caution, or are contraindicated, when used concomitantly with ritonavir, which resulted in the discontinuation of this regimen in Japan. A regimen including ribavirin for genotype 2 was also approved, and efficacy in non-CKD patients was high 48 , but it cannot be administered to patients with severe renal impairment.

Elbasvir/grazoprevir
Elbasvir/grazoprevir combination therapy was approved in 2016 in Japan. A Japanese phase 3 study investigated 336 patients with chronic HCV genotype 1 infection; those with renal dysfunction and a creatinine clearance lower than 50 mL/min were excluded. The SVR rate was 96.5% in patients with chronic hepatitis C infection and 97.1% in patients with compensated liver cirrhosis 17 Table 3. The SVR rate in CKD patients, including hemodialysis patients, was 97.2% to 98.1%, indicating high effetiveness [50][51][52] . As of 2020, elbasvir/grazoprevir combination therapy is a first-line treatment for chronic HCV infection complicated by CKD but is indicated only for genotype 1 23 .

Pibrentasvir/glecaprevir
The CERTAIN-1 and CERTAIN-2 Japanese phase 3 studies reported outcomes for pibrentasvir/glecaprevir combination therapy [53][54][55] . The SVR rate for pibrentasvir/glecaprevir combination therapy was investigated in patients with severe renal dysfunction and in hemodialysis patients in the Japanese phase 3 study CERTAIN-1, but the number of patients was small. Thus, we performed a prospective multicenter study and reported treatment outcomes and safety for pibrentasvir/glecaprevir combination therapy in patients with CKD stage 4/5 56  The details of these reports are shown in Table 4. Pibrentasvir/glecaprevir combination therapy required a minimum of 8 weeks and safety was high.
Pruritus was reported as an adverse event in many CKD patients, but efficacy was high for all genotypes. This regimen is now the first choice for CKDcomplicated chronic hepatitis C 23 . Furthermore, pibrentasvir/glecaprevir combination therapy was effective for re-treatment of patients who failed to achieve SVR after previous treatment with DAAs. In clinical practice, Suda et al.
reported that pibrentasvir/glecaprevir combination therapy was effective for 2 hemodialysis patients who failed to achieve SVR after daclatasvir/asunaprevir combination therapy 59 .

Sofosbuvir/velpatasvir
All the DAA-combining regimens described above are indicated for chronic hepatitis and compensated liver cirrhosis; however, no regimen was available for decompensated liver cirrhosis in Japan. A phase 3 Japanese study of patients with decompensated liver cirrhosis reported an SVR rate of 92% 20 . In addition, hepatic functional reserve improved in some patients who achieved SVR, which resulted in Japanese approval of sofosbuvir/velpatasvir combination therapy for decompensated liver cirrhosis, in 2019. In clinical practice, we reported a high SVR rate in a Japanese multicenter study of 71 patients with decompensated liver cirrhosis. This rate was similar to that reported in the phase 3 study 60 . However, this regimen is not indicated for patients with severe renal impairment because it includes sofosbuvir; thus, no DAA treatment option exists for decompensated liver cirrhosis complicated by CKD.

Discussion
Although we reviewed some DAAs regimens and their efficacy for patients with chronic hepatitis C with CKD, the current Japan Society of Hepatology guidelines recommend a 12-week elbasvir/grazoprevir regimen for genotype 1, and an 8-or 12-week pibrentasvir/glecaprevir regimen for all genotypes as the first choice for chronic hepatitis C complicated by CKD 23  The main purpose of eliminating HCV from chronic hepatitis C patients is prevention of progression to liver cirrhosis and hepatocellular carcinoma. In addition, the effects of HCV elimination on multiple organs other than the liver in chronic hepatitis C patients has frequently been reported. In 2011, Arase et al.
reported that the rate of progression to CKD was markedly reduced by HCV elimination by interferon-based therapy 62 . In addition, insulin resistance was improved by achieving SVR with DAA treatment in patients with chronic hepatitis C 63 . Moreover, 50% to 70% of cardiovascular events were inhibited by achieving SVR with DAA treatment 64  In patients at high risk for hepatocellular carcinoma development after SVR, strict surveillance for early detection of hepatocellular carcinoma and curative treatments such as radiofrequency ablation and low-invasive surgery are strongly recommended 70 .

Conclusion
Antiviral therapy for chronic hepatitis C has markedly improved, and a virological cure is now possible for almost all patients, including those with CKD.
Outcomes are substantially worse for patients with chronic hepatitis C with CKD than for those without CKD. Thus, DAA treatment should be actively introduced for patients with chronic hepatitis C complicated by CKD, including those receiving hemodialysis.