Abstract
Objective: Combination therapy with glecaprevir and pibrentasvir (G/P) has been shown to provide a sustained virologic response (SVR) rate of >97% in patients with chronic hepatitis C virus (HCV) infection in the first published real-world Japanese data. However, a recently published study showed that the treatment was often discontinued in patients ≥75 years old, resulting in low SVR in intention-to-treat (ITT) analysis. Thus, our aim was to evaluate real-world data for G/P therapy in patients ≥75 years of age, the population density of which is high in “rural” regions.
Patients and Methods: We conducted a multicenter study to assess the efficacy and safety of G/P therapy for chronic HCV infection, in the North Kanto area in Japan.
Results: Of the 308 patients enrolled, 294 (95.5%) completed the treatment according to the protocol. In ITT and per-protocol analyses, the overall SVR12 rate was 97.1% and 99.7%, respectively. The old-aged patients group consisted of 59 participants, 56 of whom (94.9%) completed the scheduled protocol. Although old-aged patients tended to have non-SVR factors such as liver cirrhosis, history of HCC, and prior DAA therapies, the SVR12 rates in old-aged patients were 98.3% and 100% in the ITT and PP analyses, respectively. Of 308 patients enrolled, adverse events were observed in 74 patients (24.0%), with grade ≥3 events in 8 patients (2.6%). There was no significant difference in any grade and grade ≥3 adverse events between the old-aged group and the rest of the study participants. Only one patient discontinued the treatment because of adverse events.
Conclusion: G/P therapy is effective and safe for old-aged patients.
Keywords: age disparities, chronic hepatitis C, glecaprevir, pibrentasvir
Introduction
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) in Japan1, 2) and results in heavy health-care burden. Interferon (IFN)-based therapy was used to treat HCV infection until 2014. The issues of IFN-based treatment were the high rate of adverse events and long duration of treatment. Hence, it was difficult for elderly patients to achieve sustained virologic response (SVR) due to dropout from treatment3, 4). As a result, 1–1.5 million patients still have HCV infection in Japan5) despite the nationwide campaign to promote the treatment of chronic HCV infection.
In 2014, an interferon (IFN)-free direct-acting antiviral (DAA) treatment regimen was approved for patients with chronic HCV infection in Japan. Because IFN-free DAA treatments were associated with low rates of adverse events and short duration of treatment in comparison to IFN-based therapy, IFN-free DAA treatments provided SVR rate >95%, as observed in many studies6,7,8). In addition, SVR achieved by IFN-free DAA treatment improved health-related quality of life in patients with chronic HCV infection9). Furthermore, SVR achieved by IFN-free DAA treatment suppressed recurrence of HCC and improved overall survival10). Thus, increased SVR can provide a lot of benefits for patients with chronic HCV infection, including old-aged patients.
In 2017, the combination of glecaprevir and pibrentasvir (G/P) was approved in Japan that showed potent anti-viral effects for pan-genotype HCV including GT1-6. A phase-3 Japanese study showed that SVR12 rates in GT1 and GT2 increased to 99.2–100%11) and 97.8–100%12), respectively. In addition, G/P therapy showed favorable results in “difficult-to-treat patients” from previous DAA treatments, including GT2-infected patients with severe renal failure, GT3-6, and prior DAA-treated patients13,14,15). Currently, several studies using G/P therapy have published real-world data from the general as well as special populations with HCV infection in Japan, and have demonstrated extremely high SVR rates16, 17).
Although previous studies included many patients ≥65 years of age, little information is available on another “special population”, patients ≥75 years of age. These old-aged patients tend to have non-SVR factors, including liver cirrhosis18), history of HCC6, 19), and prior DAA treatment6, 8). In addition, adverse events are of concern in this population. Indeed, patients ≥75 years of age tended to discontinue the treatment20). Furthermore, the population of these old-aged patients is increasing in Japan; their population density is high in “rural” regions (https://www8.cao.go.jp/kourei/whitepaper/w-2018/html/zenbun/s1_1_4.html). We therefore performed a multicenter study to evaluate the efficacy and safety of G/P therapy in patients ≥75 years of age.
Patients and Methods
Patients with chronic HCV infection were enrolled in this retrospective study, which was conducted at 16 institutions in the North Kanto area in Japan between December 2017 and October 2018. The following institutions participated in this study: Jichi Medical University, Dokkyo Medical University, Saiseikai Utsunomiya Hospital, Nasu Red Cross Hospital, Shin-Oyama City Hospital, Nasu Minami Hospital, Sano Kousei General Hospital, Tochigi Medical Center Shimotsuga, Haga Red Cross Hospital, Tochigi Medical Center, Koga Red Cross Hospital, JCHO Utsunomiya Hospital, Utsunomiya Higashi Hospital, Ashikaga Red Cross Hospital, Kamitsuga General Hospital, and Yuai Memorial Hospital.
Patients with compensated liver cirrhosis, GT3-6, and previously DAA-treated patients were scheduled to undergo 12 weeks of the G/P combination (Maviret®, Abbvie, Tokyo, Japan) treatment. The remaining patients were scheduled to receive 8 weeks of treatment. In all patients, treatment was initiated with 3 tablets of Maviret®, which contains 300 mg of glecaprevir and 120 mg of pibrentasvir. The main exclusion criteria were 1) decompensated liver cirrhosis (Child-Pugh grade B or C), 2) the presence of HCC, and 3) other contraindications for treatment. The old-aged group was determined as ≥75 years old in the present study. No upper-limit age was imposed on this study.
The study consisted of 308 consecutive patients; 10 patients (3.2%) deviated from the protocol. Four patients (1.3%) dropped out during or after the end of treatment. Thus, ITT and per protocol (PP) analyses were performed for 308 and 294 patients, respectively. We recorded the age, gender, history of HCC, previous DAA treatments, liver status (chronic hepatitis or liver cirrhosis), and GT or serotype (ST). The HCV GT was available for 260 patients (84.4%). In the present study, ST1 and ST2 were counted in GT1 and GT2, respectively. The diagnosis of liver cirrhosis was made by chief doctors based on laboratory and imaging examinations. Alcohol users were determined by consuming 60 g/day of ethanol for men and 40 g/day for women for over 5 years, including the patients who stopped drinking before the entry to the present study. The FIB-4 index, a marker for liver fibrosis, was determined using the following formula: (age × AST[U/L])/ (Plt [109/L] × ALT[U/L]1/2). Serum HCV-RNA was measured by quantitative real-time polymerase chain reaction (COBAS® TaqMan® HCV Test, version 2.0; Roche Diagnostics, Tokyo, Japan, or AccuGENE® m-HCV RNA quantitative assay; Abbott Japan, Tokyo, Japan). HCV ST and GT were examined at SRL (Tokyo, Japan). The severity of chronic kidney disease (CKD) was determined according to the guidelines of the Japanese Society of Nephrology. In the present study, severe CKD was defined as grade 4, grade 5, and grade 5D based on the estimated glomerular-filtration rate (eGFR) being 15-30 min/mL/1.73m2, <15 min/mL/1.73 m2, and dialysis-dependent, respectively. Achievement of SVR at 12 weeks post-treatment (SVR12) was used for the evaluation of the virologic response. Adverse events were recorded according to the Common Terminology Criteria for Adverse Events v4.0.
This study was approved by the Institutional Review Board of Jichi Medical University (A18-091) as well as independent ethics committees at all participating sites, and was conducted in accordance with the Declaration of Helsinki. Because of the retrospective nature of this study, written informed consent was waived except in case of Jichi Medical University. However, opt-out consent documents were shown on the website of Jichi Medical University for patients who reconsidered participation even after agreeing to the study.
Analysis of resistance-associated substitutions (RASs)
RASs in previously DAA-treated patients were determined by direct sequencing (SRL Laboratory, Tokyo, Japan or LSI Laboratory, Tokyo, Japan)21), or Cycleave polymerase chain reaction (SRL Laboratory). An RAS was considered present when it exceeded 10% and 1% by direct sequencing and Cycleave polymerase chain reaction, respectively.
Statistical analyses
Statistical analyses were performed using the SPSS Statistics (version 23.0, IBM Corp., Armonk, NY, USA) and EZR Statistics (Saitama Medical Center, Jichi Medical University, Japan) software programs. Continuous variables were expressed as the median. Fisher’s exact test and the Mann-Whitney U test were performed as appropriate. P-values of <0.05 were considered to indicate statistical significance.
Results
Characteristics of patients
Table 1 shows the characteristics of the 308 patients enrolled in the present study. The median age was 65 years; the number of patients was 59 (19.2%) in the old-aged group (age ≥75 years old). Patients with GT4-GT6 were not enrolled, and all patients with GT3 were <75 years of age. The prevalence of cirrhotic and previously DAA-treated patients tended to be higher in the old-aged group. As a result, the proportion of 12 weeks of G/P therapy was larger in the old-aged group because a 12-week protocol is required for cirrhotic and previously DAA-treated patients. The prevalence of patients with severe CKD was similar between the old-aged and the other group. The old-aged group had a higher proportion of HCC history but a smaller proportion with alcohol use. Patients in the old-aged group were also characterized by low levels of white blood cells, hemoglobin, platelet, ALT, albumin, eGFR, and PIVKA-II but high Fib4-index and M2BPGi in comparison to the other, non-old-aged group.
Table 1. Characteristics of 308 patients enrolled in the present study.
| Overall (n=308) | Age <75 (n=249) | Age ≥75 (n=59) | P-value | |
|---|---|---|---|---|
| Age (years) [Range] | 65 [26–96] | 61 [26−74] | 80 [75−96] | <0.001 |
| Male | 176 (57.1%) | 148 (59.4%) | 28 (47.5%) | 0.108 |
| Genotype 1/2/3 | 147/156/5 | 117/127/5 | 30/29/0 | 0.701 |
| Liver cirrhosis | 68 (22.1%) | 50 (20.1%) | 18 (30.5%) | 0.115 |
| DAA-experienced | 46 (14.9%) | 36 (14.5%) | 10 (16.8%) | 0.685 |
| 12 w of treatment | 112 (36.4%) | 85 (34.1%) | 27 (45.8%) | 0.100 |
| Severe CKD | 32 (10.4%) | 26 (10.4%) | 6 (10.2%) | 1.000 |
| Hemodialysis | 24 (7.8%) | 21 (8.4%) | 3 (10.2%) | 0.589 |
| History of HCC | 22 (7.1%) | 14 (5.6%) | 8 (13.6%) | 0.047 |
| Alcohol | 49 (15.9%) | 45 (18.1%) | 4 (6.8%) | 0.031 |
| Diabetes mellitus | 63 (20.5%) | 53 (21.3%) | 10 (16.9%) | 0.590 |
| HCV-RNA (LogIU/mL) | 6.3 [2.7–8.1] | 6.3 [2.7–8.1] | 6.1 [3.3–7.3] | 0.360 |
| WBC (/μL) | 5,100 [1,600–10,800] | 5,300 [1,600–10,800] | 4,600 [2,580–8,900] | 0.009 |
| Hemoglobin (g/dL) | 13.6 [8.4–17.4] | 13.8 [8.4–17.4] | 12.5 [9.6–15.4] | <0.001 |
| Platelet (×104 /μL) | 17.7 [1.9–98.5] | 18.1 [1.9–98.5] | 16.1 [6.2–46.0] | 0.011 |
| AST (U/L) | 36 [10–359] | 36 [10–359] | 35 [15–193] | 0.682 |
| ALT (U/L) | 34 [4–519] | 38 [8–519] | 28 [4–137] | 0.004 |
| Albumin (mg/dL) | 4.1 [2.1–5.2] | 4.1 [2.1–5.2] | 3.9 [2.8–4.8] | <0.001 |
| Total bilirubin (mg/dL) | 0.6 [0.2–4.5] | 0.6 [0.2–4.5] | 0.7 [0.2–1.7] | 0.631 |
| Creatinine (mg/dL) | 0.76 [0.39–9.66] | 0.76 [0.39–9.66] | 0.80 [0.5–9.15] | 0.040 |
| eGFR (mL/min/1.73m3) | 71.0 [3.7–152.8] | 74.1 [4.5–152.8] | 57.7 [3.7–119.5] | <0.001 |
| α-fetoprotein (ng/mL) | 4.0 [0.7–146] | 4.0 [1.0–146.0] | 3.8 [0.7–22.0] | 0.106 |
| PIVKA-II (mAU/mL) | 18.9 [1.79–200] | 19.0 [1.79–200] | 18.0 [8.2–30.0] | 0.017 |
| Fib-4 index | 2.4 [0.29–23.3] | 2.07 [0.29–23.33] | 3.92 [1.56–17.91] | <0.001 |
| M2BPGi | 2.3 [0.27–14.79] | 2.01 [0.27–14.79] | 2.77 [0.93–14.70] | 0.002 |
CKD: chronic kidney disease, DAA: direct acting antivirals, HCC: hepatocellular carcinoma, HCV: hepatitis C virus, WBC: white blood cell, AST: aspartate aminotransferase, ALT: alanine aminotransferase, eGFR: estimated glomerular-filtration rate, PIVKA-II: protein induced by vitamin K absence or antagonist II, M2BPGi: Mac-2 binding protein glycosylated isomers.
Virologic response to G/P therapy
We next evaluated the virologic responses. The overall SVR12 rate was 97.1% (299/308) and 99.7% (293/294) in the ITT and PP analyses, respectively (Figure 1a). The SVR12 rate of the old-aged group was similar to that of non-old-aged group in both ITT and PP analyses (Figure 1a). The SVR12 rates in patients with GT1, GT2 and GT3 were 97.3%, 96.8%, and 100% in the ITT analysis, respectively (Figure 1b). The SVR12 rates of the old-aged group in GT1 and GT2 were similar to those of non-old-aged group (Figure 1b).
Figure 1.
SVR12 rates in each parameter and comparison between the old-aged group and non-old-aged group. (a) ITT and PP analyses. (b) Each genotype. (c) Status of the liver. (d) Prior DAA treatment. (e) Duration of treatment. (f) Gender. (g) Presence of severe CKD. (h) History of HCC. SVR12 rates in the ITT analysis are shown from (b) to (h).
Further, we compared the SVR12 rates for the old-aged group and non-old-aged group using several parameters including liver status, prior DAA treatment, duration of treatment, gender, presence of severe CKD, history of HCC, FIB4 index >3.25, and M2BPGi >3.15. We found that the SVR12 rate was not significantly influenced by these parameters in the old-aged group (Figures 1c–1h, data not shown). In 32 patients with severe CKD, the SVR rate of 6 patients from the old-aged group was 100%, with 4 and 2 patients being of the GT1 and GT2 status, respectively. GT3-infected patients with severe CKD were not enrolled in the present study. Among 46 previously DAA-treated patients, 32 and 14 were GT1- and GT2-infected patients, respectively. The SVR12 rate of 10 previously DAA-treated patients in the old-aged group was 100%, with 6 GT1- and 4 GT2-infected patients, respectively. Patients with p32 deletion (NS5A) were not enrolled in the present study. HCV relapsed in a 61-year-old man with liver cirrhosis and a history of DAA treatments including simeprevir, Daclatasvir + asunaprevir, and sofosbuvir/ledipasvir for GT1b infection. A detailed analysis showed that HCV had P29del, C85C/Y, and T95A/T in NS5A, S122G in NS3, and C316N in NS5B but not L31, A92, Y93, and p32 deletion in NS5A.
Treatment safety and adherence
We next evaluated safety and adherence of G/P therapy. Of the 308 patients initially enrolled, 74 patients (24.0%) showed adverse events, with eczema/pruritus (n=38, 12.3%) and malaise (n=11, 3.6%) being the most frequent (Table 2). Although the frequency of eczema/pruritus was higher in the old-aged group, the rates of grade ≥3 adverse events as well as other adverse events were not significantly different between the old-aged group and non-old-aged group (Table 2). All grade-3 adverse events in the old-aged group were observed at the end of treatment. Among the 74 patients with adverse events, 64 completed the scheduled protocol since the adverse events were managed. However, 5 patients discontinued treatment and the other 5 deviated from the protocol because of the adverse events (Table 3). Among these 10 patients, 3 were old-aged patients. Patients who received ≥75% of the scheduled dose achieved an SVR (Table 3).
Table 2. Adverse events.
| Events | Overall (n=308) | Age <75 (n=249) | Age ≥75 (n=59) | P-value | ||||
|---|---|---|---|---|---|---|---|---|
| Any grade | ≥ Grade 3 | Any grade | ≥ Grade 3 | Any grade | ≥ Grade 3 | Any grade | ≥ Grade 3 | |
| Any | 74 (24.0%) | 8 (2.6%) | 55 (22.1%) | 6 (2.4%) | 19 (32.2%) | 2 (3.4%) | 0.127 | 0.652 |
| Eczema/Pruritus | 38 (12.3%) | 2 (0.6%) | 26 (10.4%) | 1 (0.4%) | 12 (20.3%) | 1 (1.7%) | 0.047 | 0.347 |
| Malaise | 11 (3.6%) | 8 (3.2%) | 3 (5.1%) | 0.446 | ||||
| Headache/Myalgia | 6 (1.9%) | 5 (2.0%) | 1 (1.7%) | 1.000 | ||||
| Bilirubin increased | 5 (1.6%) | 2 (0.6%) | 5 (2.0%) | 2 (0.8%) | ||||
| Constipation | 3 (1.0%) | 3 (1.2%) | ||||||
| Nausea | 3 (1.0%) | 1 (0.4%) | 2 (3.4%) | 0.095 | ||||
| Lung infection | 2 (0.6%) | 1 (0.3%) | 2 (0.8%) | 1 (0.4%) | ||||
| ALT increased | 2 (0.6%) | 1 (0.3%) | 1 (0.4%) | 1 (0.4%) | 1 (1.7%) | 0.347 | ||
| Dizziness | 2 (0.6%) | 2 (0.8%) | ||||||
| Heart failure | 2 (0.6%) | 2 (0.6%) | 1 (0.4%) | 1 (0.4%) | 1 (1.7%) | 1 (1.7%) | 0.347 | 0.347 |
| Cough | 1 (0.3%) | 1 (0.4%) | ||||||
| Others | 4 (1.3%) | 4 (1.6%) | ||||||
ALT: alanine aminotransferase.
Table 3. Characteristics and outcome in patients who discontinued or deviated from the protocol.
| Patient | Age / sex | GT | CH/LC | CKD grade | AEs | AE grade | Drug adherence | Outcome |
|---|---|---|---|---|---|---|---|---|
| #1 | 40 / F | 2 | CH | 1 | Eczema | 1 | 12.5% (1W/8W) | Non SVR |
| #2 | 77 / F | 2b | LC | 3b | Nausea | 1 | 16.7% (2W/12W) | Non SVR |
| #3 | 72 / M | 1b | CH | 3a | Cough | 1 | 41.7% (5W/12W) | Non SVR |
| #4 | 65 / M | 1b | CH | 1 | Lung infection | 2 | 50.0% (4W/8W) | Non SVR |
| #5 | 66 / M | 2b | LC | HD | Eczema | 3 | 75.0% (9W/12W) | SVR |
| #6 | 65 / M | 1b | CH | 4 | Lung infection | 3 | 100% (8W/8W) | SVR |
| #7 | 76 / F | 2a | CH | 2 | Malaise | 2 | 100% (12W/12W) | SVR |
| #8 | 87 / M | 2 | LC | 4 | ALT increased | 2 | 100% (12W/12W) | SVR |
| #9 | 70 / F | 2 | LC | 2 | Malaise | 2 | 100% (12W/12W) | SVR |
| #10 | 41 / F | 3a | CH | 1 | ALT increased | 3 | 100% (12W/12W) | SVR |
Case #3 is a prior DAA-treated patient. Cases #1–5 are patients who did not resume the G/P therapy after discontinuation. Cases #6–10 are patients who deviated from the protocol. Cases #6 and #7 completed the scheduled dose but temporally discontinued G/P therapy. Cases #8–10 completed the scheduled dose by reducing daily dose. GT: genotype, CH: chronic hepatitis, LC: liver cirrhosis, CKD: chronic kidney disease, AEs: adverse events, ALT: alanine aminotransferase, SVR: sustained virologic response, HD: hemodialysis.
Discussion
In the present study, the overall SVR12 rates in the ITT and PP analyses were 97.1% and 99.7%, respectively. Although the old-aged group tended to have non-SVR factors, including liver cirrhosis, history of HCC, and experience of DAA therapies, the SVR12 rates were 98.3% and 100% in the ITT and PP analyses, respectively. There were no significant differences in grade ≥3 adverse events between the old-aged and non-old-aged group. Only one patient in the old-aged group did not achieve SVR due to adverse events. Thus, G/P therapy was effective and safe for old-aged patients.
G/P therapy showed high SVR12 rate in many studies13, 14, 16, 1713, 14, 16, 17), in which half of the enrolled patients were ≥65 years of age. Thus, the age disparities in the IFN-free DAA therapy seemed to disappear with high adherence to the treatment. Indeed, Ogawa et al. reported that the SVR rate in patients ≥75 years old was 100%, in PP analysis16). However, they did not show SVR rate in ITT analysis, which could potentially include the patients who discontinued the treatment. We showed extremely high rates of SVR with ITT analysis in the old-aged group, which suggests that only a small number of patients discontinued the treatment. In addition, the present study did not include patients with p32 deletion in NS5A who are highly resistant to DAAs, including G/P therapy22). Because RASs is a non-SVR factor regardless of age6, 8), it is important to examine RAS before G/P treatment. Thus, G/P therapy is effective for old-aged patients as well as “difficult-to-treat patients” under appropriate entry to the treatment.
In general, although hepatologists select patients expecting that they would complete the G/P therapy, old-aged patients sometimes unexpectedly discontinue the treatment. In a study performed in metropolitan areas, the frequency of dropout from G/P therapy was 7.1%20) while the rate in the present study was 1.3%. The major reason for dropout in the metropolitan areas was transfer to other hospitals. Because patients can choose any medical resources in Japan, patients may transfer to other medical facilities when experiencing unexpected events during the DAA treatment. Tamori et al. reported that patients ≥75 years of age tended to drop out from the treatment owing to other diseases that occurred during G/P therapy20). In the present study, no patients in the old-aged group dropped out from the treatment. In Tochigi Prefecture, a part of North Kanto (https://www.mhlw.go.jp/toukei/saikin/hw/iryosd/m18/is1802.html), alternative medical resources are not readily available, resulting in no transfer to other hospitals during G/P therapy. In addition, we made efforts to communicate with hospitals during the G/P therapy by having several meetings to exchange information on the present study. These efforts might have helped to decrease the number of patients who dropped out from the treatment.
The G/P therapy accomplished a high SVR rate, as observed in other DAA treatments. Indeed, modified ITT analysis demonstrated high SVR rates despite low SVR rates in ITT analysis20). In our study, 5 patients achieved an SVR with modification of the protocol to receive 100% of the scheduled dose; 2 were old-aged patients. Of note, the duration of treatment was extended for 3 patients by reducing the daily dose due to adverse events. We believe that this modification of the treatment protocol is acceptable because a 16-week regimen is approved in other countries23). However, 5 patients discontinued treatment due to adverse events. Our study showed that a patient who received ≥75% of the scheduled dose achieved an SVR, while this was not observed in patients who received 50% or less. These data indicate that receiving the scheduled dose as possible is important for achieving an SVR. In addition, successful management of adverse events is essential for achieving an SVR.
Although we demonstrated that G/P therapy was effective and safe in old-aged patients, a couple of patient selection and condition need to be mentioned. First, some patients with severe comorbidities were not enrolled in the present study. Second, we did not enter some patients who might have had difficulties in visiting medical resources every 2 weeks during the treatment. Old-aged patients may have such problems, though age is not a restriction for entry into IFN-free DAA treatments such as G/P therapy. Interestingly, the proportion of alcohol use was low in old-aged patients. Alcohol use may have progressed to decompensated liver cirrhosis and/or HCC in old-aged patients with chronic HCV infection, which were excluded from the present study. Thus, patients who enrolled in the present study might have presented favorable conditions. These results also indicate that close attention needs to be given to who should be treated, i.e., to the patients’ selection.
Conclusion
G/P therapy is effective and safe in patients ≥75 years of age. While the accomplishment of G/P therapy yields a high SVR rate, appropriate management is required to achieve SVR in patients ≥75 years of age.
Conflicts of interest
N.M., T.M., Y.O., N.I., and H.Y. received lecture fees from AbbVie. T.M., N.I., and H.Y. received research fees from AbbVie. The other authors have no conflicts of interest associated with this study.
Acknowledgement
We thank Dr. Namiki Izumi and Masayuki Kurosaki (Musashino Red Cross Hospital) for the analysis of RASs.
References
- 1.Kanda T, Lau GKK, Wei L. APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation. Hepatol Int 2019; 13: 649–661. doi: 10.1007/s12072-019-09988-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Tanaka J, Akita T, Ko K. Epidemiological Research Group on Viral Hepatitis and its Long -term Course, Ministry of Health, Labour and Welfare of JapanCountermeasures against viral hepatitis B and C in Japan: an epidemiological point of view. Hepatol Res 2019; 49: 990–1002. doi: 10.1111/hepr.13417 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ebinuma H, Saito H, Tada S. Disadvantages of peginterferon and ribavirin treatment in older patients with chronic hepatitis C: an analysis using the propensity score. Hepatol Int 2012; 6: 744–752. doi: 10.1007/s12072-011-9312-9 [DOI] [PubMed] [Google Scholar]
- 4.Honda T, Katano Y, Shimizu J. Efficacy of peginterferon-α-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int 2010; 30: 527–537. doi: 10.1111/j.1478-3231.2009.02064.x [DOI] [PubMed] [Google Scholar]
- 5.Tanaka J, Akita T, Ohisa M. Trends in the total numbers of HBV and HCV carriers in Japan from 2000 to 2011. J Viral Hepat 2018; 25: 363–372. doi: 10.1111/jvh.12828 [DOI] [PubMed] [Google Scholar]
- 6.Iio E, Shimada N, Takaguchi K. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res 2017; 47: 1308–1316. doi: 10.1111/hepr.12898 [DOI] [PubMed] [Google Scholar]
- 7.Atsukawa M, Tsubota A, Kondo C. Effectiveness and safety of community-based treatment with sofosbuvir plus ribavirin for elderly patients with genotype 2 chronic hepatitis C. Dig Liver Dis 2017; 49: 1029–1035. doi: 10.1016/j.dld.2017.04.012 [DOI] [PubMed] [Google Scholar]
- 8.Takeuchi Y, Akuta N, Sezaki H. Efficacy and safety of elbasvir plus grazoprevir combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. Hepatol Res 2019; 49: 256–263. doi: 10.1111/hepr.13242 [DOI] [PubMed] [Google Scholar]
- 9.Younossi ZM, Stepanova M, Henry L. Sofosbuvir and ledipasvir are associated with high sustained virologic response and improvement of health-related quality of life in East Asian patients with hepatitis C virus infection. J Viral Hepat 2018; 25: 1429–1437. doi: 10.1111/jvh.12965 [DOI] [PubMed] [Google Scholar]
- 10.Nagaoki Y, Imamura M, Nishida Y. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: comparison with interferon-based therapy. J Med Virol 2019; 91: 650–658. doi: 10.1002/jmv.25352 [DOI] [PubMed] [Google Scholar]
- 11.Chayama K, Suzuki F, Karino Y. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis. J Gastroenterol 2018; 53: 557–565. doi: 10.1007/s00535-017-1391-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Toyoda H, Chayama K, Suzuki F. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection. Hepatology 2018; 67: 505–513. doi: 10.1002/hep.29510 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kumada H, Watanabe T, Suzuki F. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J Gastroenterol 2018; 53: 566–575. doi: 10.1007/s00535-017-1396-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kusakabe A, Kurosaki M, Itakura J. Efficacy and safety of glecaprevir/pibrentasvir as retreatment therapy for patients with genotype 2 chronic hepatitis C who failed prior sofosbuvir plus ribavirin regimen. Hepatol Res 2019; 49: 1121–1126. doi: 10.1111/hepr.13387 [DOI] [PubMed] [Google Scholar]
- 15.Watanabe S, Miura K, Morimoto N. Efficacy and safety of glecaprevir /pibrentasvir combination therapy for patients with genotype 2 chronic hepatitis C infection who failed HCV eradication by SOF+RBV treatment. Kanzo 2019; 60: 77–79(in Japanese, Abstract in English). doi: 10.2957/kanzo.60.77 [DOI] [Google Scholar]
- 16.Ogawa E, Furusyo N, Nakamuta M. Kyushu University Liver Disease Study (KULDS) GroupGlecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: results from a multicenter, real-world cohort study. Hepatol Res 2019; 49: 617–626. doi: 10.1111/hepr.13328 [DOI] [PubMed] [Google Scholar]
- 17.Atsukawa M, Tsubota A, Toyoda H. The efficacy and safety of glecaprevir plus pibrentasvir in 141 patients with severe renal impairment: a prospective, multicenter study. Aliment Pharmacol Ther 2019; 49: 1230–1241. doi: 10.1111/apt.15218 [DOI] [PubMed] [Google Scholar]
- 18.Ogawa E, Furusyo N, Nomura H. Kyushu University Liver Disease Study (KULDS) GroupEffectiveness and safety of sofosbuvir plus ribavirin for HCV genotype 2 patients 65 and over with or without cirrhosis. Antiviral Res 2016; 136: 37–44. doi: 10.1016/j.antiviral.2016.10.012 [DOI] [PubMed] [Google Scholar]
- 19.Hirosawa T, Morimoto N, Miura K. No regional disparities in Sofosbuvir Plus Ribavirin Therapy for HCV Genotype 2 infection in Tochigi prefecture and its vicinity. Intern Med 2019; 58: 477–485. doi: 10.2169/internalmedicine.1194-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Tamori A, Inoue K, Kagawa T. Intention-to-treat assessment of glecaprevir + pibrentasvir combination therapy for patients with chronic hepatitis C in the real world. Hepatol Res 2019; 49: 1365–1373. doi: 10.1111/hepr.13410 [DOI] [PubMed] [Google Scholar]
- 21.Itakura J, Kurosaki M, Hasebe C. Complex pattern of resistance-associated substitutions of hepatitis c virus after daclatasvir/asunaprevir treatment failure Jun Itakura. PLoS One 2016; 11: e0165339. doi: 10.1371/journal.pone.0165339 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Uemura H, Uchida Y, Kouyama JI. NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir. J Gastroenterol 2019; 54: 459–470. doi: 10.1007/s00535-018-01543-9 [DOI] [PubMed] [Google Scholar]
- 23.D’Ambrosio R, Pasulo L, Puoti M. NAVIGATORE-Lombardia Study GroupReal-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C. J Hepatol 2019; 70: 379–387. doi: 10.1016/j.jhep.2018.11.011 [DOI] [PubMed] [Google Scholar]