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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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Efficacy and Safety of Glecaprevir/Pibrentasvir in Korean Patients with Chronic Hepatitis C: A Pooled Analysis of Five Phase II/III Trials

Jeong Heo1 , Yoon Jun Kim2 , Jin-Woo Lee3 , Ji Hoon Kim4 , Young-Suk Lim5 , Kwang-Hyub Han6 , Sook-Hyang Jeong7 , Mong Cho8 , Ki Tae Yoon8 , Si Hyun Bae9 , Eric D. Crown10 , Linda M. Fredrick10 , Negar Niki Alami10 , Armen Asatryan10 , Do Hyun Kim11 , Seung Woon Paik12 , and Youn-Jae Lee13

1Department of Internal Medicine, Pusan National University College of Medicine and Medical Research Institute, Pusan National University Hospital, Busan, 2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 3Department of Internal Medicine, Inha University School of Medicine, Incheon, 4Department of Internal Medicine, Korea University College of Medicine, 5Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 6Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 7Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 8Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University College of Medicine, Yangsan, 9Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea, 10Abbvie Inc., North Chicago, IL, USA, 11AbbVie Korea, Ltd., 12Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, and 13Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Seung Woon Paik
ORCID https://orcid.org/0000-0002-6746-6652
E-mail swpaik@skku.edu

Youn-Jae Lee
ORCID https://orcid.org/0000-0003-3854-3388
E-mail yjyh0105@inje.ac.kr

Received: October 28, 2020; Revised: December 24, 2020; Accepted: January 4, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2021; 15(6): 895-903

Published online November 15, 2021 https://doi.org/10.5009/gnl20321

Copyright © Gut and Liver.

Background/Aims: Glecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection.
Methods: The study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments.
Results: The analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12: one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%).
Conclusions: G/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.

Keywords: Glecaprevir and pibrentasvir, Pan-genotypic antivirals, Hepatitis C virus, Korea

Hepatitis C virus (HCV) infection affects up to 71 million individuals worldwide and causes substantial morbidity and mortality.1,2 Patients who do not receive antiviral treatment are at high risk of serious long-term hepatic complications which include cirrhosis, decompensation, hepatocellular cancer and death.1,3-5 Among Korean patients with advanced liver diseases including liver cirrhosis and hepatocellular carcinoma, 11% to 17% present with HCV infection.6 The estimated seroprevalence of anti-HCV antibodies in Korean adults is 0.8% (about 300,000 individuals), which increases steeply with age to 2.3% in individuals aged ≥70 years.7,8 Among patients with chronic HCV infection in South Korea, virus genotypes (GTs) 1 and 2 collectively account for the vast majority (99%) and the most common subtypes are GT1B (45% to 59%) and GT2A (26% to 51%).6,9

With the advances in antiviral treatment, a cure to the HCV infection is achievable, which is defined as a sustained reduction in HCV RNA levels below the lower limit of quantification (LLOQ; 15 IU/mL) at 12 or 24 weeks after completion of treatment (referred to as sustained virologic response [SVR]; SVR12 or SVR24, respectively).2 Patients who achieve SVR have a very low risk of late relapse, indicating long-term control of the infection.2,10 Until recently, the choice of treatment was based on previous treatment status, presence of cirrhosis and comorbidities, and genotyping and resistance profiles.11,12 However, the introduction of pan-genotypic combination direct-acting antiviral (DAA) regimens, using drugs with different modes of action, has simplified the care pathway for patients with HCV infection.3,11,13

Glecaprevir/pibrentasvir (G/P), a fixed-dose combination of two DAAs, is the first pan-genotypic, once-daily treatment regimen approved in South Korea for patients with chronic HCV infection regardless of genotypes.14,15 The international and Korean guidelines recommend the use of G/P therapy for both treatment-naïve and treatment-experienced patients.2,11,12

G/P therapy is also approved for a shortened 8-week treatment regimen. An integrated analysis of nine phase II and III global clinical trials, including treatment-naïve and treatment-experienced patients with chronic HCV GT1-6 infection without cirrhosis (n=2,041), demonstrated high rates of SVR with the G/P regimen regardless of 8-week (98%) or 12-week (99%) therapy.16 In another study enrolling 343 treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis, 97.7% of patients achieved SVR12 with 8-week G/P therapy.17

Several regional and country-level differences exist in the disease characteristics of patients with HCV infection. The screening practices, care pathways and treatment access also differ across countries.18 Hence, local data on clinical characteristics and treatment efficacy and tolerability is highly desirable, particularly in Asian countries that are generally under-represented in global clinical trials. A pooled analysis of data from six phase II and III clinical trials demonstrated high SVR12 rates with 8-week G/P therapy in Japanese and international patients with non-cirrhotic chronic HCV GT1-2 infection (n=899).19 However, there are currently no data on the efficacy and safety of the G/P regimen in Korean subjects with HCV infection. Five phase II and III clinical trials of G/P therapy, including three global trials (ENDURANCE 120 and 221 and SURVEYOR II [part 4]21) and two Asian clinical trials (VOYAGE I22 and II22), enrolled patients from South Korea. Therefore, using pooled data from these five clinical trials, this analysis aimed to evaluate the efficacy and safety of G/P in Korean patients with GT1 or GT2 HCV infection with or without compensated cirrhosis.

1. Study design and population

An integrated analysis was conducted using data from Korean patients with HCV GT1 or GT2 infection enrolled in five phase II and III trials evaluating the efficacy and safety of G/P therapy. In all five trials, patients received oral G/P therapy (300 mg/120 mg), administered as three 100/40 mg tablets once daily with food, for either 8 or 12 weeks. The detailed study methodology and primary outcomes of the following registrational clinical trials have been published: ENDURANCE 1 (NCT02604017),20 ENDURANCE 2 (NCT02640482),21 SURVEYOR II part 4 (NCT02243293),21 VOYAGE I (NCT03222583)22 and VOYAGE II (NCT03235349)22 (Supplementary Table 1). All the trials required a written informed consent from enrolled patients and were designed and conducted in accordance with the ethical principles laid down in the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulations and were approved by independent ethics or institutional review committees.

A comparison of the inclusion and exclusion criteria across studies is described in Supplementary Table 2. For all the five trials, eligible patients were adults aged ≥18 years with chronic HCV GT1 or GT2 infection (confirmed by HCV RNA ≥1,000 IU/mL at screening; chronic HCV infection was confirmed by anti-HCV seropositivity or plasma HCV RNA ≥6 months prior to screening or liver biopsy). In addition, eligible patients were non-cirrhotic (except for VOYAGE II trial), treatment naïve or previously treated for HCV (interferon±ribavirin or sofosbuvir+ribavirin±interferon). Patients with prior treatment experience were required to have completed their previous HCV treatment at least 8 weeks prior to screening. The absence of cirrhosis was documented by screening FibroTest ≤0.48, and aspartate aminotransferase platelet ratio index <1, or FibroScan <12.5 kPa, or liver biopsy at screening. Patients with documented compensated cirrhosis were included only in the VOYAGE II trial. ENDURANCE 1, VOYAGE I and II allowed patients with HCV/human immunodeficiency virus (HIV) coinfection, defined as positive test result for HIV antibody at screening (HIV-1 RNA <1,000 copies/mL for treatment naïve or HIV-1 RNA <LLOQ for those receiving antiretroviral treatment regimen)–however none of the patients enrolled in the VOYAGE trials had HIV coinfection. Hepatitis B coinfection was exclusionary for all clinical trials.

In the ENDURANCE-1 trial, patients were randomized to receive either 8-week or 12-week treatment with G/P, whereas in the SURVEYOR II part 4 and VOYAGE I trials, patients received G/P treatment for 8 weeks. In the ENDURANCE-2 and VOYAGE II (which included patients with compensated cirrhosis), patients with GT1 or GT2 HCV infection received 12-week G/P therapy.

2. Assessments

For the assessment of baseline viral load and SVR12, plasma HCV RNA was quantified for each sample using COBAS AmpliPrep/TaqMan real-time reverse-transcriptase polymerase chain reaction assay (version 2.0; Roche Molecular Diagnostics, Rotkreuz, Switzerland), which has a LLOQ of 15 IU/mL. HCV genotyping was done at screening using LiPA assay (Versant HCV Genotype 2.0 Assay; Siemens Healthcare Diagnostics, Erlangen, Germany) or a Sanger sequencing assay (if the LiPA assay failed) and was confirmed by phylogenetic analysis. For patients who experienced virologic failure, HCV resistance analysis to check for NS3 and NS5A polymorphisms was done at baseline and at the time of virologic failure using next-generation sequencing (detection limit: 2%).

Adverse events (AEs) and abnormalities in physical examinations and laboratory test assessments were monitored in all five studies; the causal relationship with the study treatment (G/P) was assessed by the study investigator.

3. Endpoints

The primary outcome of this analysis was the efficacy of G/P therapy in Korean patients with HCV infection as assessed by SVR12, which is defined as achieving an HCV RNA level below the LLOQ (15 IU/mL) 12 weeks after the last dose of G/P. Safety evaluations included treatment-emergent AEs (occurring from day 1 of dosing until 30 days after the last dose of G/P) and laboratory abnormalities occurring during treatment. Secondary outcomes included incidence of on-treatment virologic failure and posttreatment relapse. On-treatment virologic failure was defined as a confirmed increase in HCV RNA of: >1 log10 IU/mL above nadir or ≥100 IU/mL after achieving HCV RNA level <LLOQ during treatment; or HCV RNA ≥LLOQ at the end of treatment with ≥6 weeks of treatment. Posttreatment relapse was assessed in patients who completed treatment as planned and achieved an HCV RNA <LLOQ at the end of treatment, and was defined as a confirmed HCV RNA ≥LLOQ between the last dose of G/P and 12 weeks thereafter. A summary of AEs and laboratory abnormalities from a previously reported pooled analysis of a global population of patients with non-cirrhotic pan-genotypic HCV infection treated with G/P (n=2,041) is also presented.16

4. Statistical analysis methods

Efficacy and safety outcomes were analyzed for the intention-to-treat population, defined as patients receiving ≥1 dose of G/P (300/120 mg). The SVR12 rates and two-sided 95% confidence intervals (CI; using Wilson score method) were calculated for the overall population and for subgroups based on genotype (GT1 or GT2), subgenotype (1A, 1B, 2, 2A, 2A/2C, or 2B), cirrhosis status (no cirrhosis or compensated cirrhosis), and treatment duration (8 weeks and 12 weeks). Secondary efficacy and safety endpoints were summarized with numbers and percentages of patients.

1. Baseline patient demographics and disease characteristics

This pooled analysis of data from five phase II or III clinical trials included 265 South Korean patients with chronic HCV infection who received 8-week or 12-week G/P treatment. Of these, 133 (50.2%) were GT1-infected and 132 (49.8%) were GT2-infected, and the most common subtypes were 1B (48.7%, 129/265) and 2A (44.5%, 118/265). The baseline patient demographics and disease characteristics are described in Table 1. The median age was 60 years (range, 21 to 87 years) and 46.4% of the study population were male; the median HCV RNA level at baseline was 6.3 log10 IU/mL (range, 2.5 to 7.7 log10 IU/mL). Most patients were HCV treatment naïve (67.5%, 179/265), without cirrhosis (86.0%, 228/265), and not using injection drugs (94.3%, 250/265); more than half of the study population received 8-week G/P treatment (57.7%, 153/265). The analysis population included 101 (38.1%) patients with cardiovascular disease, 92 (34.7%) patients with hypertension, 41 (15.5%) patients with diabetes, and 35 (13.2%) patients with HIV coinfection.

Table 1. Demographics and Disease Characteristics at Baseline in the Intention-to-Treat Population

CharacteristicGT1 (n=133)GT2 (n=132)Overall (n=265)
Male sex63 (47.4)60 (45.5)123 (46.4)
Age, yr59 (21–85)62 (25–87)60 (21–87)
BMI, kg/m223.8 (17.9–36.7)24.3 (17.9–33.9)24.2 (17.9–36.7)
HCV treatment experience
Naïve93 (69.9)86 (65.2)179 (67.5)
IFN based39 (29.3)42 (31.8)81 (30.6)
SOF based1 (0.8)4 (3.0)5 (1.9)
Enrolled study
M13-590 (ENDURANCE 1)35 (26.3)035 (13.2)
M15-464 (ENDURANCE 2)*1 (0.8)63 (47.7)64 (24.2)
M14-868 (SURVEYOR II part 4)05 (3.8)5 (1.9)
M15-592 (VOYAGE I)*74 (55.6)50 (37.9)124 (46.8)
M15-593 (VOYAGE II)23 (17.3)14 (10.6)37 (14.0)
HCV subgenotype
1A4 (3.0)04 (1.5)
1B129 (97.0)0129 (48.7)
203 (2.3)3 (1.1)
2A0118 (89.4)118 (44.5)
2A/2C03 (2.3)3 (1.1)
2B08 (6.1)8 (3.0)
Cirrhosis status
No cirrhosis110 (82.7)118 (89.4)228 (86.0)
Compensated cirrhosis23 (17.3)14 (10.6)37 (14.0)
Baseline HCV RNA level, IU/mL
<1.0×106123 (92.5)118 (89.4)241 (90.9)
≥1.0×10610 (7.5)14 (10.6)24 (9.1)
Baseline HCV RNA level, log10 IU/mL6.4 (2.5–7.7)6.2 (2.5–7.3)6.3 (2.5–7.7)
IL28B
CC99 (74.4)105 (79.5)204 (77.0)
Non-CC34 (25.6)27 (20.5)61 (23.0)
History of disorders
Diabetes23 (17.3)18 (13.6)41 (15.5)
Depression or bipolar disorder6 (4.5)7 (5.3)13 (4.9)
Bleeding disorder1 (0.8)1 (0.8)2 (0.8)
Hypertension48 (36.1)44 (33.3)92 (34.7)
Cardiovascular disease51 (38.3)50 (37.9)101 (38.1)
HIV coinfection35 (26.3)035 (13.2)
G/P treatment duration
8 Weeks98 (73.7)55 (41.7)153 (57.7)
12 Weeks35 (26.3)77 (58.3)112 (42.3)
History of injection drug use
Yes7 (5.3)8 (6.1)15 (5.7)
No126 (94.7)124 (93.9)250 (94.3)

Data are presented as number (%) or median (range).

GT, genotype; BMI, body mass index; HCV, hepatitis C virus; IFN, interferon; SOF, sofosbuvir; IL28B, interleukin 28B; HIV, human immunodeficiency virus; G/P, glecaprevir/pibrentasvir.

*Including patients who received placebo during the double-blind treatment period followed by G/P during the open-label treatment period.



2. Efficacy outcomes

Overall, 98.9% of patients achieved SVR12 (262/265; 95% CI, 96.7 to 99.6) (Fig. 1). The proportions of patients with GT1 and GT2 achieving SVR12 were 99.2% (132/133; 95% CI, 95.9 to 99.9), and 98.5% (130/132; 95% CI, 94.6 to 99.6), respectively. All patients with compensated cirrhosis (included in VOYAGE II trial and received 12-week G/P therapy) achieved SVR12 (100%, 37/37); among patients without cirrhosis, 98.7% (225/228; 95% CI, 96.2 to 99.6) achieved SVR12 (Table 2). All patients with subgenotypes 1A, 2, 2A/2C and 2B (Fig. 2A), and with a 12-week treatment duration achieved SVR12, whereas, 98.0% (150/153; 95% CI, 94.4 to 99.3) of subjects with 8-week treatment duration achieved SVR12 (Fig. 2B).

Table 2. Primary (SVR12) and Secondary (on-Treatment Virologic Failure and Posttreatment Relapse) Outcomes in the Intention-to-Treat Population

OutcomeNo cirrhosis (n=228)Compensated cirrhosis (VOYAGE II) (n=37)Overall
(n=265)
All patients
(n=228)
GT1
(n=110)
GT2
(n=118)
All patients
(n=37)
GT1
(n=23)
GT2
(n=14)
SVR12225 (98.7)109 (99.1)116 (98.3)37 (100)23 (100)14 (100)262 (98.9)
Virologic failure
On-treatment0000000
Relapse*1 (0.4)01 (0.8)0001 (0.4)
Non-virologic failure
Premature G/P discontinuation 1 (0.4) 1 (0.9)00001 (0.4)
Missing SVR12 data1 (0.4)01 (0.8)0001 (0.4)

Data are presented as number (%).

SVR12, sustained virologic response at 12 weeks posttreatment; GT, genotype; G/P, glecaprevir/pibrentasvir.

*Among patients who completed treatment as planned and achieved an hepatitis C virus RNA level less than lower limit of quantification at final treatment visit and had posttreatment data (n=262).



Figure 1.Number and percentage of Korean subjects with SVR12 in the intention-to-treat population. Rates of SVR12 by genotype, cirrhosis status and treatment duration (8 or 12 weeks). Error bars represent 95% confidence intervals.
GT, genotype; SVR12, sustained virologic response at 12 weeks posttreatment. *4 Patients were GT1A and 129 patients were GT1B; 118 Patients were GT2A, 8 were GT2B, 3 were GT2A/2C, and 3 had unknown subtype.

Figure 2.Number and percentage of Korean subjects with SVR12 by subgroup in the intention-to-treat population. Rates of SVR12 by (A) subgenotype (1A, 1B, 2, 2A, 2A/2C, and 2B) and (B) G/P treatment duration (8 weeks and 12 weeks). Error bars represent 95% confidence intervals.
SVR12, sustained virologic response at 12 weeks posttreatment; G/P, glecaprevir/pibrentasvir.

A total of three patients did not achieve SVR12, including one virologic failure and two non-virologic failures (Table 3). Two patients with GT2A infection did not achieve SVR12; one patient experienced virologic failure due to posttreatment relapse at 12 weeks, and another patient was missing HCV RNA data in the SVR12 analysis window. One patient with GT1B infection experienced hyperbilirubinemia leading to premature discontinuation of G/P treatment, which was assessed as not related to the treatment by the study investigators. All three patients who did not achieve SVR12 were non-cirrhotic, had no HIV coinfection, and received 8-week G/P therapy.

Table 3. Characteristics of Patients Experiencing Virologic and Non-Virologic Failure at Baseline and the Time of Failure from the VOYAGE I Clinical Trial

CharacteristicPatient 1Patient 2Patient 3
Reason for nonresponseRelapseMissing SVR12 data*Premature G/P discontinuation
Sex/age, yrMale/66Female/74Female/77
Treatment historySOF-experiencedNaïveNaïve
HCV subtype2A2A1B
Compensated cirrhosisNoNoNo
Baseline HCV RNA level, IU/mL8.6×10621×10613.1×106
IL28B subtypeCCCCCC
Treatment duration, wk888
HIV coinfectionNoNoNo
NS3 variants
BaselineNoneNoneS122T, V170I
At failureNoneNANA
NS5A variants
BaselineL31MT24A, L31MQ54Y, Q62D, Y93H
At failureL31M, C92SNANA

HCV, hepatitis C virus; IL28B, interleukin 28B; HIV, human immunodeficiency virus; NS, nonstructural protein; SVR12, sustained virologic response at 12 weeks posttreatment; G/P, glecaprevir/pibrentasvir; SOF, sofosbuvir; NA, not available.

*No detectable HCV RNA at last visit (posttreatment week 4, posttreatment day 27); did not return for SVR12 visit. Baseline polymorphisms and treatment-emergent substitutions at signature amino acid positions: NS3 (36, 43, 54, 55, 56, 80, 107, 122, 155, 156, 158, 168, 170, 175) and NS5A (24, 28, 29, 30, 31, 32, 54, 58, 62, 92, 93) at 2% detection threshold.



We also analyzed the long-term follow-up data (as of date/month/year) available from the included trials for the incidence of relapse or reinfections. None of the Korean patients included in the trials experience relapse or reinfections. Overall, there was only one case of reinfection in SURVEYOR II part 4 study in a non-Korean participant.

3. Safety outcomes

Overall, 119 patients (44.9%) experienced an AE, with most being grade 1 or 2; eight patients (3.0%) reported at least one AE of grade 3 or higher severity (Table 4). AEs related to study treatment were reported in 30 patients (11.3%); none of these AEs were of grade 3 or higher severity. Serious AEs occurred in seven patients (2.6%) and were unlikely to be related to G/P therapy as assessed by the investigator: bile duct stone (0.8%), urinary tract infection (0.4%), radius fracture (0.4%), ligament rupture (0.4%), papillary thyroid cancer (0.4%), and depression (0.4%). The most commonly reported AEs were upper respiratory tract infection (7.2%), fatigue (4.2%), diarrhea (3.0%) headache (2.6%), and pruritus (2.3%). Only one patient (0.4%) experienced an AE which led to treatment discontinuation (blood bilirubin increased); this AE was considered not related to G/P. The incidence of laboratory abnormalities of grade ≥3 severity was rare and none of the patients experienced grade ≥3 abnormalities in aspartate aminotransferase levels. Only two patients experienced grade 3 abnormalities in bilirubin and alanine aminotransferase, respectively.

Table 4. Overview of AEs and Laboratory Abnormalities in the Intention-to-Treat Population

AEKorean population (n=265)Pooled analysis of global phase II&III (n=2,041)
Any AE119 (44.9)1,343 (65.8)
Serious AE7 (2.6)*42 (2.1)
G/P-related AE30 (11.3)NA
G/P-related serious AE01 (<0.1)
AE leading to G/P discontinuation1 (0.4)10 (0.5)
AEs in ≥10% of all patients0
Headache344 (16.9)
Fatigue281 (13.8)
Laboratory abnormalities
ALT, grade ≥3 (>5×ULN)1 (0.4)1 (<0.1)
AST, grade ≥3 (>5×ULN)07 (0.3)
Total bilirubin, grade ≥3 (>3×ULN)1 (0.4)7 (0.3)

Data are presented as number (%). This table is presenting “data in perspective” from two separate analyses.16

AE, adverse event; G/P, glecaprevir/pibrentasvir; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal; NA, not available.

*Bile duct stone (n=2), followed by urinary tract infection, radius fracture, ligament rupture, papillary thyroid cancer, and depression (n=1 each); Five most frequent AEs: upper respiratory tract infection (7.2%), fatigue (4.2%), diarrhea (3.0%), headache (2.6%), and pruritus (2.3%); This is not a comparison performed in the current study of Korean patients.



The safety profile of G/P therapy in the Korean population was comparable with that observed in the integrated analysis of nine global phase II and III clinical trials in which patients with non-cirrhotic HCV GT1-6 infection were treated with G/P therapy (Table 4).16 The incidence of AEs was slightly lower in the Korean population (44.9%, 119/265) than in the global pooled analysis (65.8%, 1,343/2,041). Serious AEs were reported in 2.6% (7/265), and 2.1% (42/2,041) of patients in the Korean and global pooled analyses, respectively. Serious AEs related to treatment occurred only in one patient in the global pooled analysis. AEs leading to drug discontinuation were reported in 0.4% (1/265), and 0.5% (10/2,041) of patients in the Korean and global pooled analyses, respectively. Among the Korean population, no AEs occurred in ≥10% of the subjects whereas in the global pooled analysis, the most common AEs were headache (16.9%), and fatigue (13.8%). Incidence of grade 3 or higher hepatic laboratory abnormalities was low in both Korean and global analyses (alanine aminotransferase 0.4% and <0.1%; aspartate aminotransferase 0% and 0.3%; and total bilirubin 0.4% and 0.3%, respectively).

The findings from this pooled analysis demonstrated high efficacy of 8-week or 12-week G/P therapy in Korean patients with HCV infection, regardless of genotype, subgenotype, presence of cirrhosis, and treatment duration. As in the global integrated analysis, G/P therapy was well tolerated in Korean patients with HCV infection, with low incidence of serious AEs or AEs leading to treatment discontinuation. Findings from this analysis of Korean patients also indicate that the study population and disease characteristics were representative of Korean patients with HCV; for instance, genotypes GT1B and GT2A were the most common subtypes, accounting for 93% of all patients.9

This is the first analysis evaluating the efficacy and safety of G/P in Korean HCV GT1- or GT2-infected patients with or without compensated cirrhosis. HCV genotypes appear to be a key predictive factor of liver disease severity and treatment response, with a distinct geographical distribution. Among the Korean population GT1 and GT2 account for 99% of HCV infection.6 Previous studies investigating treatment response in Korean patients with HCV infection have shown high therapeutic efficacy in this population, even before the introduction of new pan-genotypic DAA agents. For example, results from a retrospective study evaluating the efficacy of pegylated interferon and ribavirin therapy in Korean patients with chronic HCV infection showed a superior therapeutic efficacy of this regimen in Koreans as compared with Caucasians, with overall SVR rates ranging between 63% and 81%.23 Even though the evidence on the efficacy of first-generation DAA in Korean patients with HCV infection is very limited,11 data from a real-world study conducted in Korean patients demonstrated high SVR12 rates of 93% with the first-generation DAA treatment combination daclatasvir plus asunaprevir.24 Another study comparing the efficacy of several DAA regimens in Asian patients with HCV showed SRV12 rates of 99.2%, and a significant improvement in quality of life with ledipasvir/sofosbuvir combination, the previous standard treatment for HCV GT1A infection.25 Furthermore, a retrospective study evaluating sofosbuvir-based therapy showed an SVR12 rate as high as 100% in Korean patients with HCV infection.26

Results from the current study demonstrated high efficacy of an 8-week regimen of the pan-genotypic G/P therapy, which can have significant implications on the treatment burden and care pathway for patients with HCV. For example, the G/P regimen as first-line therapy would reduce the treatment duration without compromising efficacy. Shortened treatment duration also implies less on-treatment monitoring and physician visits, enabling cost-reductions in terms of reduced number of diagnostic procedures and clinic visits, thus improving the accessibility of treatment for a larger number of patients. In addition, as G/P is effective across all genotypes, use of this regimen may preclude baseline assessments, such as genotyping. The promotion of a simplified pretreatment evaluation in patients with HCV GT1 or GT2 infection receiving the G/P pan-genotypic regimen would help prevent liver disease complications and further HCV transmission; thereby contributing towards HCV elimination.27 However, genotyping is still considered as an essential component of HCV diagnosis in South Korea.9

The incidence of AEs was slightly lower in the Korean population than in the global integrated analysis, 44.9% (119/265) versus 65.8% (1,343/2,041); however, statistical analysis of this difference was not performed.16

Limitations of this pooled analysis include small sample size (n=265) as compared with the global integrated analysis (n=2,041).16 Additionally, when comparing the AE pattern with the global pooled population, no differentiation between genotypes was considered, and data from all genotypes (GT1-6) were included. Furthermore, the present analysis in the Korean population included a small number of high-risk patients such as previous injection drug users (IDU; 5.7%), those with sofosbuvir-based treatment-experience (1.9%), compensated cirrhosis (14.0%), HIV coinfection (13.2%), and non-CC interleukin 28B subtype (23.0%). Most of the population were not previous IDUs (94.3%, 250/265), which may have resulted in better treatment adherence and compliance than in the global integrated analysis (61%, 1,243/2,041).16 Nevertheless, a recent pooled analysis of seven phase III trials evaluating efficacy and safety of 8-week or 12-week G/P treatment demonstrated that treatment adherence and compliance in recent IDUs were high despite enduring concerns.28 The current international guidelines (European Association for the Study of the Liver2 and American Association for the Study of Liver Diseases12) emphasize that treatment response among IDUs is similar to that in non-IDU populations. Moreover, this high-risk group could benefit from a shorter treatment duration (8 weeks).28 Interleukin 28B CC genotype, which is estimated to be present in around 90% of the Korean population, has been strongly associated with spontaneous viral clearance and favorable clinical outcomes.29 However, it is still unclear whether Interleukin 28B genotype has a strong influence on the effects of DAAs, or which DAAs are best for people with non-CC genotypes.

In conclusion, results from this analysis indicate that treatment with G/P combination therapy for 8 or 12 weeks is highly efficacious and well tolerated in Korean patients with HCV GT1 or GT2 infections, supporting the current Korean Association for the Study of the Liver recommendation.11

The design, study conduct, analysis, and financial support of the trials (ENDURANCE 1, ENDURANCE 2, SURVEYOR II part 4, VOYAGE I and VOYAGE II) was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. All authors had access to all relevant data.

The authors would like to express their gratitude to the trial participants, investigators, and coordinators who made this study possible. Medical writing assistance was provided by Syed Abdul Haseeb and Julia Ventura from MediTech Media (Singapore), which was funded by AbbVie in accordance with Good Publication Practice guidelines.


Y.S.L. is an advisory board member of Bayer Healthcare and Gilead Sciences. E.D.C., L.M.F., and N.N.A. are employees of AbbVie, Inc. and may hold stock or stock options. A.A. and D.H.K. are former employees of AbbVie, Inc. and may hold stock or stock options. Other authors have no conflicts of interest to declare.

Y.J.K. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.


Study design: D.H.K., E.D.C. Formal analysis: E.D.C., L.M.F., N.N.A., A.A. Study conduction and data collection: J.H., Y.J.K., J.W.L., J.H.K., Y.S.L., K.H.H., S.H.J., M.C., K.T.Y., S.H.B., S.W.P., Y.J.L. Data Interpretation, review, approval of final manuscript: all authors.

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Article

Original Article

Gut and Liver 2021; 15(6): 895-903

Published online November 15, 2021 https://doi.org/10.5009/gnl20321

Copyright © Gut and Liver.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Korean Patients with Chronic Hepatitis C: A Pooled Analysis of Five Phase II/III Trials

Jeong Heo1 , Yoon Jun Kim2 , Jin-Woo Lee3 , Ji Hoon Kim4 , Young-Suk Lim5 , Kwang-Hyub Han6 , Sook-Hyang Jeong7 , Mong Cho8 , Ki Tae Yoon8 , Si Hyun Bae9 , Eric D. Crown10 , Linda M. Fredrick10 , Negar Niki Alami10 , Armen Asatryan10 , Do Hyun Kim11 , Seung Woon Paik12 , and Youn-Jae Lee13

1Department of Internal Medicine, Pusan National University College of Medicine and Medical Research Institute, Pusan National University Hospital, Busan, 2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 3Department of Internal Medicine, Inha University School of Medicine, Incheon, 4Department of Internal Medicine, Korea University College of Medicine, 5Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 6Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 7Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 8Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University College of Medicine, Yangsan, 9Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea, 10Abbvie Inc., North Chicago, IL, USA, 11AbbVie Korea, Ltd., 12Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, and 13Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Seung Woon Paik
ORCID https://orcid.org/0000-0002-6746-6652
E-mail swpaik@skku.edu

Youn-Jae Lee
ORCID https://orcid.org/0000-0003-3854-3388
E-mail yjyh0105@inje.ac.kr

Received: October 28, 2020; Revised: December 24, 2020; Accepted: January 4, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Glecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection.
Methods: The study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments.
Results: The analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12: one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%).
Conclusions: G/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.

Keywords: Glecaprevir and pibrentasvir, Pan-genotypic antivirals, Hepatitis C virus, Korea

INTRODUCTION

Hepatitis C virus (HCV) infection affects up to 71 million individuals worldwide and causes substantial morbidity and mortality.1,2 Patients who do not receive antiviral treatment are at high risk of serious long-term hepatic complications which include cirrhosis, decompensation, hepatocellular cancer and death.1,3-5 Among Korean patients with advanced liver diseases including liver cirrhosis and hepatocellular carcinoma, 11% to 17% present with HCV infection.6 The estimated seroprevalence of anti-HCV antibodies in Korean adults is 0.8% (about 300,000 individuals), which increases steeply with age to 2.3% in individuals aged ≥70 years.7,8 Among patients with chronic HCV infection in South Korea, virus genotypes (GTs) 1 and 2 collectively account for the vast majority (99%) and the most common subtypes are GT1B (45% to 59%) and GT2A (26% to 51%).6,9

With the advances in antiviral treatment, a cure to the HCV infection is achievable, which is defined as a sustained reduction in HCV RNA levels below the lower limit of quantification (LLOQ; 15 IU/mL) at 12 or 24 weeks after completion of treatment (referred to as sustained virologic response [SVR]; SVR12 or SVR24, respectively).2 Patients who achieve SVR have a very low risk of late relapse, indicating long-term control of the infection.2,10 Until recently, the choice of treatment was based on previous treatment status, presence of cirrhosis and comorbidities, and genotyping and resistance profiles.11,12 However, the introduction of pan-genotypic combination direct-acting antiviral (DAA) regimens, using drugs with different modes of action, has simplified the care pathway for patients with HCV infection.3,11,13

Glecaprevir/pibrentasvir (G/P), a fixed-dose combination of two DAAs, is the first pan-genotypic, once-daily treatment regimen approved in South Korea for patients with chronic HCV infection regardless of genotypes.14,15 The international and Korean guidelines recommend the use of G/P therapy for both treatment-naïve and treatment-experienced patients.2,11,12

G/P therapy is also approved for a shortened 8-week treatment regimen. An integrated analysis of nine phase II and III global clinical trials, including treatment-naïve and treatment-experienced patients with chronic HCV GT1-6 infection without cirrhosis (n=2,041), demonstrated high rates of SVR with the G/P regimen regardless of 8-week (98%) or 12-week (99%) therapy.16 In another study enrolling 343 treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis, 97.7% of patients achieved SVR12 with 8-week G/P therapy.17

Several regional and country-level differences exist in the disease characteristics of patients with HCV infection. The screening practices, care pathways and treatment access also differ across countries.18 Hence, local data on clinical characteristics and treatment efficacy and tolerability is highly desirable, particularly in Asian countries that are generally under-represented in global clinical trials. A pooled analysis of data from six phase II and III clinical trials demonstrated high SVR12 rates with 8-week G/P therapy in Japanese and international patients with non-cirrhotic chronic HCV GT1-2 infection (n=899).19 However, there are currently no data on the efficacy and safety of the G/P regimen in Korean subjects with HCV infection. Five phase II and III clinical trials of G/P therapy, including three global trials (ENDURANCE 120 and 221 and SURVEYOR II [part 4]21) and two Asian clinical trials (VOYAGE I22 and II22), enrolled patients from South Korea. Therefore, using pooled data from these five clinical trials, this analysis aimed to evaluate the efficacy and safety of G/P in Korean patients with GT1 or GT2 HCV infection with or without compensated cirrhosis.

MATERIALS AND METHODS

1. Study design and population

An integrated analysis was conducted using data from Korean patients with HCV GT1 or GT2 infection enrolled in five phase II and III trials evaluating the efficacy and safety of G/P therapy. In all five trials, patients received oral G/P therapy (300 mg/120 mg), administered as three 100/40 mg tablets once daily with food, for either 8 or 12 weeks. The detailed study methodology and primary outcomes of the following registrational clinical trials have been published: ENDURANCE 1 (NCT02604017),20 ENDURANCE 2 (NCT02640482),21 SURVEYOR II part 4 (NCT02243293),21 VOYAGE I (NCT03222583)22 and VOYAGE II (NCT03235349)22 (Supplementary Table 1). All the trials required a written informed consent from enrolled patients and were designed and conducted in accordance with the ethical principles laid down in the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulations and were approved by independent ethics or institutional review committees.

A comparison of the inclusion and exclusion criteria across studies is described in Supplementary Table 2. For all the five trials, eligible patients were adults aged ≥18 years with chronic HCV GT1 or GT2 infection (confirmed by HCV RNA ≥1,000 IU/mL at screening; chronic HCV infection was confirmed by anti-HCV seropositivity or plasma HCV RNA ≥6 months prior to screening or liver biopsy). In addition, eligible patients were non-cirrhotic (except for VOYAGE II trial), treatment naïve or previously treated for HCV (interferon±ribavirin or sofosbuvir+ribavirin±interferon). Patients with prior treatment experience were required to have completed their previous HCV treatment at least 8 weeks prior to screening. The absence of cirrhosis was documented by screening FibroTest ≤0.48, and aspartate aminotransferase platelet ratio index <1, or FibroScan <12.5 kPa, or liver biopsy at screening. Patients with documented compensated cirrhosis were included only in the VOYAGE II trial. ENDURANCE 1, VOYAGE I and II allowed patients with HCV/human immunodeficiency virus (HIV) coinfection, defined as positive test result for HIV antibody at screening (HIV-1 RNA <1,000 copies/mL for treatment naïve or HIV-1 RNA <LLOQ for those receiving antiretroviral treatment regimen)–however none of the patients enrolled in the VOYAGE trials had HIV coinfection. Hepatitis B coinfection was exclusionary for all clinical trials.

In the ENDURANCE-1 trial, patients were randomized to receive either 8-week or 12-week treatment with G/P, whereas in the SURVEYOR II part 4 and VOYAGE I trials, patients received G/P treatment for 8 weeks. In the ENDURANCE-2 and VOYAGE II (which included patients with compensated cirrhosis), patients with GT1 or GT2 HCV infection received 12-week G/P therapy.

2. Assessments

For the assessment of baseline viral load and SVR12, plasma HCV RNA was quantified for each sample using COBAS AmpliPrep/TaqMan real-time reverse-transcriptase polymerase chain reaction assay (version 2.0; Roche Molecular Diagnostics, Rotkreuz, Switzerland), which has a LLOQ of 15 IU/mL. HCV genotyping was done at screening using LiPA assay (Versant HCV Genotype 2.0 Assay; Siemens Healthcare Diagnostics, Erlangen, Germany) or a Sanger sequencing assay (if the LiPA assay failed) and was confirmed by phylogenetic analysis. For patients who experienced virologic failure, HCV resistance analysis to check for NS3 and NS5A polymorphisms was done at baseline and at the time of virologic failure using next-generation sequencing (detection limit: 2%).

Adverse events (AEs) and abnormalities in physical examinations and laboratory test assessments were monitored in all five studies; the causal relationship with the study treatment (G/P) was assessed by the study investigator.

3. Endpoints

The primary outcome of this analysis was the efficacy of G/P therapy in Korean patients with HCV infection as assessed by SVR12, which is defined as achieving an HCV RNA level below the LLOQ (15 IU/mL) 12 weeks after the last dose of G/P. Safety evaluations included treatment-emergent AEs (occurring from day 1 of dosing until 30 days after the last dose of G/P) and laboratory abnormalities occurring during treatment. Secondary outcomes included incidence of on-treatment virologic failure and posttreatment relapse. On-treatment virologic failure was defined as a confirmed increase in HCV RNA of: >1 log10 IU/mL above nadir or ≥100 IU/mL after achieving HCV RNA level <LLOQ during treatment; or HCV RNA ≥LLOQ at the end of treatment with ≥6 weeks of treatment. Posttreatment relapse was assessed in patients who completed treatment as planned and achieved an HCV RNA <LLOQ at the end of treatment, and was defined as a confirmed HCV RNA ≥LLOQ between the last dose of G/P and 12 weeks thereafter. A summary of AEs and laboratory abnormalities from a previously reported pooled analysis of a global population of patients with non-cirrhotic pan-genotypic HCV infection treated with G/P (n=2,041) is also presented.16

4. Statistical analysis methods

Efficacy and safety outcomes were analyzed for the intention-to-treat population, defined as patients receiving ≥1 dose of G/P (300/120 mg). The SVR12 rates and two-sided 95% confidence intervals (CI; using Wilson score method) were calculated for the overall population and for subgroups based on genotype (GT1 or GT2), subgenotype (1A, 1B, 2, 2A, 2A/2C, or 2B), cirrhosis status (no cirrhosis or compensated cirrhosis), and treatment duration (8 weeks and 12 weeks). Secondary efficacy and safety endpoints were summarized with numbers and percentages of patients.

RESULTS

1. Baseline patient demographics and disease characteristics

This pooled analysis of data from five phase II or III clinical trials included 265 South Korean patients with chronic HCV infection who received 8-week or 12-week G/P treatment. Of these, 133 (50.2%) were GT1-infected and 132 (49.8%) were GT2-infected, and the most common subtypes were 1B (48.7%, 129/265) and 2A (44.5%, 118/265). The baseline patient demographics and disease characteristics are described in Table 1. The median age was 60 years (range, 21 to 87 years) and 46.4% of the study population were male; the median HCV RNA level at baseline was 6.3 log10 IU/mL (range, 2.5 to 7.7 log10 IU/mL). Most patients were HCV treatment naïve (67.5%, 179/265), without cirrhosis (86.0%, 228/265), and not using injection drugs (94.3%, 250/265); more than half of the study population received 8-week G/P treatment (57.7%, 153/265). The analysis population included 101 (38.1%) patients with cardiovascular disease, 92 (34.7%) patients with hypertension, 41 (15.5%) patients with diabetes, and 35 (13.2%) patients with HIV coinfection.

Table 1 . Demographics and Disease Characteristics at Baseline in the Intention-to-Treat Population.

CharacteristicGT1 (n=133)GT2 (n=132)Overall (n=265)
Male sex63 (47.4)60 (45.5)123 (46.4)
Age, yr59 (21–85)62 (25–87)60 (21–87)
BMI, kg/m223.8 (17.9–36.7)24.3 (17.9–33.9)24.2 (17.9–36.7)
HCV treatment experience
Naïve93 (69.9)86 (65.2)179 (67.5)
IFN based39 (29.3)42 (31.8)81 (30.6)
SOF based1 (0.8)4 (3.0)5 (1.9)
Enrolled study
M13-590 (ENDURANCE 1)35 (26.3)035 (13.2)
M15-464 (ENDURANCE 2)*1 (0.8)63 (47.7)64 (24.2)
M14-868 (SURVEYOR II part 4)05 (3.8)5 (1.9)
M15-592 (VOYAGE I)*74 (55.6)50 (37.9)124 (46.8)
M15-593 (VOYAGE II)23 (17.3)14 (10.6)37 (14.0)
HCV subgenotype
1A4 (3.0)04 (1.5)
1B129 (97.0)0129 (48.7)
203 (2.3)3 (1.1)
2A0118 (89.4)118 (44.5)
2A/2C03 (2.3)3 (1.1)
2B08 (6.1)8 (3.0)
Cirrhosis status
No cirrhosis110 (82.7)118 (89.4)228 (86.0)
Compensated cirrhosis23 (17.3)14 (10.6)37 (14.0)
Baseline HCV RNA level, IU/mL
<1.0×106123 (92.5)118 (89.4)241 (90.9)
≥1.0×10610 (7.5)14 (10.6)24 (9.1)
Baseline HCV RNA level, log10 IU/mL6.4 (2.5–7.7)6.2 (2.5–7.3)6.3 (2.5–7.7)
IL28B
CC99 (74.4)105 (79.5)204 (77.0)
Non-CC34 (25.6)27 (20.5)61 (23.0)
History of disorders
Diabetes23 (17.3)18 (13.6)41 (15.5)
Depression or bipolar disorder6 (4.5)7 (5.3)13 (4.9)
Bleeding disorder1 (0.8)1 (0.8)2 (0.8)
Hypertension48 (36.1)44 (33.3)92 (34.7)
Cardiovascular disease51 (38.3)50 (37.9)101 (38.1)
HIV coinfection35 (26.3)035 (13.2)
G/P treatment duration
8 Weeks98 (73.7)55 (41.7)153 (57.7)
12 Weeks35 (26.3)77 (58.3)112 (42.3)
History of injection drug use
Yes7 (5.3)8 (6.1)15 (5.7)
No126 (94.7)124 (93.9)250 (94.3)

Data are presented as number (%) or median (range)..

GT, genotype; BMI, body mass index; HCV, hepatitis C virus; IFN, interferon; SOF, sofosbuvir; IL28B, interleukin 28B; HIV, human immunodeficiency virus; G/P, glecaprevir/pibrentasvir..

*Including patients who received placebo during the double-blind treatment period followed by G/P during the open-label treatment period..



2. Efficacy outcomes

Overall, 98.9% of patients achieved SVR12 (262/265; 95% CI, 96.7 to 99.6) (Fig. 1). The proportions of patients with GT1 and GT2 achieving SVR12 were 99.2% (132/133; 95% CI, 95.9 to 99.9), and 98.5% (130/132; 95% CI, 94.6 to 99.6), respectively. All patients with compensated cirrhosis (included in VOYAGE II trial and received 12-week G/P therapy) achieved SVR12 (100%, 37/37); among patients without cirrhosis, 98.7% (225/228; 95% CI, 96.2 to 99.6) achieved SVR12 (Table 2). All patients with subgenotypes 1A, 2, 2A/2C and 2B (Fig. 2A), and with a 12-week treatment duration achieved SVR12, whereas, 98.0% (150/153; 95% CI, 94.4 to 99.3) of subjects with 8-week treatment duration achieved SVR12 (Fig. 2B).

Table 2 . Primary (SVR12) and Secondary (on-Treatment Virologic Failure and Posttreatment Relapse) Outcomes in the Intention-to-Treat Population.

OutcomeNo cirrhosis (n=228)Compensated cirrhosis (VOYAGE II) (n=37)Overall
(n=265)
All patients
(n=228)
GT1
(n=110)
GT2
(n=118)
All patients
(n=37)
GT1
(n=23)
GT2
(n=14)
SVR12225 (98.7)109 (99.1)116 (98.3)37 (100)23 (100)14 (100)262 (98.9)
Virologic failure
On-treatment0000000
Relapse*1 (0.4)01 (0.8)0001 (0.4)
Non-virologic failure
Premature G/P discontinuation 1 (0.4) 1 (0.9)00001 (0.4)
Missing SVR12 data1 (0.4)01 (0.8)0001 (0.4)

Data are presented as number (%)..

SVR12, sustained virologic response at 12 weeks posttreatment; GT, genotype; G/P, glecaprevir/pibrentasvir..

*Among patients who completed treatment as planned and achieved an hepatitis C virus RNA level less than lower limit of quantification at final treatment visit and had posttreatment data (n=262)..



Figure 1. Number and percentage of Korean subjects with SVR12 in the intention-to-treat population. Rates of SVR12 by genotype, cirrhosis status and treatment duration (8 or 12 weeks). Error bars represent 95% confidence intervals.
GT, genotype; SVR12, sustained virologic response at 12 weeks posttreatment. *4 Patients were GT1A and 129 patients were GT1B; 118 Patients were GT2A, 8 were GT2B, 3 were GT2A/2C, and 3 had unknown subtype.

Figure 2. Number and percentage of Korean subjects with SVR12 by subgroup in the intention-to-treat population. Rates of SVR12 by (A) subgenotype (1A, 1B, 2, 2A, 2A/2C, and 2B) and (B) G/P treatment duration (8 weeks and 12 weeks). Error bars represent 95% confidence intervals.
SVR12, sustained virologic response at 12 weeks posttreatment; G/P, glecaprevir/pibrentasvir.

A total of three patients did not achieve SVR12, including one virologic failure and two non-virologic failures (Table 3). Two patients with GT2A infection did not achieve SVR12; one patient experienced virologic failure due to posttreatment relapse at 12 weeks, and another patient was missing HCV RNA data in the SVR12 analysis window. One patient with GT1B infection experienced hyperbilirubinemia leading to premature discontinuation of G/P treatment, which was assessed as not related to the treatment by the study investigators. All three patients who did not achieve SVR12 were non-cirrhotic, had no HIV coinfection, and received 8-week G/P therapy.

Table 3 . Characteristics of Patients Experiencing Virologic and Non-Virologic Failure at Baseline and the Time of Failure from the VOYAGE I Clinical Trial.

CharacteristicPatient 1Patient 2Patient 3
Reason for nonresponseRelapseMissing SVR12 data*Premature G/P discontinuation
Sex/age, yrMale/66Female/74Female/77
Treatment historySOF-experiencedNaïveNaïve
HCV subtype2A2A1B
Compensated cirrhosisNoNoNo
Baseline HCV RNA level, IU/mL8.6×10621×10613.1×106
IL28B subtypeCCCCCC
Treatment duration, wk888
HIV coinfectionNoNoNo
NS3 variants
BaselineNoneNoneS122T, V170I
At failureNoneNANA
NS5A variants
BaselineL31MT24A, L31MQ54Y, Q62D, Y93H
At failureL31M, C92SNANA

HCV, hepatitis C virus; IL28B, interleukin 28B; HIV, human immunodeficiency virus; NS, nonstructural protein; SVR12, sustained virologic response at 12 weeks posttreatment; G/P, glecaprevir/pibrentasvir; SOF, sofosbuvir; NA, not available..

*No detectable HCV RNA at last visit (posttreatment week 4, posttreatment day 27); did not return for SVR12 visit. Baseline polymorphisms and treatment-emergent substitutions at signature amino acid positions: NS3 (36, 43, 54, 55, 56, 80, 107, 122, 155, 156, 158, 168, 170, 175) and NS5A (24, 28, 29, 30, 31, 32, 54, 58, 62, 92, 93) at 2% detection threshold..



We also analyzed the long-term follow-up data (as of date/month/year) available from the included trials for the incidence of relapse or reinfections. None of the Korean patients included in the trials experience relapse or reinfections. Overall, there was only one case of reinfection in SURVEYOR II part 4 study in a non-Korean participant.

3. Safety outcomes

Overall, 119 patients (44.9%) experienced an AE, with most being grade 1 or 2; eight patients (3.0%) reported at least one AE of grade 3 or higher severity (Table 4). AEs related to study treatment were reported in 30 patients (11.3%); none of these AEs were of grade 3 or higher severity. Serious AEs occurred in seven patients (2.6%) and were unlikely to be related to G/P therapy as assessed by the investigator: bile duct stone (0.8%), urinary tract infection (0.4%), radius fracture (0.4%), ligament rupture (0.4%), papillary thyroid cancer (0.4%), and depression (0.4%). The most commonly reported AEs were upper respiratory tract infection (7.2%), fatigue (4.2%), diarrhea (3.0%) headache (2.6%), and pruritus (2.3%). Only one patient (0.4%) experienced an AE which led to treatment discontinuation (blood bilirubin increased); this AE was considered not related to G/P. The incidence of laboratory abnormalities of grade ≥3 severity was rare and none of the patients experienced grade ≥3 abnormalities in aspartate aminotransferase levels. Only two patients experienced grade 3 abnormalities in bilirubin and alanine aminotransferase, respectively.

Table 4 . Overview of AEs and Laboratory Abnormalities in the Intention-to-Treat Population.

AEKorean population (n=265)Pooled analysis of global phase II&III (n=2,041)
Any AE119 (44.9)1,343 (65.8)
Serious AE7 (2.6)*42 (2.1)
G/P-related AE30 (11.3)NA
G/P-related serious AE01 (<0.1)
AE leading to G/P discontinuation1 (0.4)10 (0.5)
AEs in ≥10% of all patients0
Headache344 (16.9)
Fatigue281 (13.8)
Laboratory abnormalities
ALT, grade ≥3 (>5×ULN)1 (0.4)1 (<0.1)
AST, grade ≥3 (>5×ULN)07 (0.3)
Total bilirubin, grade ≥3 (>3×ULN)1 (0.4)7 (0.3)

Data are presented as number (%). This table is presenting “data in perspective” from two separate analyses.16.

AE, adverse event; G/P, glecaprevir/pibrentasvir; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal; NA, not available..

*Bile duct stone (n=2), followed by urinary tract infection, radius fracture, ligament rupture, papillary thyroid cancer, and depression (n=1 each); Five most frequent AEs: upper respiratory tract infection (7.2%), fatigue (4.2%), diarrhea (3.0%), headache (2.6%), and pruritus (2.3%); This is not a comparison performed in the current study of Korean patients..



The safety profile of G/P therapy in the Korean population was comparable with that observed in the integrated analysis of nine global phase II and III clinical trials in which patients with non-cirrhotic HCV GT1-6 infection were treated with G/P therapy (Table 4).16 The incidence of AEs was slightly lower in the Korean population (44.9%, 119/265) than in the global pooled analysis (65.8%, 1,343/2,041). Serious AEs were reported in 2.6% (7/265), and 2.1% (42/2,041) of patients in the Korean and global pooled analyses, respectively. Serious AEs related to treatment occurred only in one patient in the global pooled analysis. AEs leading to drug discontinuation were reported in 0.4% (1/265), and 0.5% (10/2,041) of patients in the Korean and global pooled analyses, respectively. Among the Korean population, no AEs occurred in ≥10% of the subjects whereas in the global pooled analysis, the most common AEs were headache (16.9%), and fatigue (13.8%). Incidence of grade 3 or higher hepatic laboratory abnormalities was low in both Korean and global analyses (alanine aminotransferase 0.4% and <0.1%; aspartate aminotransferase 0% and 0.3%; and total bilirubin 0.4% and 0.3%, respectively).

DISCUSSION

The findings from this pooled analysis demonstrated high efficacy of 8-week or 12-week G/P therapy in Korean patients with HCV infection, regardless of genotype, subgenotype, presence of cirrhosis, and treatment duration. As in the global integrated analysis, G/P therapy was well tolerated in Korean patients with HCV infection, with low incidence of serious AEs or AEs leading to treatment discontinuation. Findings from this analysis of Korean patients also indicate that the study population and disease characteristics were representative of Korean patients with HCV; for instance, genotypes GT1B and GT2A were the most common subtypes, accounting for 93% of all patients.9

This is the first analysis evaluating the efficacy and safety of G/P in Korean HCV GT1- or GT2-infected patients with or without compensated cirrhosis. HCV genotypes appear to be a key predictive factor of liver disease severity and treatment response, with a distinct geographical distribution. Among the Korean population GT1 and GT2 account for 99% of HCV infection.6 Previous studies investigating treatment response in Korean patients with HCV infection have shown high therapeutic efficacy in this population, even before the introduction of new pan-genotypic DAA agents. For example, results from a retrospective study evaluating the efficacy of pegylated interferon and ribavirin therapy in Korean patients with chronic HCV infection showed a superior therapeutic efficacy of this regimen in Koreans as compared with Caucasians, with overall SVR rates ranging between 63% and 81%.23 Even though the evidence on the efficacy of first-generation DAA in Korean patients with HCV infection is very limited,11 data from a real-world study conducted in Korean patients demonstrated high SVR12 rates of 93% with the first-generation DAA treatment combination daclatasvir plus asunaprevir.24 Another study comparing the efficacy of several DAA regimens in Asian patients with HCV showed SRV12 rates of 99.2%, and a significant improvement in quality of life with ledipasvir/sofosbuvir combination, the previous standard treatment for HCV GT1A infection.25 Furthermore, a retrospective study evaluating sofosbuvir-based therapy showed an SVR12 rate as high as 100% in Korean patients with HCV infection.26

Results from the current study demonstrated high efficacy of an 8-week regimen of the pan-genotypic G/P therapy, which can have significant implications on the treatment burden and care pathway for patients with HCV. For example, the G/P regimen as first-line therapy would reduce the treatment duration without compromising efficacy. Shortened treatment duration also implies less on-treatment monitoring and physician visits, enabling cost-reductions in terms of reduced number of diagnostic procedures and clinic visits, thus improving the accessibility of treatment for a larger number of patients. In addition, as G/P is effective across all genotypes, use of this regimen may preclude baseline assessments, such as genotyping. The promotion of a simplified pretreatment evaluation in patients with HCV GT1 or GT2 infection receiving the G/P pan-genotypic regimen would help prevent liver disease complications and further HCV transmission; thereby contributing towards HCV elimination.27 However, genotyping is still considered as an essential component of HCV diagnosis in South Korea.9

The incidence of AEs was slightly lower in the Korean population than in the global integrated analysis, 44.9% (119/265) versus 65.8% (1,343/2,041); however, statistical analysis of this difference was not performed.16

Limitations of this pooled analysis include small sample size (n=265) as compared with the global integrated analysis (n=2,041).16 Additionally, when comparing the AE pattern with the global pooled population, no differentiation between genotypes was considered, and data from all genotypes (GT1-6) were included. Furthermore, the present analysis in the Korean population included a small number of high-risk patients such as previous injection drug users (IDU; 5.7%), those with sofosbuvir-based treatment-experience (1.9%), compensated cirrhosis (14.0%), HIV coinfection (13.2%), and non-CC interleukin 28B subtype (23.0%). Most of the population were not previous IDUs (94.3%, 250/265), which may have resulted in better treatment adherence and compliance than in the global integrated analysis (61%, 1,243/2,041).16 Nevertheless, a recent pooled analysis of seven phase III trials evaluating efficacy and safety of 8-week or 12-week G/P treatment demonstrated that treatment adherence and compliance in recent IDUs were high despite enduring concerns.28 The current international guidelines (European Association for the Study of the Liver2 and American Association for the Study of Liver Diseases12) emphasize that treatment response among IDUs is similar to that in non-IDU populations. Moreover, this high-risk group could benefit from a shorter treatment duration (8 weeks).28 Interleukin 28B CC genotype, which is estimated to be present in around 90% of the Korean population, has been strongly associated with spontaneous viral clearance and favorable clinical outcomes.29 However, it is still unclear whether Interleukin 28B genotype has a strong influence on the effects of DAAs, or which DAAs are best for people with non-CC genotypes.

In conclusion, results from this analysis indicate that treatment with G/P combination therapy for 8 or 12 weeks is highly efficacious and well tolerated in Korean patients with HCV GT1 or GT2 infections, supporting the current Korean Association for the Study of the Liver recommendation.11

Supplemental Materials

ACKNOWLEDGMENTS

The design, study conduct, analysis, and financial support of the trials (ENDURANCE 1, ENDURANCE 2, SURVEYOR II part 4, VOYAGE I and VOYAGE II) was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. All authors had access to all relevant data.

The authors would like to express their gratitude to the trial participants, investigators, and coordinators who made this study possible. Medical writing assistance was provided by Syed Abdul Haseeb and Julia Ventura from MediTech Media (Singapore), which was funded by AbbVie in accordance with Good Publication Practice guidelines.

CONFLICTS OF INTEREST


Y.S.L. is an advisory board member of Bayer Healthcare and Gilead Sciences. E.D.C., L.M.F., and N.N.A. are employees of AbbVie, Inc. and may hold stock or stock options. A.A. and D.H.K. are former employees of AbbVie, Inc. and may hold stock or stock options. Other authors have no conflicts of interest to declare.

Y.J.K. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

AUTHOR CONTRIBUTIONS


Study design: D.H.K., E.D.C. Formal analysis: E.D.C., L.M.F., N.N.A., A.A. Study conduction and data collection: J.H., Y.J.K., J.W.L., J.H.K., Y.S.L., K.H.H., S.H.J., M.C., K.T.Y., S.H.B., S.W.P., Y.J.L. Data Interpretation, review, approval of final manuscript: all authors.

Fig 1.

Figure 1.Number and percentage of Korean subjects with SVR12 in the intention-to-treat population. Rates of SVR12 by genotype, cirrhosis status and treatment duration (8 or 12 weeks). Error bars represent 95% confidence intervals.
GT, genotype; SVR12, sustained virologic response at 12 weeks posttreatment. *4 Patients were GT1A and 129 patients were GT1B; 118 Patients were GT2A, 8 were GT2B, 3 were GT2A/2C, and 3 had unknown subtype.
Gut and Liver 2021; 15: 895-903https://doi.org/10.5009/gnl20321

Fig 2.

Figure 2.Number and percentage of Korean subjects with SVR12 by subgroup in the intention-to-treat population. Rates of SVR12 by (A) subgenotype (1A, 1B, 2, 2A, 2A/2C, and 2B) and (B) G/P treatment duration (8 weeks and 12 weeks). Error bars represent 95% confidence intervals.
SVR12, sustained virologic response at 12 weeks posttreatment; G/P, glecaprevir/pibrentasvir.
Gut and Liver 2021; 15: 895-903https://doi.org/10.5009/gnl20321

Table 1 Demographics and Disease Characteristics at Baseline in the Intention-to-Treat Population

CharacteristicGT1 (n=133)GT2 (n=132)Overall (n=265)
Male sex63 (47.4)60 (45.5)123 (46.4)
Age, yr59 (21–85)62 (25–87)60 (21–87)
BMI, kg/m223.8 (17.9–36.7)24.3 (17.9–33.9)24.2 (17.9–36.7)
HCV treatment experience
Naïve93 (69.9)86 (65.2)179 (67.5)
IFN based39 (29.3)42 (31.8)81 (30.6)
SOF based1 (0.8)4 (3.0)5 (1.9)
Enrolled study
M13-590 (ENDURANCE 1)35 (26.3)035 (13.2)
M15-464 (ENDURANCE 2)*1 (0.8)63 (47.7)64 (24.2)
M14-868 (SURVEYOR II part 4)05 (3.8)5 (1.9)
M15-592 (VOYAGE I)*74 (55.6)50 (37.9)124 (46.8)
M15-593 (VOYAGE II)23 (17.3)14 (10.6)37 (14.0)
HCV subgenotype
1A4 (3.0)04 (1.5)
1B129 (97.0)0129 (48.7)
203 (2.3)3 (1.1)
2A0118 (89.4)118 (44.5)
2A/2C03 (2.3)3 (1.1)
2B08 (6.1)8 (3.0)
Cirrhosis status
No cirrhosis110 (82.7)118 (89.4)228 (86.0)
Compensated cirrhosis23 (17.3)14 (10.6)37 (14.0)
Baseline HCV RNA level, IU/mL
<1.0×106123 (92.5)118 (89.4)241 (90.9)
≥1.0×10610 (7.5)14 (10.6)24 (9.1)
Baseline HCV RNA level, log10 IU/mL6.4 (2.5–7.7)6.2 (2.5–7.3)6.3 (2.5–7.7)
IL28B
CC99 (74.4)105 (79.5)204 (77.0)
Non-CC34 (25.6)27 (20.5)61 (23.0)
History of disorders
Diabetes23 (17.3)18 (13.6)41 (15.5)
Depression or bipolar disorder6 (4.5)7 (5.3)13 (4.9)
Bleeding disorder1 (0.8)1 (0.8)2 (0.8)
Hypertension48 (36.1)44 (33.3)92 (34.7)
Cardiovascular disease51 (38.3)50 (37.9)101 (38.1)
HIV coinfection35 (26.3)035 (13.2)
G/P treatment duration
8 Weeks98 (73.7)55 (41.7)153 (57.7)
12 Weeks35 (26.3)77 (58.3)112 (42.3)
History of injection drug use
Yes7 (5.3)8 (6.1)15 (5.7)
No126 (94.7)124 (93.9)250 (94.3)

Data are presented as number (%) or median (range).

GT, genotype; BMI, body mass index; HCV, hepatitis C virus; IFN, interferon; SOF, sofosbuvir; IL28B, interleukin 28B; HIV, human immunodeficiency virus; G/P, glecaprevir/pibrentasvir.

*Including patients who received placebo during the double-blind treatment period followed by G/P during the open-label treatment period.


Table 2 Primary (SVR12) and Secondary (on-Treatment Virologic Failure and Posttreatment Relapse) Outcomes in the Intention-to-Treat Population

OutcomeNo cirrhosis (n=228)Compensated cirrhosis (VOYAGE II) (n=37)Overall
(n=265)
All patients
(n=228)
GT1
(n=110)
GT2
(n=118)
All patients
(n=37)
GT1
(n=23)
GT2
(n=14)
SVR12225 (98.7)109 (99.1)116 (98.3)37 (100)23 (100)14 (100)262 (98.9)
Virologic failure
On-treatment0000000
Relapse*1 (0.4)01 (0.8)0001 (0.4)
Non-virologic failure
Premature G/P discontinuation 1 (0.4) 1 (0.9)00001 (0.4)
Missing SVR12 data1 (0.4)01 (0.8)0001 (0.4)

Data are presented as number (%).

SVR12, sustained virologic response at 12 weeks posttreatment; GT, genotype; G/P, glecaprevir/pibrentasvir.

*Among patients who completed treatment as planned and achieved an hepatitis C virus RNA level less than lower limit of quantification at final treatment visit and had posttreatment data (n=262).


Table 3 Characteristics of Patients Experiencing Virologic and Non-Virologic Failure at Baseline and the Time of Failure from the VOYAGE I Clinical Trial

CharacteristicPatient 1Patient 2Patient 3
Reason for nonresponseRelapseMissing SVR12 data*Premature G/P discontinuation
Sex/age, yrMale/66Female/74Female/77
Treatment historySOF-experiencedNaïveNaïve
HCV subtype2A2A1B
Compensated cirrhosisNoNoNo
Baseline HCV RNA level, IU/mL8.6×10621×10613.1×106
IL28B subtypeCCCCCC
Treatment duration, wk888
HIV coinfectionNoNoNo
NS3 variants
BaselineNoneNoneS122T, V170I
At failureNoneNANA
NS5A variants
BaselineL31MT24A, L31MQ54Y, Q62D, Y93H
At failureL31M, C92SNANA

HCV, hepatitis C virus; IL28B, interleukin 28B; HIV, human immunodeficiency virus; NS, nonstructural protein; SVR12, sustained virologic response at 12 weeks posttreatment; G/P, glecaprevir/pibrentasvir; SOF, sofosbuvir; NA, not available.

*No detectable HCV RNA at last visit (posttreatment week 4, posttreatment day 27); did not return for SVR12 visit. Baseline polymorphisms and treatment-emergent substitutions at signature amino acid positions: NS3 (36, 43, 54, 55, 56, 80, 107, 122, 155, 156, 158, 168, 170, 175) and NS5A (24, 28, 29, 30, 31, 32, 54, 58, 62, 92, 93) at 2% detection threshold.


Table 4 Overview of AEs and Laboratory Abnormalities in the Intention-to-Treat Population

AEKorean population (n=265)Pooled analysis of global phase II&III (n=2,041)
Any AE119 (44.9)1,343 (65.8)
Serious AE7 (2.6)*42 (2.1)
G/P-related AE30 (11.3)NA
G/P-related serious AE01 (<0.1)
AE leading to G/P discontinuation1 (0.4)10 (0.5)
AEs in ≥10% of all patients0
Headache344 (16.9)
Fatigue281 (13.8)
Laboratory abnormalities
ALT, grade ≥3 (>5×ULN)1 (0.4)1 (<0.1)
AST, grade ≥3 (>5×ULN)07 (0.3)
Total bilirubin, grade ≥3 (>3×ULN)1 (0.4)7 (0.3)

Data are presented as number (%). This table is presenting “data in perspective” from two separate analyses.16

AE, adverse event; G/P, glecaprevir/pibrentasvir; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal; NA, not available.

*Bile duct stone (n=2), followed by urinary tract infection, radius fracture, ligament rupture, papillary thyroid cancer, and depression (n=1 each); Five most frequent AEs: upper respiratory tract infection (7.2%), fatigue (4.2%), diarrhea (3.0%), headache (2.6%), and pruritus (2.3%); This is not a comparison performed in the current study of Korean patients.


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Gut and Liver

Vol.15 No.6
November, 2021

pISSN 1976-2283
eISSN 2005-1212

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