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Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients with Chronic HCV Infection

  • Xiaoqing Liu and
  • Peng Hu* 
Journal of Clinical and Translational Hepatology   2021;9(1):125-132

doi: 10.14218/JCTH.2020.00078

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Citation: Liu X, Hu P. Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients with Chronic HCV Infection. J Clin Transl Hepatol. 2021;9(1):125-132. doi: 10.14218/JCTH.2020.00078.

Abstract

Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease, including decompensated cirrhosis and hepatocellular carcinoma. Over 95% of patients with HCV infection have achieved sustained virologic response at 12 weeks under the treatment of several pan-genotypic regimens approved for patients with HCV infection. The glecaprevir/pibrentasvir (G/P) regimen has some features that distinguish it from others and is the only 8-week regimen approved for treatment-naive patients and patients experienced in regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, without an HCV NS3/4A protease inhibitor or NS5A inhibitor (except those with genotype 3). This review aims to summarize the efficacy and safety of G/P in HCV-infected patients from clinic trials and real-world studies, including those who have historically been considered difficult to cure.

Keywords

Hepatitis C, Mavyret, Glecaprevir, Pibrentasvir, Treatment outcome

Introduction

Hepatitis C virus (HCV) infection threatens the health of people around the world. According to the World Health Organization, about 71 million people worldwide suffer from chronic HCV infection, and in 2016 approximately 399,000 patients died from end-stage HCV infection, mainly from cirrhosis and hepatocellular carcinoma.1 Direct-acting antiviral agent (DAA)-induced sustained virologic response (SVR) has been associated with a reduction in the risk of cirrhosis, hepatocellular carcinoma, and mortality.2,3

All of the three pan-genotypic antiviral regimens [sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, glecaprevir/pibrentasvir (G/P)] approved for the treatment of patients with chronic HCV infection in recent years have high efficacy, and more than 95% of patients administered them have achieved SVR at 12-week post-treatment (SVR12).3–7

However, the fixed-dose combination of Glecaprevir (300 mg) and pibrentasvir (120 mg), an all-oral, once-daily, ribavirin-free pan-genotypic regimen approved in 2017, has certain characteristics that distinguish it from other pan-genotypic antiviral regimens, including shorter duration of therapy for most patients; it has been approved for use in patients with end-stage renal disease and adolescent patients aged 12–17 years.8

Both glecaprevir and pibrentasvir have potent anti-HCV activity across genotypes 1 through 6 in vitro, which harbor a high genetic barrier to resistance.8 The former is a second-generation NS3/4A protease inhibitor (PI), essential for the cleavage of the HCV unprocessed polyprotein and viral replication; the latter is a second-generation NS5A inhibitor, critical for viral RNA replication and virion assembly.9

Glecaprevir and pibrentasvir are mainly excreted through the biliary-fecal route, with only a minor fraction (less than 1%) excreted in urine; renal impairment and hemodialysis appeared to have no significant influence on glecaprevir or pibrentasvir exposures.8,10 Compared with patients with normal renal function, HCV-infected patients with end-stage renal disease, including dialysis, were observed to have an 86% increase in glecaprevir and a 54% increase in area under the curve for pibrentasvir.8 In chronic HCV-infected patients with compensated cirrhosis, exposure to glecaprevir was 160% higher and pibrentasvir exposures showed little difference in outcome compared to patients without cirrhosis.10 Meanwhile, there was no statistically significant difference in the exposure rates of gelcaprevir and pibrentasvir between Japanese or Han Chinese and Whites.11 But, we should note that patients with decompensated cirrhosis are not recommended for treatment with a PI-containing regimen (e.g., glecaprevir, grazoprevir, and voxilaprevir).

Most patients with chronic HCV infection are at risk of drug-drug interactions (DDIs) with co-medication.12 Both glecaprevir and pibrentasvir are substrates and inhibitors of P-glycoprotein and breast cancer resistance protein. Moreover, glecaprevir is a substrate and inhibitor for organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Pibrentasvir is an inhibitor of OATP1B1/3. Therefore, coadministration of G/P with drugs that inhibit hepatic P-glycoprotein, breast cancer resistance protein, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir.8 As per the drug label, G/P is contraindicated in combination with atazanavir or rifampin.8

The main purpose of this review is to comprehensively evaluate the efficacy and safety of G/P in patients with HCV infection, including those in the so-called “special population” that have historically been considered difficult to treat.

Efficacy

The clinic trails and real-world studies that have evaluated the efficacy of G/P against HCV are summarized in Tables 1 and 2,13–47 respectively.

Table 1

Efficacy of G/P in clinical trials

StudyHCV genotypePopulationNumberDurationSVR12, n/total (%)a
EXPEDITION-1181, 2, 4, 5, 6TN with CC
PRS-exp with CC		110
36		12 w110/110 (100)
35/36 (97.2)
EXPEDITION-2291–6TN or PRS-expb, HIV coinfection, ±CC1538/12 w150/153 (98.0)
EXPEDITION-4251–6TN or PRS-exp, ±CC, CKD stages 4-510412 w102/104(98.1)
EXPEDITION-5261–6TN or PRS-exp, ±CC, CKD stages 3b, 4, 51018/12/16 w98/101 (97.0)
EXPEDITION-8171–6TN with CC3438 w335/343 (97.7)
Fontana411–6TN with NC23012 w222/230 (96.5)
ENDURANCE-5, 6155,6TN or PRS-exp,
NC
CC		84
8 w
12 w		82/84 (97.6)
74/75 (98.7)
8/9 (88.9)
ENDURANCE-1391TN or PRS-exp, NC7038 w
12 w		348/351 (99.1)
351/352 (99.7)
ENDURANCE-2382TN or PRS-exp, NC20212 w201/202 (99.5)
ENDURANCE-3393TN with NC3908 w
12 w		149/157 (94.9)
222/233 (95.3)
ENDURANCE-4384–6TN or PRS-exp, NC12112 w120/121 (99.2)
SURVEYOR-I, II, part 1, 2191–6TN or PRS-exp, NC2308 w
12 we		114/117 (97.4)
108/113 (95.6)
SURVEYOR-II, part 3203TN or PRS-exp, ±CC13112 w
16 w		59/62 (95.2)
66/69 (95.7)
SURVEYOR-II, part 4382,4–6TN or PRS-exp, NC2038 w196/203 (96.6)
CERTAIN-1, substudy 1, 2131TN or PRS-exp, without CC
with CC		167
8 w
12 w		166/167 (99.4)
128/129 (99.2)
38/38 (100)
CERTAIN-2142TN or PRS-exp, NC908 w88/90 (97.8)
MAGELLAN-1, part 11TE with NS3/4A and/or NS5A inhibitor, NC2212w19/22 (86.4)
MAGELLAN-1, part 2321,4cTE with NS3/4A and/or NS5A inhibitor, ±CC9112 w
16 w		39/44 (88.6)
43/47 (91.5)
MAGELLAN-2301–6TN or PRS-exp, NC, with liver or kidney transplant10012 w98/100 (98.0)
Lok et al.421TE with sofosbuvir plus an NS5A inhibitor, ±CC17712 wd
16 w		88/99 (88.9)
74/78 (94.9)
DORA part 1341–4TN or PRS-exp, ±CC, adolescent478/16 w47/47 (100)
a

SVR12 rates in the ITT population.

b

Patients with treatment experience and genotype 3 infection were excluded.

c

In MAGELLAN-1 part 2, only four patients had the genotype 4 infection.

d

Patients with CC received G/P+ribavirin for 12 weeks.

e

Genotype 3-infected patients with TN received G/P for 8 weeks, with PR-exp for 12 weeks.

Abbreviations: ±CC, with or without compensated cirrhosis; HIV, human immunodeficiency virus; NC, non-cirrhotic; PRS-exp, prior treatment experience with regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor; TE, treatment-experienced; TN, treatment-naïve; w, week.

Table 2

Efficacy of G/P in real-world studies

StudyCountry/regionHCV genotypeNumberPopulationDurationSVR, n/total (%)
D’Ambrosio et al.35Italy1–4723TN or PR-exp, ±CC8/12/16 w680/723 (94.1)
Atsukawa et al.27Japan1–3141With CKD stages 4-58 w
12 w		90/91 (98.9)
50/50 (100)
Hsu et al.36Taiwan1–3, 6110With hepatic fibrosis F3-48 w
12/16 w		45/45 (100)
65/65 (100)
Ikeda et al.37Japan1, 2a571DAA-naïve, NC8 w530/571 (92.8)
Osawa et al.40Japan1–330DAA-exp, ±CC12 w28/30 (93.3)
Persico et al.43Italy1–41,177TN (85%), genotype 3 (10%), CC (9%)8/12/16 w (1,061/109/6)1,163/1,177 (98.8)
Tamori et al.23Japan1–4423NC, DAA-naïve
CC/DAA-exp/genotype 3 or 4		8 w
12 w		220/246 (89.4)
164/177 (92.7)d
Toyoda et al.24Japan1–3a509DAA-exp/CC/genotype 312 w504/509 (99.0)
Ueda et al.31Japan1, 225With liver transplant8/12 w24/25 (96.0)
Liu et al.28Taiwan1, 2, 3, 6108With CKD stage 4 or 58/12 w107/108 (99.1)
Nozaki et al.22Japan1–3a1,439TN or TE, NC or CC8/12 w1,397/1,439(97.1)
Liu et al.44Taiwan1–3, 6658TN or TE, ±CC8/12/16 w646/658 (98.2)
Soria et al.21Italy3152TN or TE, ±CC8/12/16 w147/152 (96.7)
Berg et al. (DHC-R)16German1–6552bTN or TE, ±CC8/12/16 w534/552 (96.7)
Sugiura et al.45Japan1–3182TN or TE, ±CC8/12/16 w178/182 (97.8)
Uemura et al.33Japan1–342DAA-exp, ±CC12 w39/42 (92.9)c
Kusakabe et al.46Japan228PRS-exp12 w28/28 (100)
Sezak et al.47Japan1–3a271TN or PR-exp
DAA-exp		8/12 w
12 w		180/183 (98.4)
85/88 (96.6)
a

Patients with baseline P32del were excluded.

b

Patients with on-label treatment.

c

Three patients with genotype 1b HCV with NS5A P32del experienced virologic failure.

d

The SVR rate of genotype 3 patients is 4/7 (57), and there are 2 genotype 3b patients among patients who do not reach SVR12.

Abbreviations: ±CC, with or without compensated cirrhosis; NC: non-cirrhotic; PRS-exp, prior treatment experience with regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor; TE, treatment-experienced; TN, treatment-naïve.

Treatment-naïve or patients experienced in regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, without an HCV NS3/4A PI or NS5A inhibitor, without cirrhosis

In a pooled analysis of nine clinical trials, treatment-naïve or patients experienced in regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, without an HCV NS3/4A PI or NS5A inhibitor (PRS) with HCV genotypes 1-6 infections but without cirrhosis achieved an overall SVR12 rate of 98% (943/965) in the intention-to-treat (ITT) population when treated for 8 weeks, which showed no significant difference from patients treated with 12 weeks (1,060/1,076, 99%).48 But, all 478 patients infected with genotype 3 were treatment-naïve in that study. CRETIN-1 and CRETAIN-2 were not included in the pooled analysis described previously, and the authors also demonstrated that G/P treatment for 8 weeks was highly effective in patients with HCV genotypes 1-2 infections without cirrhosis, of which 99.2% (128/129) and 98% (88/90) patients achieved SVR12, respectively.13,14 The ENDURANCE-5,6 trial, an open-label, multicenter, phase 3b trial, demonstrated that 98.6% (74/75) of non-cirrhotic patients infected with HCV genotype 5 or 6 treated with G/P for 8 weeks achieved SVR12.15

Data from a combined analysis of 18 real-world studies showed that the SVR rate for treatment-naïve patients without cirrhosis who received G/P treatment for 8 weeks was 98.2% (n=697) in the ITT population and 99.3% (n=3,657) in the modified ITT population.49 For patients with treatment experience, the SVR rate was 90.7% (49/54), among which 4 patients were lost to follow-up.16

Treatment-naïve or PRS-experienced patients with compensated cirrhosis

The efficacy of 8-week G/P reported in the EXPEDITION-8 clinical trial is comparable to the 12-week regimen for treatment-naïve patients with genotypes 1-6 infections and compensated cirrhosis.17 The SVR rate was 97.7% (335/343) in the ITT population and 99.7% (334/335) in the per protocol population after treatment with G/P once daily for 8 weeks.17 After 12 weeks of treatment with G/P, the SVR12 rates of HCV genotype 3- and non-genotype 3-infected compensated cirrhosis patients without treatment experience were 97.1% (67/69)50 and 100% (110/110),18 respectively.

For PRS-experienced patients with compensated cirrhosis and non-genotype 3 infection, the EXPEDITION-1 trial reported that 97.2% (35/36) of patients treated for 12 weeks achieved SVR12, with one genotype 1a-infected patient relapsing at post-treatment week 8.18 The CRETAIN-1, subgroup 2 trial evaluated the efficacy of a 12-week course of G/P in 38 genotype 1-infected patients with compensated cirrhosis. All of the 38 patients (100%) achieved SVR12, of which 12 were interferon-experienced.13

Data from real-world studies showed that the SVR12 rate for patients with compensated cirrhosis who received G/P treatment was 97.8% (n=676) in the ITT population and 98.2% (N=822) in the modified ITT population.49 For treatment-naive patients with compensated cirrhosis treated for 12 weeks, the SVR12 rate was 99.0% (n=362).49 To our knowledge, currently there is no real-world data to evaluate the efficacy of G/P treatment for 8 weeks in treatment-naïve patients with compensated cirrhosis.

“Special population”

Patients with HCV genotype 3 infection

Patients with HCV genotype 3 infection are among the most difficult to treat in the DAA-era. According to the studies described above, treatment-naïve and genotype 3-infected patients treated with G/P for 8 weeks had high SVR12 rate, regardless of cirrhosis, but the efficacy in PRS-experienced patients is still uncertain.

In the SURVEYOR-II trial, parts 1 and 2, the efficacy of G/P for 12 weeks was studied in PR-experienced patients with genotype 3 infection and without cirrhosis. In total, 91.7% (22/24) achieved SVR12, with 1 patient having a breakthrough at treatment week 6 and 1 other relapsing at post-treatment week 8.19 The SURVEYOR-II trial, part 3, a partially-randomized, open-label, phase 3 study, assessed the efficacy of G/P in patients with genotype 3 infection with prior treatment experience, and found that 91% (20/22) and 96% (21/22) of PRS-experienced patients without cirrhosis achieved SVR12 for 12 weeks and 16 weeks, respectively. Among the 47 treatment-experienced patients with compensated cirrhosis, SVR12 were achieved by 96% (45/47) of patients treated with G/P for 16 weeks.20 An integrated cirrhosis of five phase 2 or 3 trials that evaluated G/P in patients with chronic HCV genotype 3 infection also demonstrated G/P was efficacious for those patients, regardless of cirrhosis or prior treatment experience.50

Data from real-world studies also demonstrated that over 95% of HCV genotype 3-infected patients treated with the G/P regimen achieved SVR.21,49 But, we should point out that almost all of the above-mentioned research studies were conducted in areas where subtype 3a is dominant, and subtype 3b accounts for less than 1% of all genotype 3 cases. Therefore, more attention should be paid to the efficacy of G/P in HCV subtype 3b-infected patients. Nozaki et al.22 recently reported that only 33.3% (2/6) of patients with HCV subtype 3b infection achieved SVR12. Another study conducted by Tamori et al.23 found that only 50% (2/4) of patients with HCV genotype 3b infection achieved SVR12. Moreover, one out of three patients with genotype 3a/b experienced virologic failure in the study of Toyoda et al.24

Patients with severe renal impairment

The investigators of the EXPEDITION-4 study examined the efficacy of G/P administered for 12 weeks in adults with chronic HCV genotypes 1-6 infections and stage 4 or 5 chronic kidney disease (CKD).25 Of the 104 patients enrolled, 44 (42%) had prior treatment experience for HCV, but treatment-experienced patients who had genotype 3 infection were excluded and 20 (19%) had compensated cirrhosis at baseline. Up to 98% (102/104) of the patients achieved SVR12, with no patients experiencing virologic failure.25 In the phase 3 EXPEDITION-5 trial, the rate of SVR was 97% (98/101) in the ITT population and 100% (98/98) in the modified ITT population after treatment with G/P. Of the 101 enrolled adults with CKD stages 3b, 4 or 5, 84 patients without cirrhosis were assigned to receive G/P for 8 weeks and 4 PRS-experienced patients with genotype 3 infection were assigned to 16 weeks of treatment; all others were in the 12-week treatment group.26 Real-world studies also demonstrated G/P was highly effective for patients with CKD stages 4-5 (including patients undergoing hemodialysis), and more than 98% of patients achieved SVR.22,27,28,51

Patients with human immunodeficiency virus-1/HCV coinfection

EXPEDITION-2 was a phase 3, multicenter study to evaluate the efficacy of G/P in 156 human immunodeficiency virus/HCV-coinfected adults with compensated liver diseases.29 All patients with genotype 3 infection were treatment-naïve for HCV. Patients were either antiretroviral therapy-naïve or on a qualifying antiretroviral therapy regimen for at least 8 weeks. The antiretroviral therapy drugs used by more than 20 patients included tenofovir disoproxil fumarate, abacavir, emtricitabine, lamivudine, raltegravir, dolutegravir, and rilpivirine. As high as 99.3% (136/137) of the patients without cirrhosis treated for 8 weeks achieved SVR12, and 87.6% (14/16) of the patients with compensated cirrhosis treated for 12 weeks achieved SVR12. No one experienced virologic failure, except one HCV treatment-naïve patient with genotype 3 infection and compensated cirrhosis.29

Patients with liver or kidney transplantation

MAGELLAN-2, a phase 3, open-label trial, evaluated the efficacy of G/P for 12 weeks in patients who had chronic HCV genotypes1-6 infections and had received a liver (n=80) or kidney (n=20) transplant at least 3 months prior.30 Patients with cirrhosis were excluded and all genotype 3-infected patients were treatment-naïve. Overall, SVR was achieved in 98% (98/100) of the patients, with one genotype 3a-infected patient who had received a liver transplant experiencing virologic relapse.30 Ueda et al.31 reported that 96% (24/25) of patients with recurrent HCV infection after liver transplantation treated with 8 or 12 weeks of G/P achieved SVR12, including patients with severe renal impairment, liver cirrhosis, prior DAA experience, or jaundice after liver transplantation. But, no virologic failure occurred.

Patients with psychiatric disorders

An integrated analysis of 10 phase 2 and phase 3 clinical trials assessed the efficacy of G/P for 8, 12 or 16 weeks in chronic HCV genotypes 1-6-infected patients with psychiatric disorders.52 The overall patients’ treatment adherence was very high (>95%), regardless of whether there was a psychiatric disorder. Of the 2,522 patients receiving G/P, 97.3% (768/789) of those with a psychiatric disorder achieved SVR12 compared to 97.5% (1,689/1,733) of those without a psychiatric disorder. Among all patients receiving a neuropsychiatric co-medication with potential DDIs with G/P, the SVR rate was still high, including quetiapine (100%, 47/47), oxycodone (93.8%, 76/81) and hydrocodone (97.4%, 75/77).52 Meanwhile, patients with psychiatric disorder had overall high SVR rate (98.9%) in the modified ITT population in real-word studies.49

Patients with NS3/4 PI and/or NS5A inhibitor treatment experience

In part 1 of the MAGELLAN-1 trail, 22 genotype 1-infected non-cirrhotic patients with past failure to NS3/4 PI and/or NS5A inhibitor were treated with G/P for 12 weeks.53 SVR was achieved by 86% (19/22) in the ITT population and 95% (19/20) in the modified ITT population. Virologic failure occurred in one patient with past treatment experience with both NS3/4A PI and NS5A inhibitor.53 MAGELLAN-1, part 2, a randomized, open-label, multicenter phase 3 study, enrolled 91 HCV genotypes 1 or 4-infected patients with compensated liver disease (with or without cirrhosis) who had past treatment experience with NS3/4A PI and/or NS5A inhibitor.32 Patients enrolled were randomized to receive 12 or 16 weeks of G/P. Patients with NS3/4A PI experience alone (NS5A inhibitor-naïve) had 100% SVR12, regardless of treatment duration. Patients with NS5A inhibitor experience alone (NS3/4A PI-naïve) had 88% (14/16) and 94% (17/18) SVR rate among those treated with G/P for 12 weeks and 16 weeks, respectively. Patients with both NS3/4A PI and NS5A inhibitor experience had 79% (11/14) and 81% (13/16) SVR rate among those treated for 12 weeks and 16 weeks, respectively. All (4/4) patients with genotype 4 infection achieved SVR12 and 10.3% (9/87) of patients with chronic HCV genotype 1 infection experienced virologic failure. In CRETAIN-1 and -2 trials, The SVR rate in the HCV subtype1b-infected patients with PI and NS5A inhibitor experience was 93.3% (28/30). Virologic failure occurred in two patients with NS5A P32del.54

Research conducted by Uemura et al.,33 in which 34 of 42 patients had both NS3 and NS5A inhibitors treatment experience, reported that the SVR12 rate of chronic hepatitis c patients with prior DAA treatment experience treated with G/P for 12 weeks was 92.9% (39/42). All genotype 1b-infected patients carrying the NS5A P32del (3/35) experienced virologic failure.33

Adolescent patients aged 12–17

The DORA part 1, nonrandomized, open-label, multicenter clinical trial assessed the efficacy of G/P in adolescent patients with chronic HCV genotypes 1-4 infections.34 Of the 47 enrolled patients, 36 patients were HCV treatment-naïve and the others were interferon-based regimen-experienced. Except for three patients with HCV genotype 3 infections and treatment experience, who received G/P for 16 weeks, all patients received 8 weeks of therapy. The SVR12 rate of overall patients was 100% (47/47).34

Patients who used drugs recently or were receiving opioid substitution therapy

Among 15.6 million patients who inject drugs, an estimated 52.3% are HCV-antibody positive.55 A pooled analysis of clinic trials revealed that SVR12 was achieved by 92.9% (91/98), 97.0% (592/610), and 99.5% (1,106/1,111) of recent, former, and non-drug users, respectively. But, the overall rates of virologic failure were ≤1.5%, regardless of drug use status.56 An integrated analysis of eight clinical trials compared the efficacy of G/P in HCV-infected patients receiving opioid substitution therapy (OST) and those not receiving OST. SVR rates were 96.2% (151/157) and 97.9% (2,055/2,099) in the OST and non-OST patients, respectively.57 Methadone was the most commonly prescribed OST (76%).57 An integrated analysis of 18 real-word studies demonstrated that 98.9% of chronic HCV patients using OST achieved SVR12 in the modified ITT analysis.49

Patients with concurrent use of acid-reducing agents

Proton pump inhibitors (PPIs) were among the most frequently used co-medication in patients treated for chronic HCV infection.12 An integrated analysis of nine phase 2 and phase 3 clinic trails showed that in patients treated with G/P, SVR rates were 97.0% (389/401) and 97.5% (1,918/1,968) for patients using concomitant acid-reducing agents (ARAs) and those not concurrently using ARAs, respectively.58 SVR was achieved in 96.3% (105/109) of patients taking a high-dose PPI and 97.4% (150/154) taking a low-dose PPI. The overall virologic failure rate in patients taking an ARA was less than 1% (4/401) compared with 1.5% (29/1,968) in patients not taking any ARAs.58 The SVR rate of patients with chronic HCV infection receiving PPI was 97.9% (n=180) in real-world studies.49

Tolerability and safety

HCV N3/4A PIs have been shown to have concentration-dependent hepatotoxicity and are contraindicated in patients with decompensated cirrhosis. Therefore, patients with factors known to affect the exposure to glecaprevir need to be carried out, including those on patients with renal impairment, DDIs, advanced age, female sex, and cirrhosis status.59

A pooled analysis of nine clinical trials evaluated the tolerability and safety of G/P in chronic HCV-infected patients and studied by subgroup.60 In general, the prevalence of adverse events (AEs) were 68% (1,603/2,369), and the most commonly reported AEs with an incidence rate exceeding 5% included headache, fatigue, nausea, and pruritus.60 Serious AEs occurred in 73 (3%) patients but only one (<1%) was reported as DAA-related. Although 55% (11/20) of patients with compensated cirrhosis and CKD stages 4 or 5 developed serious AEs, none were reported as G/P-related.60 No matter whether concurrent with end-stage renal disease or not, DAA-related serious AEs and AEs leading to G/P discontinuation were rare (<1%).60 Hepatic decompensation and death occurred in 1 and 7 patients, respectively, but none were considered related to G/P. Patients with laboratory abnormalities grade ≥3 were rare among both patients with compensated cirrhosis and without cirrhosis.60 Alanine aminotransferase elevations greater than 5 times the upper limit of normal occurred in two (<0.1%) patients without cirrhosis, and elevations of total bilirubin at least 3-times the upper limit of normal occurred in nine (0.4%) patients, including three (0.1%) with cirrhosis and six (0.3%) without cirrhosis. Overall, this combined analysis demonstrated that the recommended dose of G/P for patients with compensated liver disease and/or with any degree of renal impairment is safe and well-tolerated. The fixed-dose of G/P was also demonstrated safe and tolerable in patients with psychiatric disorders,52 those with recent drug use,56 those receiving OST therapy57 or acid-reducing agents,58 and patients aged 65 years or older61 by data from clinical trials and additional subgroup analysis. The safety profile of G/P in adolescents was consistent with that in adults, as demonstrated in the DORA part 1 trial published recently.34

Data from real-world studies have demonstrated that the safety is similar among clinic trials.16,27,35–37,59 The prevalence rate of patients with AEs was 17.7% (1,271/7,199), and the most commonly reported AEs were the same as in the clinical trials. Only 1% (55/5,522) of patients reported serious AEs, and 0.6% (33/5,595) of patients discontinued study treatment because of AEs. Only 4 of 2,333 (0.2%) patients experienced hepatic decompensation events.49

Although patients with G/P had a high prevalence of AEs, ENDURANCE-2 reported that the frequency and severity of AEs and laboratory abnormalities in the HCV genotype 2-infected patients treated with G/P were similar to those treated with placebo.38

Conclusions

Although the data from clinical trials and real-world studies described above demonstrated that G/P could help a vast majority of chronic hepatitis c patients to safely eliminate HCV, even in patients who are not fully adherent to G/P regimen,62 there are still some problems that deserve attention.

Several studies have demonstrated that the A30K substitution significantly decreases the SVR12 rate in genotype 3 patients treated with the G/P regimen.39,63 Patients with subtype 3b naturally possess A30K, and over 95% of patients with subtype 3b harbor the paired A30K+L31M substitutions,64,65 which showed a >20-fold increase in 50% effect concentration for pibrentasvir.64 Research conducted by Nozaki et al.22 and Tamori et al.23 showed SVR rates were 33.3% (2/6) and 50% (2/4), respectively. Therefore, the efficacy of G/P in patients with subtype 3b is worthy of attention, especially in Asia, where the prevalence of subtype 3b is much higher than that in other continents.66,67 Nevertheless, most clinical studies have been conducted in Europe and North America, where the proportion of subtype 3b is less than 1% for genotype 3.67 Evaluation of the efficacy of G/P in patients with HCV subtype 3b infection is still lacking and needs further study.

All patients with NS5A-P32del have experienced virologic failure after receiving G/P treatment, according to the limited data.23,33,40,54 P32del confers an >1,000-fold change resistance to pibrentasvir and >10,000-fold change resistance to velpatasvir in the HCV genotype 1b Con replicon54 appearing in 5% to 10% of genotype 1b patients who experienced virologic failure with daclatasvir-containing therapies and sofosbuvir/ledipasvir treatment, but which has not been found among treatment-naïve patients.68,69 Therefore, patients with prior NS5A inhibitor treatment experience, especially those with genotype 1b infection, should pay attention to P32del and switch to other treatment options when P32del occurs.

Currently, although G/P has been approved for children aged 12 years and older or weighing at least 45 kg without dose changing, the efficacy and safety of G/P for adolescents with genotypes 5 and 6 infections or previous sofosbuvir experience were inferred from adult data and have not been directly evaluated.34 More evidence from clinical trials and real-world studies is needed to prove effectiveness and safety in adolescents.

In conclusion, G/P is highly efficacious and well-tolerated in chronic HCV-infected patients with compensated liver disease, including patients with compensated cirrhosis, HCV/human immunodeficiency virus coinfection, end-stage renal disease, liver or kidney transplants, recent drug use or in adolescents, according to data from clinic trails and real-world studies. In the DAA era, the characteristics of HCV patients have changed greatly, including for treatment-experienced patients and patients with cirrhosis that has decreased over time.70,71 The fixed-dose G/P regimen for 8-week duration has been approved for treatment-naïve HCV-infected patients with compensated liver disease (with or without cirrhosis) by the European Commission72 and the USA Food and Drug Administration,8 which means a shorter duration of therapy can benefit the vast majority of chronic hepatitis c patients. However, patients with HCV subtype 3b infection or NS5A-P32del need special attention.

Abbreviations

AE: 

adverse event

ARA: 

acid-reducing agent

CKD: 

chronic kidney disease

DAA: 

direct-acting antiviral agent

DDI: 

drug-drug interaction

G/P: 

glecaprevir/pibrentasvir

HCV: 

hepatitis C virus

ITT: 

intention to treat

OATP: 

organic anion transporting polypeptide

OST: 

opioid substitution therapy

PI: 

protease inhibitor

PPI: 

proton pump inhibitor

PRS: 

prior treatment experience with regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor

SVR: 

sustained virologic response

SVR12: 

SVR at 12-week post-treatment

Declarations

Funding

This work was supported in part by the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Wrote the manuscript (XL), critically revised the manuscript and provided study supervision (PH).

References

  1. World Health Organization. Global hepatitis report, 2017. Available from: https://apps.who.int/iris/bitstream/handle/10665/255016/9789241565455-eng.pdf View Article PubMed/NCBI
  2. Ioannou GN, Feld JJ. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection?. Gastroenterology 2019;156:446-460.e2 View Article PubMed/NCBI
  3. Asselah T, Marcellin P, Schinazi RF. Treatment of hepatitis C virus infection with direct-acting antiviral agents: 100% cure?. Liver Int 2018;38(Suppl 1):7-13 View Article PubMed/NCBI
  4. Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015;373:2608-2617 View Article PubMed/NCBI
  5. Jacobson IM, Lawitz E, Gane EJ, Willems BE, Ruane PJ, Nahass RG, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology 2017;153:113-122 View Article PubMed/NCBI
  6. Hezode C, Reau N, Svarovskaia ES, Doehle BP, Shanmugam R, Dvory-Sobol H, et al. Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies. J Hepatol 2018;68:895-903 View Article PubMed/NCBI
  7. Yao BB, Fredrick LM, Schnell G, Kowdley KV, Kwo PY, Poordad F, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients with HCV genotype 5/6: An integrated analysis of phase 2/3 studies. Liver Int 2020;40:2385-2393 View Article PubMed/NCBI
  8. MAVYRET®(glecaprevir and pibrentasvir), US prescribing information. Available from: https://www.rxabbvie.com/pdf/mavyret_pi.pdf View Article PubMed/NCBI
  9. Sorbo MC, Cento V, Di Maio VC, Howe AYM, Garcia F, Perno CF, et al. Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018. Drug Resist Updat 2018;37:17-39 View Article PubMed/NCBI
  10. Suleiman AA, Lin CW, Liu W, Eckert D, Mensing S, Burroughs M, et al. Population pharmacokinetics of glecaprevir/pibrentasvir in HCV-infected Japanese subjects in phase 3 CERTAIN-1 and CERTAIN-2 trials. J Clin Pharmacol 2020;60:331-339 View Article PubMed/NCBI
  11. Lin CW, Dutta S, Ding B, Wang T, Zadeikis N, Asatryan A, et al. Pharmacokinetics, safety, and tolerability of glecaprevir and pibrentasvir in healthy white, Chinese, and Japanese adult subjects. J Clin Pharmacol 2017;57:1616-1624 View Article PubMed/NCBI
  12. Smolders EJ, Berden FA, de Kanter CT, Kievit W, Drenth JP, Burger DM. The majority of hepatitis C patients treated with direct acting antivirals are at risk for relevant drug-drug interactions. United European Gastroenterol J 2017;5:648-657 View Article PubMed/NCBI
  13. Chayama K, Suzuki F, Karino Y, Kawakami Y, Sato K, Atarashi T, et al. 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 View Article PubMed/NCBI
  14. Toyoda H, Chayama K, Suzuki F, Sato K, Atarashi T, Watanabe T, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection. Hepatology 2018;67:505-513 View Article PubMed/NCBI
  15. Asselah T, Lee SS, Yao BB, Nguyen T, Wong F, Mahomed A, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus genotype 5 or 6 infection (ENDURANCE-5,6): an open-label, multicentre, phase 3b trial. Lancet Gastroenterol Hepatol 2019;4:45-51 View Article PubMed/NCBI
  16. Berg T, Naumann U, Stoehr A, Sick C, John C, Teuber G, et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C infection: data from the German Hepatitis C-Registry. Aliment Pharmacol Ther 2019;49:1052-1059 View Article PubMed/NCBI
  17. Brown RS, Buti M, Rodrigues L, Chulanov V, Chuang WL, Aguilar H, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial. J Hepatol 2020;72:441-449 View Article PubMed/NCBI
  18. Forns X, Lee SS, Valdes J, Lens S, Ghalib R, Aguilar H, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017;17:1062-1068 View Article PubMed/NCBI
  19. Kwo PY, Poordad F, Asatryan A, Wang S, Wyles DL, Hassanein T, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol 2017;67:263-271 View Article PubMed/NCBI
  20. Wyles D, Poordad F, Wang S, Alric L, Felizarta F, Kwo PY, et al. Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial. Hepatology 2018;67:514-523 View Article PubMed/NCBI
  21. Soria A, Fava M, Bernasconi DP, Lapadula G, Colella E, Valsecchi MG, et al. Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort. Liver Int 2020;40:769-777 View Article PubMed/NCBI
  22. Nozaki A, Atsukawa M, Kondo C, Toyoda H, Chuma M, Nakamuta M, et al. The effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients with refractory factors in the real world: a comprehensive analysis of a prospective multicenter study. Hepatol Int 2020;14:225-238 View Article PubMed/NCBI
  23. Tamori A, Inoue K, Kagawa T, Takaguchi K, Nouso K, Iwasaki Y, et al. 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 View Article PubMed/NCBI
  24. Toyoda H, Atsukawa M, Watanabe T, Nakamuta M, Uojima H, Nozaki A, et al. Real-world experience of 12-week direct-acting antiviral regimen of glecaprevir and pibrentasvir in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2020;35:855-861 View Article PubMed/NCBI
  25. Gane E, Lawitz E, Pugatch D, Papatheodoridis G, Bräu N, Brown A, et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med 2017;377:1448-1455 View Article PubMed/NCBI
  26. Lawitz E, Flisiak R, Abunimeh M, Sise ME, Park JY, Kaskas M, et al. Efficacy and safety of glecaprevir/pibrentasvir in renally impaired patients with chronic HCV infection. Liver Int 2020;40:1032-1041 View Article PubMed/NCBI
  27. Atsukawa M, Tsubota A, Toyoda H, Takaguchi K, Nakamuta M, Watanabe T, et al. 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 View Article PubMed/NCBI
  28. Liu CH, Yang SS, Peng CY, Lin WT, Liu CJ, Su TH, et al. Glecaprevir/pibrentasvir for patients with chronic hepatitis C virus infection and severe renal impairment. J Viral Hepat 2020;27:568-575 View Article PubMed/NCBI
  29. Rockstroh JK, Lacombe K, Viani RM, Orkin C, Wyles D, Luetkemeyer AF, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients coinfected with hepatitis C virus and human immunodeficiency virus type 1: The EXPEDITION-2 study. Clin Infect Dis 2018;67:1010-1017 View Article PubMed/NCBI
  30. Reau N, Kwo PY, Rhee S, Brown RS, Agarwal K, Angus P, et al. Glecaprevir/pibrentasvir treatment in liver or kidney transplant patients with hepatitis C virus infection. Hepatology 2018;68:1298-1307 View Article PubMed/NCBI
  31. Ueda Y, Kobayashi T, Ikegami T, Miuma S, Mizuno S, Akamatsu N, et al. Efficacy and safety of glecaprevir and pibrentasvir treatment for 8 or 12 weeks in patients with recurrent hepatitis C after liver transplantation: a Japanese multicenter experience. J Gastroenterol 2019;54:660-666 View Article PubMed/NCBI
  32. Poordad F, Pol S, Asatryan A, Buti M, Shaw D, Hézode C, et al. Glecaprevir/Pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. Hepatology 2018;67:1253-1260 View Article PubMed/NCBI
  33. Uemura H, Uchida Y, Kouyama JI, Naiki K, Tsuji S, Sugawara K, et al. NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir. J Gastroenterol 2019;54:459-470 View Article PubMed/NCBI
  34. Jonas MM, Squires RH, Rhee SM, Lin CW, Bessho K, Feiterna-Sperling C, et al. Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir in adolescents with chronic hepatitis C virus: Part 1 of the DORA study. Hepatology 2020;71:456-462 View Article PubMed/NCBI
  35. D’Ambrosio R, Pasulo L, Puoti M, Vinci M, Schiavini M, Lazzaroni S, et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C. J Hepatol. 2019;70:379-387 View Article PubMed/NCBI
  36. Hsu SJ, Chiu MC, Fang YJ, Yang TH, Yu JJ, Chen CC, et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir in Asian patients with chronic hepatitis C. J Formos Med Assoc. 2019;118:1187-1192 View Article PubMed/NCBI
  37. Ikeda H, Watanabe T, Atsukawa M, Toyoda H, Takaguchi K, Nakamuta M, et al. Evaluation of 8-week glecaprevir/pibrentasvir treatment in direct-acting antiviral-naïve noncirrhotic HCV genotype 1 and 2infected patients in a real-world setting in Japan. J Viral Hepat 2019;26:1266-1275 View Article PubMed/NCBI
  38. Asselah T, Kowdley KV, Zadeikis N, Wang S, Hassanein T, Horsmans Y, et al. Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol 2018;16:417-426 View Article PubMed/NCBI
  39. Zeuzem S, Foster GR, Wang S, Asatryan A, Gane E, Feld JJ, et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med 2018;378:354-369 View Article PubMed/NCBI
  40. Osawa M, Imamura M, Teraoka Y, Uchida T, Morio K, Fujino H, et al. Real-world efficacy of glecaprevir plus pibrentasvir for chronic hepatitis C patient with previous direct-acting antiviral therapy failures. J Gastroenterol 2019;54:291-296 View Article PubMed/NCBI
  41. Fontana RJ, Lens S, McPherson S, Elkhashab M, Ankoma-Sey V, Bondin M, et al. Efficacy and safety of 8 weeks of glecaprevir/pibrentasvir in treatment-naïve, HCV-infected patients with APRI ≤ 1 in a single-arm, open-label, multicenter study. Adv Ther 2019;36:3458-3470 View Article PubMed/NCBI
  42. Lok AS, Sulkowski MS, Kort JJ, Willner I, Reddy KR, Shiffman ML, et al. Efficacy of glecaprevir and pibrentasvir in patients with genotype 1 hepatitis C virus infection with treatment failure after NS5A inhibitor plus sofosbuvir therapy. Gastroenterology 2019;157:1506-1517.e1 View Article PubMed/NCBI
  43. Persico M, Aglitti A, Milella M, Coppola C, Messina V, Claar E, et al. Real-life glecaprevir/pibrentasvir in a large cohort of patients with hepatitis C virus infection: The MISTRAL study. Liver Int 2019;39:1852-1859 View Article PubMed/NCBI
  44. Liu CH, Liu CJ, Hung CC, Hsieh SM, Su TH, Sun HY, et al. Glecaprevir/pibrentasvir for patients with chronic hepatitis C virus infection: Real-world effectiveness and safety in Taiwan. Liver Int 2020;40:758-768 View Article PubMed/NCBI
  45. Sugiura A, Joshita S, Yamashita Y, Yamazaki T, Fujimori N, Kimura T, et al. Effectiveness of glecaprevir/pibrentasvir for hepatitis C: Real-world experience and clinical features of retreatment cases. Biomedicines 2020;8:74 View Article PubMed/NCBI
  46. Kusakabe A, Kurosaki M, Itakura J, Joko K, Akahane T, Tsuji K, et al. 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 View Article PubMed/NCBI
  47. Sezaki H, Suzuki F, Hosaka T, Fujiyama S, Kawamura Y, Akuta N, et al. Initial- and re-treatment effectiveness of glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C virus-genotype 1/2/3 infections. J Gastroenterol 2019;54:916-927 View Article PubMed/NCBI
  48. Puoti M, Foster GR, Wang S, Mutimer D, Gane E, Moreno C, et al. High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: An integrated analysis of HCV genotype 1-6 patients without cirrhosis. J Hepatol 2018;69:293-300 View Article PubMed/NCBI
  49. Lampertico P, Carrión JA, Curry M, Turnes J, Cornberg M, Negro F, et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of patients with chronic HCV infection: A meta-analysis. J Hepatol 2020;72:1112-1121 View Article PubMed/NCBI
  50. Flamm S, Mutimer D, Asatryan A, Wang S, Rockstroh J, Horsmans Y, et al. Glecaprevir/Pibrentasvir in patients with chronic HCV genotype 3 infection: An integrated phase 2/3 analysis. J Viral Hepat 2019;26:337-349 View Article PubMed/NCBI
  51. Morishita A, Ogawa C, Moriya A, Tani J, Yoneyama H, Fujita K, et al. Clinical outcomes of hepatitis C virus elimination using glecaprevir and pibrentasvir in hemodialysis patients: A multicenter study. Hepatol Res 2020;50:557-564 View Article PubMed/NCBI
  52. Back D, Belperio P, Bondin M, Negro F, Talal AH, Park C, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV infection and psychiatric disorders: An integrated analysis. J Viral Hepat 2019;26:951-960 View Article PubMed/NCBI
  53. Poordad F, Felizarta F, Asatryan A, Sulkowski MS, Reindollar RW, Landis CS, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017;66:389-397 View Article PubMed/NCBI
  54. Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T, Dekhtyar T, et al. Integrated resistance analysis of CERTAIN-1 and CERTAIN-2 studies in hepatitis C virus-infected patients receiving glecaprevir and pibrentasvir in Japan. Antimicrob Agents Chemother 2018;62:e02217-17 View Article PubMed/NCBI
  55. Degenhardt L, Peacock A, Colledge S, Leung J, Grebely J, Vickerman P, et al. Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review. Lancet Glob Health 2017;5:e1192-e1207 View Article PubMed/NCBI
  56. Foster GR, Dore GJ, Wang S, Grebely J, Sherman KE, Baumgarten A, et al. Glecaprevir/pibrentasvir in patients with chronic HCV and recent drug use: An integrated analysis of 7 phase III studies. Drug Alcohol Depend 2019;194:487-494 View Article PubMed/NCBI
  57. Grebely J, Dore GJ, Alami NN, Conway B, Dillon JF, Gschwantler M, et al. Safety and efficacy of glecaprevir/pibrentasvir in patients with chronic hepatitis C genotypes 1-6 receiving opioid substitution therapy. Int J Drug Policy 2019;66:73-79 View Article PubMed/NCBI
  58. Flamm S, Reddy KR, Zadeikis N, Hassanein T, Bacon BR, Maieron A, et al. Efficacy and pharmacokinetics of glecaprevir and pibrentasvir with concurrent use of acid-reducing agents in patients with chronic HCV infection. Clin Gastroenterol Hepatol 2019;17:527-535.e6 View Article PubMed/NCBI
  59. Kiser JJ. Safety of hepatitis C viral protease inhibitors in compensated cirrhotics: Lingering concerns put to rest?. Clin Infect Dis 2019;69:1665-1666 View Article PubMed/NCBI
  60. Gane E, Poordad F, Zadeikis N, Valdes J, Lin CW, Liu W, et al. Safety and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1-6 hepatitis C virus infections and compensated liver disease. Clin Infect Dis 2019;69:1657-1664 View Article PubMed/NCBI
  61. Foster GR, Asselah T, Kopecky-Bromberg S, Lei Y, Asatryan A, Trinh R, et al. Safety and efficacy of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C in patients aged 65 years or older. PLoS One 2019;14:e0208506 View Article PubMed/NCBI
  62. Brown A, Welzel TM, Conway B, Negro F, Bräu N, Grebely J, et al. Adherence to pan-genotypic glecaprevir/pibrentasvir and efficacy in HCV-infected patients: A pooled analysis of clinical trials. Liver Int 2020;40:778-786 View Article PubMed/NCBI
  63. Singh AD, Maitra S, Singh N, Tyagi P, Ashraf A, Kumar R, et al. Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients. Aliment Pharmacol Ther 2020;51:490-504 View Article PubMed/NCBI
  64. Smith D, Magri A, Bonsall D, Ip CLC, Trebes A, Brown A, et al. Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors. Hepatology 2019;69:1861-1872 View Article PubMed/NCBI
  65. Wei L, Omata M, Lim YS, Xie Q, Hou JL, Jia J, et al. HCV phylogenetic signature and prevalence of pretreatment NS5A and NS5B NI-Resistance associated substitutions in HCV-Infected patients in Mainland China. Antiviral Res 2018;158:178-184 View Article PubMed/NCBI
  66. Chen Y, Yu C, Yin X, Guo X, Wu S, Hou J. Hepatitis C virus genotypes and subtypes circulating in Mainland China. Emerg Microbes Infect 2017;6:e95 View Article PubMed/NCBI
  67. Welzel TM, Bhardwaj N, Hedskog C, Chodavarapu K, Camus G, McNally J, et al. Global epidemiology of HCV subtypes and resistance-associated substitutions evaluated by sequencing-based subtype analyses. J Hepatol 2017;67:224-236 View Article PubMed/NCBI
  68. Sato K, Uraoka T. Challenge to overcome: Nonstructural protein 5A-P32 deletion in direct-acting antiviral-based therapy for hepatitis C virus. World J Gastroenterol 2018;24:4304-4310 View Article PubMed/NCBI
  69. Hikita H, Takehara T. NS5A-P32 deletion in hepatitis C genotype 1b infection is the most refractory treatment-mediated amino acid change exhibiting resistance to all NS5A inhibitors. Semin Liver Dis 2020;40:143-153 View Article PubMed/NCBI
  70. Tsai N, Bacon B, Curry M, Flamm SL, Milligan S, Wick N, et al. Changing demographics among populations prescribed HCV treatment, 2013-2017. Am J Manag Care 2019;25:319-323 View Article PubMed/NCBI
  71. Christensen S, Ingiliz P, Schulze Zur Wiesch J, Schewe K, Boesecke C, Hüppe D, et al. Significant changes of HCV patient characteristics over time in the era of direct antiviral agent therapy – are all HCV subpopulations treated similarly? – Results from the German hepatitis C Cohort. J Hepatol 2018;68:S289-S290 View Article PubMed/NCBI
  72. European Commission Grants AbbVie Marketing Authorization Shortening MAVIRET® (glecaprevir/pibrentasvir) treatment duration to eight weeks for treatment-naïve chronic HCV patients with genotype 3 and compensated cirrhosis. Available from: https://news.abbvie.com/news/press-releases/european-commission-grants-abbvie-marketing-authorization-shortening-maviret-glecaprevirpibrentasvir-treatment-duration-to-eight-weeks-for-treatment-nave-chronic-hcv-patients-with-genotype-3-and-compensated-cirrhosis.htm?view_id=4284 View Article PubMed/NCBI

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