Glecaprevir/pibrentasvir Research Articles

Impact of HCV eradication by directly acting antivirals on glycemic indices in chronic hepatitis C patients -a nationwide Taiwan HCV registry

Background/AimsHepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive. MethodsData from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%). ResultsSerum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00–1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48–3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05–1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000–1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006–1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52–4.45, P < 0.001). ConclusionsThe HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes.

Real-life effectiveness of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients previously treated with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir.

Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct-acting antivirals (DAAs). Data are limited on the effectiveness of this treatment after the current first-line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022. In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non-GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR. SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first-line therapy with SOF/VEL were not associated with lower SVRs.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitisC (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitisC virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Phase 1 study of safety and tolerability of an oral contraceptive containing low-dose ethinyl oestradiol combined with glecaprevir/pibrentasvir treatment in healthy premenopausal women.

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 μg/250 μg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 μg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 μg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.

Comparison of Glecaprevir/Pibrentasvir and Sofosbuvir/Ledipasvir in Patients with Hepatitis C Virus Genotype 1 and 2 in South Korea.

This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Efficacy and safety of DAA in children and adolescents with chronic HCV infection: A systematic review and meta-analysis.

We evaluated the effectiveness and safety of pan-genotypic regimens, glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/daclatasvir (SOF/DCV) and other direct-acting antivirals (DAA) regimens for the treatment of hepatitis C virus (HCV)-infected adolescents (12-18 years), older children (6-11 years), and young children (3-5 years). The purpose of this systematic review and meta-analysis was to inform the World Health Organization (WHO) guidelines. We included clinical trials and observational studies published up to August 11, 2021, that evaluated DAA regimens in HCV-infected adolescents, older children, and young children. We searched MEDLINE, EMBASE, and CENTRAL databases and key conference abstracts. Sustained virological response 12 weeks after the end of treatment (SVR12), adverse events (AEs), and treatment discontinuation were the outcomes evaluated. Risk of bias was assessed using a modified version of the ROBINS-I tool. Data were pooled using random-effects models, and certainty of the evidence was assessed using the GRADE approach. A total of 49 studies including 1882 adolescents, 436 older children, and 166 young children were considered. The SVR12 was 100% (95% Confidence Interval: 96-100), 96% (90-100), and 96% (83-100) for GLE/PIB in adolescents, older, and young children, respectively; 95% (90-99), 93% (86-98), and 83% (70-93), for SOF/VEL, respectively; and 100% (97-100) and 100% (94-100) for SOF/DCV in adolescent and older children, respectively. There was a clear trend towards a higher rate of any reported AE from adolescents (50%), older children (53%), to young children (72%). Serious AEs and treatment discontinuations were uncommon in adolescents and older children (<1%) but slightly higher in young children (3%). All three pan-genotypic DAA regimens were highly effective and well-tolerated and are now recommended by the WHO for use in adults, adolescents, and children down to 3 years, which will simplify procurement and supply chain management. The evidence was based largely on single-arm non-randomized controlled studies. Moreover, there were also missing data regarding key variables such as route of HCV acquisition, presence or absence of cirrhosis, or HIV co-infection that precluded evaluation of the impact of these factors on outcomes. CRD42020146752.

Real-World Safety and Effectiveness of an 8-Week Regimen of Glecaprevir/Pibrentasvir in Patients with HepatitisC and Cirrhosis.

In 2019, an 8-week regimen of glecaprevir/ pibrentasvir (GLE/PIB) was FDA-approved for treatment of chronic hepatitisC (HCV) in patients with cirrhosis. We used data from the Chronic HepatitisCohort Study (CHeCS) to evaluate treatment response and adverse events among patients with HCV and cirrhosis under routine clinical care. Using an intention-to-treat (ITT)/modified ITT (mITT) approach, endpoints were (1) sustained virological response (SVR) at 12weeks (SVR12) post-treatment; and (2) adverse events (AEs)/serious AEs during treatment. Patients with cirrhosis from two CHeCS sites were included if they were prescribed GLE/PIB from August 2017 to June 2020. Detailed treatment and clinical data were collected. Patient baseline characteristics were described with mean/standard deviation (std) for continuous variables, and proportions for categorical variables. Analyses were propensity score adjusted. The final model retained variables that were significant with pvalue < 0.05. The ITT sample included 166 patients, with 43, 116, and 7 patients in the 8-week, 12-week, and > 12-week planned treatment groups. Among them, 159had confirmed SVR (95.8%, LCL 93.2%). The mITT analysis included 160 patients after excluding 6 with unknown HCV RNA results; 159 achieved SVR (99.4%, LCL 98.3%). There were no significant differences in rates of SVR between the 8-weekand 12-week regimens in either analysis, nor any association with patient characteristics. SAEs were experienced by 1 patient (2%) in the 8-week group, 7 (5%) in the 12-week group (including one death), and 2 (29%) in the > 12-week group; 4 patients (from the 12-week group) experienced serious AEs or hepatic events that were "likely attributable" to GLE/PIB treatment. An 8-week regimen of GLE/PIB is well tolerated and highly effective among US patients with HCV and cirrhosis receiving routine clinical care.

Эффективность 8-недельного курса глекапревир/пибрентасвир у пациентов с хроническим гепатитом С и компенсированным циррозом печени (исследование “EASY”)

Objective. To determine how the efficacy and safety of an 8-week course of glecaprevir/pibrentasvir (GLE/PIB) in patients with chronic hepatitis C (CHC) and compensated cirrhosis, as demonstrated in the respective clinical trial, translate to real-world clinical practice. Patients and methods. A prospective multicenter observational study was conducted in treatment-naive patients aged ≥12 years with CHC (viral genotypes 1–6) and compensated liver cirrhosis taking GLE/PIB for 8 weeks in routine clinical practice in Russia. GLE/PIB was prescribed in accordance with the Russian label prior to patient inclusion in the study. Patients were followed for 8 weeks of GLE/PIB therapy and at least 12 weeks after its termination to assess the rate of sustained virologic response (SVR). Diagnostic methods, procedures, and visits were consistent with routine clinical practice. Each patient's data were documented in the electronic database. Results. Ninety-nine patients at 6 centers were enrolled; in 93 of these patients, follow-up data were sufficient to assess SVR 12 weeks (ie, ≥70 days) after completion of GLE/PIB therapy (SVR12). The overall SVR12 rate was 98.9% (92/93); only 1 patient did not achieve SVR12 due to virologic failure (non-response). The following SVR12 rates were found in the subgroups to which this patient belonged: 98.3% (59/60) among non-drug users, 97.1% (33/34) among those infected with GT1b virus, 98.7% (78/79) among young and middle-aged patients (&lt;65 years), and 98.5% (65/66) among patients without HIV. In contrast, SVR12 was achieved in all patients (100%) in the remaining subgroups: patients with genotype 2 (n = 8), 3 (n = 44), and other (n = 7); drug users (n = 31) and patients with unknown drug use status (n = 2); HIV co-infected (n = 27); and elderly (≥65 years, n = 14) patients. No adverse events, including cases of hepatic failure, were observed in patients during this study. Conclusion. An 8-week course of GLE/PIB demonstrated high efficacy and favorable safety profile in treatment-naive patients with compensated cirrhosis infected with different genotypes of hepatitis C virus, including genotype 3 in routine clinical practice in Russia. These results are consistent with data obtained in GLE/PIB clinical trials and real-world studies conducted in other countries. Key words: chronic hepatitis C, compensated cirrhosis, glecaprevir/pibrentasvir combination, 8 weeks

Опыт лечения больных хронической ВГС‑инфекцией пангенотипной комбинацией препаратов прямого противовирусного действия (глекапревир/пибрентасвир) в Ставропольском крае

Objective. To analyze the results of usage of pangenotype combination glecaprevir/pibrentasvir (GLE/PIB) in real clinical practice in Stavropol Krai within the framework of the regional program on chronic hepatitis C (CHC) treatment. Materials and methods. In the framework of this study, a retrospective analysis of the use of GLE/PIB combination in the period from 2018 to 2022 within the framework of the regional program for the treatment of CHC in the Stavropol region was carried out. The drug was prescribed in accordance with the current label approved in Russia. Patients were observed during the entire period of GLE/PIB therapy and for 12 weeks after treatment completion. Data for analysis were collected from outpatient records and protocols of the “Regional Medical Commission on Diagnosis, Treatment and Drug Supply of Patients with Chronic Viral Hepatitis B and C in Stavropol Krai”. Results. The analysis included 405 patients treated within the framework of the regional program on drug supply of patients with chronic viral hepatitis B and C in the territory of the Stavropol region. The scope of the examination allowed to assess the sustained virologic response 12 weeks after the end of GLE/PIB therapy (SVR12). 92.6% (375/405) of patients had not previously received antiviral therapy. Absence or minimal manifestations of hepatic fibrosis (F0-1) were noted in 50.9% of patients, advanced stage of fibrosis (F3-4 by METAVIR scale) in 34.6%. The distribution by fibrosis stage was as follows: F0 – 21.98% (89/405), F1 – 28.9% (117/405), F2 – 14.6% (59/405), F3 – 13.1% (53/405), F4 (CP-A) – 21.5% (87/405). All patients with liver cirrhosis had compensated stage of the disease – class A according to Child-Pugh. In the study population, genotype (Gt) 3 prevailed, detected in 55.1% (223/405) of patients. Hepatitis C virus (HCV) Gt1 was diagnosed in 29.4% (119/405) of patients. Among them, 16.5% (67/405) of patients had Gt1b, 0.5% (2/405) had Gt1a, and 12.3% (50/405) of patients with Gt1 had no subtype identified. Gt2 was detected in 11.4% of patients (46/405), 3 (0.7%) patients had a genotype other than 1–3, and 14 (3.5%) patients had no HCV genotype determined. 14 (3.6%, 14/405) patients were co-infected with HCV and HIV. 23.5% (95/405) of patients belonged to the age group older than 60 years. The distribution of patients according to the duration of antiviral therapy was as follows: 8 weeks – 89.4% (362/405), 12 weeks – 6.4% (26/405) and 16 weeks – 4,2% (17/405). 405 (100,0%) out of 405 patients achieved SVR12. There were no cases of serious adverse events and treatment withdrawal during antiviral therapy. Conclusion. GLE/PIB has demonstrated high efficacy in patients with different HCV genotypes (including Gt3) and different stages of liver fibrosis (including compensated cirrhosis) in the real-world setting. The SVR12 rate obtained in this analysis is fully consistent with the data of clinical trials and real clinical practice published earlier. Key words: chronic hepatitis C, glecaprevir/pibrentasvir, pangenotypic, real clinical practice

Efficacy and safety of glecaprevir and pibrentasvir in Saudi patients with chronic hepatitis C virus infection at a major tertiary hospital.

To evaluate the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) in chronic hepatitis C (HCV) patients, and to assess the prescribers' adherence to Food and Drug Administration recommendations on treatment duration. A retrospective cohort study was carried out on chronic HCV patients of ≥18 years, with or without cirrhosis, naive or experienced, and with normal kidney function or chronic kidney disease (including dialysis patients) at Prince Sultan Military Medical City in Riyadh, Saudi Arabia, between February 2020 and March 2021. The primary effectiveness end-point was the number and percentage of patients who achieved a sustained virologic response (SVR12), virologic failure, and non-response. Safety was determined considering both serious and non-serious adverse events. A total of 92 patients were enrolled in this study. Among patients, 52 (56.5%) were female, 84 (91.3%) were naive, and 45 (48.9 %) had HCV genotype 4. The SVR12 was achieved in 91 (98.9%, 95% CI: [94-99.8]) patients. Only one patient (1.1%, 95% CI: [0.2-5.9]) developed virologic non-response and there were missing data on virologic failure. Overall, non-serious adverse events were observed in 26 (28.5%) patients, and none of them had serious adverse events that led to treatment discontinuation. Approximately 75% of the patients received an inappropriate treatment duration (12 weeks vs. the recommended 8 weeks) and most (n=40, 58%; p<0.022) of the exceedingly long treatments were prescribed by registrars. The GLE/PIB was highly effective and safe in chronic HCV Saudi patients.

Hepatitis C Virus Infection in the Elderly in the Era of Direct-Acting Antivirals: Evidence from Clinical Trials and Real Life.

The introduction of direct-acting antiviral agents (DAAs) into clinical practice has revolutionized the therapeutic approach to patients with chronic hepatitis C virus (HCV) infection. According to the most recent guidelines, the first line of treatment for HCV infection involves the use of one of three pan-genotypic DAA combinations, sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). These drugs have been shown to be effective and safe in numerous clinical trials and real-world studies, but special populations have been neglected. Among the special populations to be treated are elderly patients, whose numbers are increasing in clinical practice. The management of these patients can be challenging, in particular due to multiple comorbidities, polypharmacotherapy, and potential drug-drug interactions. This narrative review aims to summarize the current scientific evidence on the efficacy and safety of DAAs in the elderly population, both in clinical trials and in real-life settings. Although there is still a paucity of real-world data and no clinical trials have yet been conducted in the population aged ≥ 75 years old, some considerations about the efficacy and safety of DAAs in the elderly can be made based on the results of these studies. The pan-genotypic associations of DAAs appear to be as efficacious and safe in the elderly population as in the general population; this is both in terms of similar sustained virologic response (SVR) rates and similar frequencies of adverse events (AEs). However, further studies specifically involving this patient population would be necessary to confirm this evidence.

Real-World Efficacy and Safety of an 8-Week Glecaprevir/Pibrentasvir Regimen in Children and Adolescents with Chronic Hepatitis C-Results of a Multicenter EpiTer-2 Study.

The aim of the study was to analyze the effectiveness and safety of anti-HCV treatment based on a pangenotypic direct-acting antiviral (DAA) regimen with glecaprevir/pibrentasvir (GLE/PIB) in children. The multi-center study was conducted in HCV-infected children who were treated in the period from November 2022 to January 2023. The analysis included 23 pediatric patients with a mean (SD) age of 9.61 (3.68) years. The cohort included 13 girls and 10 boys. The most common HCV genotypes were GT1b (n = 9, 39.1%), GT1a (n = 6, 26.1%) and GT3 (n = 5, 21.7%). The SVR was assessed at 12 weeks after the end of treatment and was 100% for both girls and boys. The conducted study showed a very good tolerance of the treatment in the entire analyzed group and confirmed a very high efficacy and safety for 8-week treatment with GLE/PIB in children over three years of age. It seems that our study is the first on the real-world use of an 8-week GLE/PIB pangenotypic therapy in a group of children aged 3-12 years and the first in Europe for adolescents aged 12-17.

Ledipasvir/Sofosbuvir Is Effective for Relapsed Genotype 1b Hepatitis C Virus Patients after Achieving a Sustained Virological Response at Post-treatment Week 12 with Glecaprevir/Pibrentasvir.

A patient with genotype 1b chronic hepatitis C virus who had been treated with pegylated interferon and ribavirin (RBV) was treated with glecaprevir/pibrentasvir (GLE/PIB) for 12 weeks. A sustained virological response at post-treatment week 12 (SVR12) was achieved, but relapse occurred approximately 31 weeks after the end of treatment. The patient had a history of allergy to RBV and was treated with ledipasvir/sofosbuvir (LDV/SOF), achieving SVR12 and remaining hepatitis C virus-negative until 24 weeks after the completion of treatment. LDV/SOF can thus be a secondary treatment for GLE/PIB.

Sofosbuvir plus glecaprevir/pibrentasvir as salvage therapy after liver transplantation in NS5A inhibitor-experienced patients. A case series.

Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals achieves a sustained virologic response rate higher than 95%. However, virologic failure remains a clinical challenge, and data on retreatment are limited, especially in special populations such as liver transplant (LT) recipients. This study evaluated the sofosbuvir plus glecaprevir-pibrentasvir (GLE/PIB) regimen in LT recipients who had failed to a nonstructural protein 5A (NS5A) inhibitor-based regimen. Retrospective study of 111 liver transplant recipients between January 2018 and December 2020; 18 patients presented with HCV recurrent infection after LT, out of whom three had a history of at least one NS5A inhibitor-based regimen. Salvage therapy with sofosbuvir plus GLE/PIB was started for 12 weeks; baseline characteristics and outcomes were recorded. All three patients (100%) achieved an undetectable HCV viral load 12 weeks after treatment completion. No serious adverse events were observed. In our series, sofosbuvir plus GLE/PIB for 12 weeks is an effective and safe salvage therapy after LT in patients previously treated with NS5A inhibitors.

Assessment of Drug-Drug Interaction Risk Between Intravenous Fentanyl and the Glecaprevir/Pibrentasvir Combination Regimen in Hepatitis C Patients Using Physiologically Based Pharmacokinetic Modeling and Simulations.

An unsafe injection practice is one of the major contributors to new hepatitis C virus (HCV) infections; thus, people who inject drugs are a key population to prioritize to achieve HCV elimination. The introduction of highly effective and well-tolerated pangenotypic direct-acting antivirals, including glecaprevir/pibrentasvir (GLE/PIB), has revolutionized the HCV treatment landscape. Glecaprevir is a weak cytochrome P450 3A4 (CYP3A4) inhibitor, so there is the potential for drug-drug interactions (DDIs) with some opioids metabolized by CYP3A4, such as fentanyl. This study estimated the impact of GLE/PIB on the pharmacokinetics of intravenous fentanyl by building a physiologically based pharmacokinetic (PBPK) model. A PBPK model was developed for intravenous fentanyl by incorporating published information on fentanyl metabolism, distribution, and elimination in healthy individuals. Three clinical DDI studies were used to verify DDIs within the fentanyl PBPK model. This model was integrated with a previously developed GLE/PIB PBPK model. After model validation, DDI simulations were conducted by coadministering GLE 300mg + PIB 120mg with a single dose of intravenous fentanyl (0.5µg/kg). The predicted maximum plasma concentration ratio between GLE/PIB + fentanyl and fentanyl alone was 1.00, and the predicted area under the curve ratio was 1.04, suggesting an increase of only 4% in fentanyl exposure. The administration of a therapeutic dose of GLE/PIB has very little effect on the pharmacokinetics of intravenous fentanyl. This negligible increase would not be expected to increase the risk of fentanyl overdose beyond the inherent risks related to the amount and purity of the fentanyl received during recreational use.

Effectiveness of Glecaprevir/Pibrentasvir in Patients with Chronic HCV-infection Genotypes 1 to 6 in the real-world settings in Russia (EVEREST study)

Background: Glecaprevir/pibrentasvir (GLE/PIB) is the first pangenotypic ribavirin-free regimen allowing for treatment duration as short as 8 weeks for the majority of patients with chronic hepatitis C (CHC) genotypes (GT) 1 to 6. The results of clinical trials showed good tolerability of GLE/PIB and high virologic response rate (mostly &gt;95%) among different patient populations. The main objective of this study was to determine how the efficacy and safety of GLE/PIB translates into real-world clinical settings in Russia.Materials and Methods: This was a prospective, multicenter observational study in patients with CHC who received the GLE/PIB regimen. The treatment regimen was prescribed by a physician in accordance with all applicable requirements before the enrollment in the study. Patients were observed for the duration of GLE/PIB therapy and at least for up to 12 weeks after the treatment completion. Real-world data were collected in patient records. Follow-up visits, procedures, and diagnostic methods followed physicians’ routine clinical practice.Results: Overall 161 patients were enrolled in the study in 11 study sites of them 128 patients had sufficient follow-up data to assess sustained virological response 12 weeks [i.e. ≥70 days] after the end of treatment with GLE/PIB (SVR12). Overall, 127 out of 128 patients (99.2%) achieved SVR12. Depending on treatment duration the following SVR12 rates were achieved: 98.7% in 8-week group (75/76), 100% in 12-week group (49/49) and 100% in 16-week group (3/3). One patient failed to achieve SVR, the exact reasons of failure couldn’t be established by the Investigator.Since only one patient didn’t achieve primary endpoint the following SVR12 rates were achieved in different subpopulations: 91.7% in patients with GT2 (11/12); 98.9% in non-cirrhotic patients (88/89); 99.1% in treatment-naïve patients (113/114); 99.1% in patients without HIV co-infection (116/117); 99.2% in patients younger than 65 years (120/121).On the other hand, SVR12 was achieved by all patients (100%) in the following subpopulations: patients with GT3 (n=76), GT1a (n=5), GT1b (n=29) and other GTs (n=6); cirrhotic patients (n=36) and those with unknown cirrhosis status (n=3); treatment-experienced patients (n=14); HIV/HCV co-infected patients (n=11); patients older than 65 years (n=7); and drug users (n=10).No clinically significant abnormalities in the key laboratory parameters were noted during the study. On contrary, the overall improvement of the liver enzymes was observed at SVR12 Visit. There were 3 patients with 3 adverse events (AEs): 2 cases were mild (cough and rash), and 1 case was severe and evaluated as a serious AE (hepatic decompensation). Hepatic decompensation led to the patient withdrawal from the study; this serious AE was preceded by 2 months of daily alcohol consumption and in the investigator’s opinion was not related to GLE/PIB intake. Of all AEs only rash was related to GLE/PIB administration according to investigator’s opinion.Conclusion: GLE/PIB has proven to be a highly effective treatment regimen in the routine clinical practice in patients with all hepatitis C virus genotypes, including those with GT3 and compensated liver cirrhosis. SVR12 rates demonstrated in this study are fully consistent with the previously published data. The regimen was well tolerated by patients.

Histological improvement in chronic hepatitis C-autoimmune hepatitis overlap syndrome by glecaprevir and pibrentasvir.

A 60-year-old man with type-2 diabetes and chronic hepatitis C (HCV) was diagnosed with single hepatocellular carcinoma (HCC) of 67mm in the hepatic posterior right lobe. Lenvatinib 8mg was initiated but discontinued because of grade 3 liver injury. The patient continued to have prolonged liver injury and persistently high immunoglobulin G levels. Antinuclear antibody titer increased from 1:40 to 1:320. Histopathological examination of a liver biopsy specimen revealed interface hepatitis with lymphocyte and plasma cell infiltration, rosette formation, and emperipolesis, suggesting the possibility of autoimmune hepatitis (AIH). First, treatment with prednisolone was initiated; however, the response was poor. After starting glecaprevir/pibrentasvir (GLE/PIB) as direct-acting antivirals (DAA), HCV RNA rapidly disappeared, and serological liver function improved. After confirmation of sustained virological response 24, HCC recurrence was observed, and partial hepatectomy was performed. Background liver findings showed that liver parenchymal inflammation improved compared with that before DAA treatment. This is the first case of HCV-AIH overlap syndrome treated with DAA using GLE/PIB. Liver function improved within a short treatment period of 8weeks, as confirmed using serology and histology.

Effectiveness and safety of 8-week glecaprevir/pibrentasvir in HCV treatment-naïve patients with compensated cirrhosis: real-world experience from Taiwan nationwide HCV registry.

Large-scale real-world data of the 8-week glecaprevir/pibrentasvir (GLE/PIB) therapy for treatment-naïve patients of chronic hepatitis C virus (HCV) infection with compensated cirrhosis is scarce. The TASL HCV Registry (TACR) is an ongoing nationwide registry program that aims to set up a database and biobank of patients with chronic HCV infection in Taiwan. In this study, data were analyzed as of 31 October 2021 for treatment-naïve HCV patients with compensated cirrhosis receiving 8-week GLE/PIB therapy. Effectiveness reported as sustained virologic response at off-therapy week 12 (SVR12) and safety profiles were assessed. Patient characteristics potentially related to SVR12 were also evaluated. Of the 301 patients enrolled, 275 had available SVR12 data. The SVR12 rate was 98.2% (270/275) in the modified intention-to-treat (mITT) population and 89.7% (270/301) in the ITT population. For those mITT patients with genotype 3, FibroScan > 20kPa, platelet < 150,000/µl, and FibroScan > 20kPa and platelet < 150,000/µl, the SVR12 rates were 100% (6/6), 100% (12/12), 98.0% (144/147), 100% (7/7), respectively. Overall, 24.9% (75/301) patients experienced adverse events (AEs). The most frequent AEs (> 5%) included fatigue (9.0%) and pruritus (7.0%). Seven (2.3%) patients experienced serious AEs and two (0.7%) resulted in permanent drug discontinuation. None of them were considered as GLE/PIB-related. In this large-scale real-world Taiwanese cohort, 8-week GLE/PIB therapy was efficacious and well tolerated for treatment-naïve compensated cirrhosis patients. SVR12 rates were similarly high as in the clinical trials, including those with characteristics of advanced liver disease.

Risk Factors of Glecaprevir/Pibrentasvir-Induced Liver Injury and Efficacy of Ursodeoxycholic Acid.

Although glecaprevir/pibrentasvir (GP) therapy is recommended as a first-line treatment for hepatitis C virus (HCV) infection, serious drug-induced liver injury occasionally develops. The present study aimed to elucidate real-world risk factors for GP-induced liver injury and to evaluate the efficacy of add-on ursodeoxycholic acid (UDCA) for liver injury. We analyzed 236 HCV patients who received GP therapy. GP-induced liver injury was defined as any elevation to grade ≥ 1 in total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or γ-glutamyl transferase (γ-GT) during treatment without other cause. The frequency of GP-induced liver injury was 61.9% (146/236). Serious elevation to grade ≥ 3 in TB, AST, ALT, ALP, and γ-GT was identified in 3.8% (9/236), 0%, 0%, 0%, and 0.4% (1/209), respectively. Therapy discontinuation and dose reduction were seen in one patient each. Multivariate analysis revealed age and TB as independent risk factors for GP-induced liver injury. In patients with grade ≥ 2 hyperbilirubinemia, TB after onset significantly decreased in the add-on UDCA group but not in the no UDCA group. Careful attention to GP-induced liver injury is warranted for elderly patients with cirrhosis. Add-on UDCA could suppress the aggravation of GP-induced liver injury.

Italian Real-World Analysis of the Impact of Polypharmacy and Aging on the Risk of Multiple Drug–Drug Interactions (DDIs) in HCV Patients Treated with Pangenotypic Direct-Acting Antivirals (pDAA)

The study aims at investigating the impact of polymedication and aging in the prevalence of multiple drug-drug interactions (DDIs) on HCV patients treated with sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). This is a retrospective analysis based on administrative data covering around 6.9 million individuals. Patients treated with SOF/VEL or GLE/PIB over November 2017-March 2020 were included. Index date corresponded to SOF/VEL or GLE/PIB first prescription during such period; patients were followed up for treatment duration. Analyses were then focused on patients with ≥2 comedications at risk of multiple DDIs. The severity and the effect of multiple DDI were identified using the Liverpool University tool. A total of 2057 patients with SOF/VEL and 2128 with GLE/PIB were selected. Mean age of SOF/VEL patients was 58.5 years, higher than GLE/PIB ones (52.5 years) (p < 0.001), and patients >50 years were more present in SOF/VEL vs GLE/PIB cohorts: 72% vs 58%, (p < 0.001). Most prescribed co-medications were cardiovascular, alimentary and nervous system drugs. Proportion of patients with ≥2 comedications was higher in SOF/VEL compared to GLE/PIB cohort (56.5% vs 32.3%, p < 0.001). Those at high-risk of multiple DDIs accounted for 11.6% (N = 135) of SOF/VEL and 19.6% (N = 135) of GLE/PIB (p < 0.001) patients with ≥2 comedications. Among them, the potential effect of DDI was a decrease of DAA serum levels (11% of SOF/VEL and GLE/PIB patients) and an increased concentration of comedication serum levels (14% of SOF/VEL and 42% of GLE/PIB patients). This real-world analysis provided a thorough characterization on the burden of polymedication regimens in HCV patients treated with SOF/VEL or GLE/PIB that expose such patients to an increased risk of DDIs. In our sample population, SOF/VEL regimen was more frequently detected on elderly patients and on those with ≥2 comedications at risk of multi-DDI, ie, among patients characterized by higher rates of comorbidities and polypharmacy.