Pangenotypic Regimen Research Articles

Prevalence of Drug Resistance Associated Substitutions in Persons With Chronic Hepatitis C Infection and Virological Failure Following Initial or Re-treatment With Pan-genotypic Direct-Acting Antivirals: A Systematic Review and Meta-analysis.

The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy. We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis. The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors. At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.

Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis.

Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure.

Key points for the management of hepatitis C in the era of pan-genotypic direct-acting antiviral therapy

Hepatitis C viral infections present a significant global health challenge, carrying substantial economic implications. These infections manifest in various clinical forms, including acute and chronic hepatitis, liver cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC). Liver cirrhosis and HCC emerge as the primary contributors to mortality in hepatitis virus-induced liver diseases. To alleviate the public health impact of this disease, it is imperative to enhance the diagnosis and treatment rates among hepatitis C virus-infected individuals. The advent of direct-acting antivirals (DAAs), especially pan-genotypic regimens such as a combination of sofosbuvir and velpatasvir, has shown remarkable progress in achieving hepatitis C cure. However, potential obstacles, such as drug adverse effects and resistance-associated substitutions (RASs), warrant attention. Managing chronic hepatitis C (CHC) requires tailored treatment plans, vigilant monitoring, and judicious re-treatment strategies.

Real-life effectiveness of antiviral therapy for HCV infection with pangenotypic regimens in HIV coinfected patients

ABSTRACT Background The aim of this study was to evaluate the real-life efficacy of pangenotypic antivirals in HIV-HCV-positive patients. Research design and methods The analysis included 5650 subjects who were treated with pangenotypic anti-HCV drugs: 5142 were HCV-positive and 508 were HIV-HCV-positive. Results Patients with HCV-monoinfection were older (p < 0.0001), however patients with HCV-monoinfection had a higher proportion of advanced fibrosis F4 (p < 0.0001). There were no differences between the study groups in the rate of SVR12 in ITT-analysis (87,6% versus 93,9% in coinfection and monoinfection group, respectively; p > 0.05). However, there was a difference between study groups in PP-analysis, HIV/HCV and HCV, respectively 95.9% vs 97.9%, p = 0.0323. Additionally, there were a higher rate of patients who did not apply for follow-up (SVR12) in coinfected patients (7,9% vs 3,6% respectively p = 0.0001). In multivariante analysis, factors associated with worse response to the pangenotypic anti-HCV therapy included male sex, HCV genotype 3, stage of fibrosis and decompensation of liver function and HIV coinfection. Conclusions The real-life results of pangenotypic anti-HCV treatment are veryeffective in the group of HIV-HCV-coinfected patients. However, the finaleffectiveness is slightly lower than that obtained in HCV monoinfectedpatients.

Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n= 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n= 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Is it time for China to prioritize pan-genotypic regimens for treating patients with hepatitis C?

IntroductionThe treatment of hepatitis C has entered the pan-genotypic era, but the effectiveness is not good for the genotype 3b patients who have a large proportion in China. The guidelines for hepatitis C recommend the use of gene-specific regimens when the regional 3b prevalence rate greater than 5%. This study is to explore rationality of this proportion and the cost-effectiveness to implement pan-genotypic regimens in China.MethodsA decision Markov model was developed from the health system perspective to evaluate the effectiveness and cost-effectiveness between pan-genotypic and gene-specific treatment regimens for hepatitis C patients. Additionally, we set a regional genotype 3b patient proportion of 0–100% to explore at which proportion it is necessary to perform genotype identification and typing therapy on patients. Model parameters were derived from published literature and public databases. Effectiveness was measured by cured patient numbers, newly diagnosed cases of decompensated cirrhosis, hepatocellular carcinoma, need for liver transplantation, and quality-adjusted life years (QALYs). Cost-effectiveness outcomes included costs and the incremental cost-effectiveness ratio (ICER). The 1–3 times 2022 Chinese per capita gross domestic product was used as the willingness-to-pay threshold. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty of the model parameters.ResultsCompared with gene-specific regimens, pan-genotypic regimens resulted in an additional 0.13 QALYs and an incremental cost of $165, the ICER was $1,268/QALY. From the view of efficacy, the pan-genotypic regimens cured 5,868 more people per 100,000 patients than gene-specific regimens, avoiding 86.5% of DC cases, 64.6% of HCC cases, and 78.2% of liver transplant needs. Identifying 3b patients before treatment was definitely cost-effectiveness when their prevalence was 12% or higher. The results remained robust in sensitivity analyses.ConclusionsIn China, the prioritized recommendation of pan-genotypic therapeutics proves to be both cost-effective and efficacious. But, in regions where the prevalence of genotype 3b exceeds 12%, it is necessary to identify them to provision of more suitable therapies.

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.

An algorithm for simplified hepatitis C virus treatment with non-specialist care based on nation-wide data from Taiwan

BackgroundBoth European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) guidelines recommend simplified hepatitis C virus (HCV) treatment with pan-genotypic sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for eligible patients. This observational study used real-world data to assess these regimens’ safety in eligible patients and develop an algorithm to identify patients suitable for simplified treatment by non-specialists.Methods7,677 HCV-infected patients from Taiwan Hepatitis C Registry (TACR) who received at least one dose of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, and fulfilled the EASL/AASLD-IDSA criteria for simplified treatment were analyzed. Multivariate analysis was conducted on patient characteristics and safety data.ResultsOverall, 92.8% (7,128/7,677) of patients achieved sustained virological response and only 1.9% (146/7,677) experienced Grades 2–4 laboratory abnormalities in key liver function parameters (alanine aminotransferase, aspartate aminotransferase, and total bilirubin), with only 18 patients (0.23%) experiencing Grades 3–4 abnormalities. Age > 70 years old, presence of hepatocellular carcinoma, total bilirubin > 1.2 mg/dL, estimated glomerular filtration rate < 60 mL/min/1.73 m2, and Fibrosis-4 > 3.25 were associated with higher risks of Grades 2–4 abnormalities. Patients with any of these had an odds of 4.53 times than that of those without in developing Grades 2–4 abnormalities (p < 0.01).ConclusionsReal-world data from Taiwan confirmed that simplified HCV treatment for eligible patients with pan-genotypic regimens is effective and well tolerated. The TACR algorithm, developed based on this study’s results, can further identify patients who can be safely managed by non-specialist care.Graphical

Does a detectable HCV RNA at the end of DAA therapy herald treatment failure?

Background & aimsThe study aimed to assess the phenomenon of achieving sustained virologic response (SVR) in patients with detectable ribonucleic acid (RNA) of hepatitis C virus (HCV) at the end of treatment (ET) with direct-acting antivirals (DAA), find how this is affected by the type of regimen, and how patients experiencing this differed from non-responders with detectable HCV RNA at the ET. MethodsThe study included all consecutive patients with detectable HCV RNA at the ET selected from the EpiTer-2 database, a retrospective national multicentre project evaluating antiviral treatment in HCV-infected patients in 2015–2023. ResultsOf the 16106 patients treated with IFN-free regimens with available HCV RNA assessment at the ET and at follow-up 12 weeks after treatment completion (FU), 1253 (7.8%) had detectable HCV RNA at the ET, and 1120 of them (89%) finally achieved SVR. This phenomenon was significantly more frequent in pangenotypic regimens, 10.3% vs. 4.7% in genotype-specific options (p < 0.001), and the highest proportion was documented for glecaprevir/pibrentasvir (13.7%), and velpatasvir/sofosbuvir ± ribavirin (6.9%). Patients ET + FU- treated with these two pangenotypic regimens (n = 668) had less advanced liver disease, were less frequently infected with genotype (GT) 3, and were significantly more likely to be treatment-naïve than 61 non-responders. ConclusionsWe documented 7.8% rate of patients with detectable HCV RNA at the ET, of whom 89% subsequently achieved SVR, significantly more frequently in the population treated with pangenotypic regimens. Less severe liver disease, more often GT3 infection, and a higher percentage of treatment-naive patients distinguished this group from non-responders.

Abstract 13912: Insights From a Multi-Center Consortium for HCV-Viremic Donor Heart Transplant: Outcomes Are Excellent Across Regimens Often Without Major Changes to Statin or PPI

Introduction: With the availability of pangenotypic direct-acting antivirals (DAA) for facile, curative treatment of hepatitis C virus (HCV) infections, HCV-viremic donors are utilized regularly to partially address the shortage of suitable organs for heart transplant (HT). This multi-center, retrospective registry characterized HT outcomes from HCV-positive donors. Methods: Of 138 isolated HT recipients from 8 sites across the US, the most common DAAs were the pangenotypic antiviral combinations sofosbuvir-velpatasvir (SOF/VEL, n=39) and glecaprevir-pibrentasvir (GLE/PIB, n=76); these 115 cases were analyzed in terms of primary graft dysfunction (PGD), episodes of rejection ≥ pAMR1 and/or Grade 2R, post-transplant infection, sustained virologic response at 12 weeks post-treatment (SVR12), and survival up to 1 year. Results: Comparing these two most common pangenotypic regimens, HT recipients differed in their listing status (p&lt;0.001), hospital stay length (p=0.04), time until HCV+ (p=0.01), DAA payor (p=0.01), induction therapy (p=0.03) and statin therapy (p=0.01). A concurrent open-label trial accounted for up to 13/39 SOF/VEL patients, partially accounting for differences in DAA payor. Despite potential interactions, statin and proton pump inhibitor (PPI) therapy typically continued uninterrupted with minimal dose adjustment. Both treatment groups showed 100% cure (SVR12) of donor-derived HCV. Although not powered for comparative effectiveness of DAA agents, there were no significant differences in study outcomes. SOF/VEL and GLE/PIB-treated patients demonstrated 97% and 96% survival at 1 year, respectively. Conclusions: As utilized to achieve cure of HT donor-derived HCV, two pangenotypic DAA regimens are safe and feasible, with coverage accessed across a variety of DAA payors. SVR12 can be achieved often without major modifications to PPIs or statins with either pangenotypic DAA regimen (with pravastatin most commonly utilized).

Alfosbuvir plus Daclatasvir for Treatment of Chronic Hepatitis C Virus Infection in China.

A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. All patients received 600mg alfosbuvir tablets plus 60mg daclatasvir tablets once daily for 12weeks. The primary endpoint was sustained virological response 12weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%-99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. Alfosbuvir plus daclatasvir for 12weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. ClinicalTrial.gov identifier, NCT04070235.

Sofosbuvir and Velpatasvir Regimen Outcome for Chronic Hepatitis C Patients With End-Stage Renal Disease Undergoing Hemodialysis.

Background Patients on hemodialysis (HD) are most likely to contract hepatitis C (HCV) infection, which is associated with significant morbidity and disease progression. Direct-acting antivirals (DAAs) are safe and tolerable in chronic kidney disease (CKD) with a 90-100% cure rate, and limited data exist regarding their efficacy in end-stage renal disease (ESRD), particularly for HDpatients in South Asia. The study aimed to assess the outcome of a 12-week sofosbuvir (SOF) and velpatasvir (VEL) treatment regimen on ESRD patients with chronic HCV infection undergoing HDin the Pakistani Asian population. Methodology This prospective cohort study was conducted between January 2022 and January2023 at the outpatient nephrology and gastroenterology clinic of Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, Pakistan. This study included a total of 220 ESRD patients fulfilling the inclusion criteria, aged 20-55 years, who had been undergoing weekly HD sessions for at least two years, with acquired HCV infection. Data on demographic and clinical characteristics were collected through patient interviews. Laboratory and dialysis profiling was executed to assess ESRD and discover the underlying cause by ultrasound abdomen, blood pressure measurement by sphygmomanometer, random blood sugarfor diabetes, and taking note of the duration and frequency of dialysis. HCV RNA PCR was done at selected intervals to evaluate the virological response to treatment. Sustained virological response (SVR), liver cirrhosis status, and number of weekly HD sessions were compared at one year of SOF/VEL regimen. Results The mean age of patients with ESRD was 41.8 with a standard deviation (SD) of 9.3 years, and HCV diagnosis was 1.3 years with SD of 0.4 years; 52.7% (n=116) were males, 47.3% (n=104) were females, 75% (n=165) were urban dwellers, and 93.6% (n=206) were married.CKD that requires dialysis was caused mainly by hypertension (78, 35%), diabetes mellitus type 2 (52, 24%), bilateral small kidney disease (40, 18%), and others (34, 16%). One hundred and six (48.2%) received dialysis thrice weekly, 83 (37.7%) twice, and 31 (14.1%) once weekly. The study monitored the rapid virological response (RVR) at four weeks of SOF/VEL regimen in 89.5% of ESRD patients, observed end-of-treatment response (ETR) at 12 weeks in 93.2%, and noted 91.4% SVR response at one year. Only four (1.8%) relapses were observed in the study, which was statistically insignificant. The status of liver cirrhosis showed a 50% improvement, decreasing from 40% to 20%. The frequency of weekly HD sessions decreased from thrice to twice-thrice a week. Conclusion The prevalence of contracting HCV is high among CKD and dialysis ESRD patients. All-oral DAA therapy has revolutionized HCV treatment with co-morbidities. Renal functions improved after the SOF/VEL regimen for chronic HCV infection in ESRD patients undergoing HD, with the number of weekly dialysis sessions reduced and SVR reaching 91.4%. Thus, a single-tablet, pan-genotypic DAA regimen of SOF/VEL for 12 weeks is safe, effective, and tolerable regardless of the underlying etiology of ESRD, complications of cirrhosis, HCV genotype, or previous treatment exposure. The successful treatment of HCV and achieving SVR lowers the risk of ESRD complications, improves extra-hepatic manifestations, and greatly enhances survival. Further studies are warranted after the availability of other DAAs to confirm findings with no limitations.

Pharmacokinetics, Tolerability, and Safety of Glecaprevir/Pibrentasvir Co-formulated Bilayer Tablet Following Repeated Administration in Healthy Chinese Adults.

Glecaprevir (GLE)/pibrentasvir (PIB) is an all-oral, interferon- and ribavirin-free, pan-genotypic fixed-dose combination regimen approved for the treatment of all major genotypes of hepatitis C virus (HCV) infection in many countries worldwide. To support clinical development in China, an open-label, single-center phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of GLE/PIB in healthy Chinese adults in Mainland China. Eighteen participants received 3 tablets of coformulated GLE/PIB 100/40mg once daily (QD) for 7 days. Following GLE/PIB 300mg/120mg administration, GLE and PIB reached maximum concentration in 4-5 hours with a terminal elimination half-life of 5.9 and 25 hours, respectively. Both GLE and PIB reached steady state by day 5, with no-to-minimal accumulation (≤17% higher). GLE/PIB exposures in healthy Chinese participants were similar to historical observations across phase 1 studies in healthy Western participants. GLE/PIB was safe and well-tolerated, with most adverse events being mild. These pharmacokinetics and safety data, together with existing global efficacy and safety data in healthy and HCV-infected Western participants, support the use of GLE/PIB 300mg/120mg QD in adult Chinese patients with chronic HCV infection.

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.

Efficacy and safety of treatment with sofosbuvir/velpatasvir in patients aged 6-18 years with chronic hepatitis C-Results of the PANDAA-PED study.

The aim of this non-commercial, open-label, real-life, non-randomized clinical trial was to analyse the efficacy and safety of a pangenotypic regimen sofosbuvir/velpatasvir (SOF/VEL) in patients aged 6-18 years with chronic hepatitis C virus (HCV) infection. Fifty patients qualified for the 12-week treatment were divided into two weight groups: 15 children weighting between 17 and <30 kg received a fixed dose of 200/50 mg of SOF/VEL (tablet) once daily, and 35 patients weighting ≥30 kg were treated with 400/100 mg SOF/VEL. The primary endpoint of the study was efficacy defined as sustained viral response (undetectable HCV RNA using an real-time polymerase chain reaction method) at 12 weeks posttreatment (SVR12). Median age of the participants was 10 (IQR 8-12) years, 47 were infected vertically, and 3 patients were previously ineffectively treated with pegylated interferon and ribavirin. Thirty-seven participants were infected with HCV genotype 1, 10 with HCV genotype 3 and the remaining 3 with genotype 4. There was no case of cirrhosis. SVR12 was 100%. Thirty-three reported adverse events (AEs) were considered related to the administration of SOF/VEL, all of them were mild or moderate. Children presenting with AEs were older compared to these without AEs: 12 (9.5-13) versus 9 (IQR 8-11) years (p = 0.008). Results of the PANDAA-PED study indicated a 100% effectiveness of a 12-week therapy with SOF/VEL in children aged 6-18 years with chronic HCV infection and its good safety profile, in particular in younger patients.

EE243 Cost-Effectiveness of Velpatasvir/Sofosbuvir for the Treatment of Hepatitis C in Colombia

Colombia reported that 1.6% of all deaths between 1997-2020 may have been linked to Hepatitis C virus (HCV) infection. In order to inform decisions to improve HCV care, we developed a Markov model to estimate the cost-effectiveness of pan-genotypic DAA regimen (velpatasvir/sofosbuvir, SOF/VEL) for the treatment of Hepatitis C most used in Colombia, an upper-middle income country with a constrained healthcare budget.

THU-215 - The most difficult to cure with pangenotypic regimens HCV infected population

THU-215 - The most difficult to cure with pangenotypic regimens HCV infected population

Efficacy and safety of pan-genotypic sofosbuvir and velpatasvir in patients with hepatitis C and HIV coinfection ondolutegravir-based antiretroviral therapy.

Hepatitis C virus (HCV) infection is more prevalent in people living with HIV-AIDS (PLHA) and portends a poorer prognosis. Pharmacokinetic studies suggest the absence of significant interaction between velpatasvir and dolutegravir which has been recently recommended as part of preferred first-line antiretroviral therapy (ART) regimens by WHO. However, clinical data on the use of velpatasvir-based regimen in PLHA taking dolutegavir is lacking. Hence, we aimed to assess the efficacy and safety of sofosbuvir and velpatasvir (SOF + VEL) in HCV and HIV coinfected patients on dolutegravir-based ART. Forty-five consecutive PLHA with HCV coinfection on dolutegravir-based ART were prospectively enrolled. All patients were treated SOF + VEL for 12 weeks. Complete haemogram, liver and renal function tests were assessed at baseline, 4 weeks and at end of treatment. Sustained virological response (SVR) was assessed at 12 weeks after end of treatment. The majority were males (95.5%) with a mean age of 32.8 ± 12.3 years. Cirrhosis was present in 6 (13.3%) patients. All patients completed 12 weeks of therapy with SOF + VEL, but SVR could not be assessed in two patients. Forty-two (97.7%) of the remaining 43 patients attained SVR-12. SVR-12 rate was 97.7% and 93.3% by per protocol and intention to treat analysis, respectively. No grade III/IV adverse events were reported, and there was no worsening of blood counts, liver or renal function test parameters. The pan-genotypic regimen of SOF + VEL is safe and effective in PLHA with HCV coinfection who are on dolutegravir-based ART.

Characterization of multi-DAA resistance using a novel hepatitis C virus genotype 3a infectious culture system.

The high HCV infection cure rates achieved with direct-acting antiviral (DAA) treatments could be compromised in the future by the emergence of antiviral resistance. Thus, it is essential to understand the viral determinants that influence DAA resistance, which is most prevalent in genotype 3. We aimed at studying how resistance to protease-, NS5A-, and NS5B-inhibitors influences the activities of glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir in cell culture, and how the HCV genome adapts to selective pressure by successive rounds of treatment failure. A previously developed in vivo infectious cDNA clone of strain S52 (genotype 3a) was adapted to efficiently replicate and propagate in human hepatoma cells (Huh7.5) using 31 adaptive substitutions. DAA escape experiments resulted in the selection of S52 variants with decreased drug susceptibility (resistance), which was linked to the emergence of known resistance-associated substitutions (RASs). NS5A-inhibitor resistance was sufficient to promote treatment failure with double-DAA but not triple-DAA regimens. Enhanced viral fitness associated with the selection of sofosbuvir resistance accelerated escape from DAAs. After serial DAA treatment failure, HCV genetic evolution led to a complex genome-wide network of substitutions, some of which coevolved with known RASs. Baseline NS5A-RAS can compromise the efficacy of double-DAA pangenotypic regimens for HCV genotype 3, and enhanced viral fitness can accelerate treatment failure. Persistence of RASs after successive treatment failure is facilitated by the remarkable evolutionary capacity and plasticity of the HCV genome. Proof-of-concept for the potential development of multi-DAA resistance is shown.