Chronic Hepatitis C Virus Genotype Research Articles

Ledipasvir/Sofosbuvir in Adolescents With Chronic Hepatitis C Genotype 4 With and Without Hematological Disorders: Virological Efficacy and Impact on Liver Stiffness.

Egypt has the highest prevalence of hepatitis C virus (HCV) infection. Anti-HCV antibodies were detectable in 3% of children in Upper Egypt. Our aim was to evaluate the efficacy of ledipasvir/sofosbuvir for chronic HCV genotype 4 in adolescents with/without hematological disorders and to determine the effect of sustained virological response (SVR) on liver stiffness. Sixty-five adolescents were recruited. There were 3 patient groups: group 1, 44 treatment-naive without hematological disorders; group 2, 6 previously treated; and group 3, 15 treatment-naive with hematological disorders. All patients received sofosbuvir 400 mg/ledipasvir 90 mg per day for 12 weeks. Serum HCV RNA levels were measured before treatment, at week 12, and at 12 weeks after the end of treatment (SVR12). Liver stiffness and the aspartate aminotransferase-platelet ratio index (APRI) score were estimated at baseline and at SVR12. SVR12 was 100%. At SVR12, there was a significant improvement in liver stiffness in all groups. The APRI score showed significant improvements in groups 1 and 3 (P < .001 and P = .004, respectively). The treatment was well tolerated, with minimal and self-limited side effects. Treatment of chronic HCV in adolescents using ledipasvir/sofosbuvir was effective, with a cure rate (at SVR12) of 100%. Significant improvement in liver stiffness was found in all groups.

From the Editor's Desk…

From the Editor's Desk…

Real Life Egyptian Experience of Daclatasvir Plus Sofosbuvir with Ribavirin in Naïve Difficult to Treat HCV Patients.

Chronic infection with Hepatitis C virus (HCV) is considered as a major cause for developing liver cirrhosis and hepatocellular carcinoma. A new era in HCV treatment is ongoing using Direct Acting Antiviral activity (DAA). The first approved DAA drug was Sofosbuvir which has a high tolerability and preferable pharmacokinetic profile. Another recently developed drug is Daclatasvir a first-in-class HCV NS5A replication complex inhibitor. Both drugs are administered orally once daily and have potent antiviral activity with wide genotypic coverage. In the outpatient clinic, one hundred and fifty naïve difficult to treat chronic HCV patients were recruited from Tropical Medicine Department at Fayoum public hospital. A combination of Daclatasvir (60 mg) and Sofosbuvir (400 mg) (DCV/SOF) has been administered for those patients once daily with Ribavirin (1200 mg or 1000 mg based on patients' weight on two divided doses) over a period of 12 weeks. All patients have been followed up for clinical, laboratory assessment and HCV PCR to detect the efficacy and safety of the therapy. Sustained Virologic Response rate (SVR12) was achieved in the vast majority of patients (90.67%). Cirrhotic patients showed lower SVR compared to non-cirrhotic patients (88.89% vs 90.91%, respectively). Around half of the patients (49.33%) developed adverse events (AEs) during treatment. The most common AEs were headache, fatigue and abdominal pain. The available evidence seems to suggest that combination therapy of (DCV/SOF with RBV) in the treatment of chronic HCV genotype IV naïve difficult to treat patients either cirrhotic or non-cirrhotic is safe and effective. Monitoring for clinical and laboratory hepatic parameters was the basis for these findings.

Association between IFN-λ 3 Gene Polymorphisms and Outcome of Treatment with Direct Acting Antivirals in Chronic HCV-Infected Egyptian Patients

ABSTRACT Background: Single nucleotide polymorphisms (SNPs) of the interferon lambda 3 (IFN-λ 3) gene are associated with viral clearance and treatment response in chronic hepatitis C virus (HCV) infection. Aim: to assess whether specific IFN-λ 3 gene SNP, known as rs12979860 (C > T), could predict the outcome of treatment with direct acting antivirals (DAAs) among Egyptian patients with chronic HCV genotype 4 infection. Methods: Tetra-primer (ARMS-PCR) and PCR-RFLP methods were used for SNP genotyping in 100 chronic HCV-infected patients and 50 healthy subjects as control group. Results: The CC (wild type) genotype of rs12979860 was identified in 20 patients, 50% of them achieved sustained virological response (SVR). SNP genotype TT was found in 17 patients and only 2 of them (11.76%) were responders. The frequency of CT genotypes was significantly higher in responders than in non-responders (p= .021). In contrast, the frequency of TT genotypes was significantly higher in non-responders (42.85%, p< .001). On univariate and multivariate logistic regression analyses of the significant predictors of SVR, there were six predictive factors (Age, diabetes mellitus, AST, albumin, type of therapy and IFN-λ 3 genotype). Conclusion: The TT genotype and T allele were significantly associated with failure to achieve SVR. However, CT genotype of IFN-λ 3 (rs12979860) may be considered as a predictor for SVR in patients who received DAAs.

Retreatment of patients with chronic hepatitis C, subtype 1b and cirrhosis, who failed previous direct-acting antiviral therapy including first- and second-generation NS5A inhibitors with ombitasvir/paritaprevir/ritonavir, dasabuvir+sofosbuvir+ribavirin.

The use of direct-acting antiviral agents (DAAs) in patients with chronic HCV genotype 1 infection results in sustained virologic response (SVR) rates of 95%-97%, but 3%-5% of patients experience virologic failure. We observed 17 patients infected with HCV subtype 1b who failed previous treatment with DAA, including 13 subjects (76.5%) with liver cirrhosis. Twelve subjects (70.6%) previously received NS5A inhibitors of the first generation (ledipasvir or daclatasvir) and five subjects (29.4%) - the second generation (velpatasvir). All patients were retreated with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) with sofosbuvir (SOF) and ribavirin (RBV). We compared SVR12 rates depending on fibrosis stage, presence of just single or double NS5A mutations (L31M/V/I and/or Y93H), and on the generation of previously used NS5A inhibitor. Observed SVR12 rates were as follows: 94.1% (16/17 patients) overall; 100% in patients without cirrhosis (n=4) vs 92.3% in those with cirrhosis (n=13); 100% with single L31M/V/I or Y93H mutation (n=7) vs 88.9% with double mutations (n=9); 100% in patients who previously failed first generation (n=12) vs 80.0% in those failed second-generation NS5A inhibitors (n=5). Retreatment with 3D+0SOF+RBV was highly effective and safe in patients with chronic HCV GT1b infection who failed previous use of NS5A inhibitors. Fibrosis stage, baseline presence of NS5A RAS mutations and the generation of previously used NS5A inhibitors may impact the probability of achieving SVR12 , but statistical significance was not demonstrated in our small retrospective cohort. Further studies in a larger population are needed to confirm or not the predictive value of these baseline factors.

HIV/HCV therapy with ledipasvir/sofosbuvir after randomized switch to emtricitabine-tenofovir alafenamide-based single-tablet regimens.

IntroductionGuidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants.MethodsParticipants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12).ResultsOf 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93–99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens.ConclusionThis study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.

Cost-Effectiveness Analysis of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir With or Without Ribavirin Regimen for Patients Infected With Chronic Hepatitis C Virus Genotype 1 in Malaysia

ObjectivesThe combination of pegylated-interferon and ribavirin (PegIFN+RBV) is currently the gold standard in treating chronic hepatitis C virus (HCV) patients in Malaysia and is reimbursed by the Malaysian authorities. This analysis evaluated the cost-effectiveness (CE) of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (OBT/PTV/r+DSB±RBV) regimen as compared with the PegIFN+RBV or no treatment in chronic HCV Genotype 1 (GT1) treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia. MethodsA Markov model based on previously published CE models of HCV was adapted for the Malaysian public healthcare payer perspective, based on good modeling practices. Treatment attributes included efficacy, regimen duration, and EQ-5D treatment-related health utility. Transitional probabilities and health state health utilities were derived from previous studies. Costs were derived from Malaysian data sources. Costs and outcomes were discounted at 3.0% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties around key variables. ResultsBased on the analysis, patients treated with the OBT/PTV/r+DSB±RBV showed less frequent progression to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths when compared with standard care (ie, PegIFN+RBV or no treatment). At a price of MYR 1846/day, the OBT/PTV/r+DSB±RBV regimen is cost-effective over PegIFN+RBV and yields better outcomes in terms of life-years (LYs) gained and quality-adjusted life-years (QALYs) at a higher cost, which is still well below the implied willingness to pay threshold of MYR 384 503/QALY. ConclusionThe OBT/PTV/r+DSB±RBV regimen is cost-effective for treatment naïve, treatment experienced, cirrhotic, and noncirrhotic GT1 chronic HCV patients in Malaysia.

Glecaprevir/Pibrentasvir to Treat Chronic Hepatitis C Virus Infection in Asia: Two Multicentre, Phase 3 Studies –&amp;nbsp;A Randomised, Double-Blind Study (VOYAGE-1) and an Open-Label, Single-Arm Study (VOYAGE-2)

Background: Glecaprevir/pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data in non-Japanese Asian patients have been minimal. Methods: Two phase 3 studies were undertaken in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection: a randomised, double-blind, placebo-controlled study recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore (VOYAGE-1; NCT03222583); a single-arm, open-label study recruited patients with compensated cirrhosis at 34 sites across China and South Korea (VOYAGE-2; NCT03235349). Glecaprevir/pibrentasvir (300 mg/120 mg) or placebo (VOYAGE-1, 2:1 ratio) was given for 8 or 12 weeks in patients without and with cirrhosis, respectively (16 weeks in treatment-experienced patients with genotype 3). Primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12; HCV RNA <15 IU/mL) in the intention-to-treat (ITT) population. Primary objective (VOYAGE-1) was comparison with historical SVR12 rates. Findings: Of 546 patients without cirrhosis enrolled (October 4, 2017-May 16, 2018), one was not treated (ITT: n=545). 352/362 patients who received glecaprevir/pibrentasvir achieved SVR12 (97·2% [95% CI 95·5–98·9]); non-inferiority to a historical SVR12 rate was demonstrated. Of 160 patients with compensated cirrhosis enrolled (September 29, 2017-June 14, 2018) (ITT: n=160), 159/160 achieved SVR12 (99·4% [95% CI 98·2–100·0]). All patients with virological failure (VOYAGE-1: n=8; VOYAGE-2: n=1) were enrolled in China; six had genotype 3b with a history of injection drug use. One patient with cirrhosis discontinued study drug due to an adverse event. Upper respiratory tract infection was the most common adverse event (VOYAGE-1: 35/362 [10%]; VOYAGE-2: 19/160 [12%]). Interpretation: Glecaprevir/pibrentasvir achieved high SVR12 rates and was well tolerated in Asian patients with chronic HCV genotype 1-6 infection, similar to other phase 3 studies. Trial Registration: (VOYAGE-1; NCT03222583), (VOYAGE-2; NCT03235349). Funding Statement: The studies were designed and conducted by the investigators and the sponsor, AbbVie. Declaration of Interests: Lai Wei: Consulting fees for Abbvie, Allergan, Ascletis, Bristol-Myers Squibb, Gilead Sciences, Johnson & Johnson, Novartis, Pfizer and Roche; research grants from Abbvie, Bristol-Myers Squibb, Gilead Sciences and Roche (all for institution) Guiqiang Wang: No conflicts of interest Negar N Alami: Employee of AbbVie and may own stock or share options Wen Xie: No conflicts of interest Jeong Heo: Research support from Roche; advisor for AbbVie, Bristol-Myers Squibb and Gilead Sciences Qing Xie: Nothing to disclose Mingxiang Zhang: Principal investigator: Abbvie Yoon Jun Kim: Consulting fees for AbbVie, Gilead Sciences, Bristol-Myers Squibb, Samil and PharmaKing; research grant support from Roche, Bristol-Myers Squibb, Gilead Sciences, LG Sciences, Hanmi, Ildong, Daewoong, Bayer, Yuhan Seng Gee Lim: Research support from Abbott, Gilead, Merck, and Roche; advisor for Abbott, AbbVie, Arbutus Biopharma, Dicerna, Kaleido, Gilead, Roche, and Springbank; speaker for Abbott and Gilead Linda M. Fredrick: Employee of AbbVie and may own stock or share options Wenjing Lu: Employee of AbbVie and may own stock or share options Wei Liu: Employee of AbbVie and may own stock or share options Hari V. Kalluri: Employee of AbbVie and may own stock or share options Preethi Krishnan: Employee of AbbVie and may own stock or share options Rakesh Tripathi: Employee of AbbVie and may own stock or share options Niloufar Mobashery: Former employee of AbbVie and owns stocks Margaret Burroughs: Employee of AbbVie and may own stock or share options Armen Asatryan: Former employee of AbbVie and may own stock or share options; currently with AveXis, a Novartis company Jidong Jia: Nothing to disclose Jinlin Hou: Consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Johnson & Johnson and Roche; grants from Bristol-Myers Squibb and Johnson & Johnson. Ethics Approval Statement: The study protocols and amendments were approved by an independent ethics committee/institutional review board for each study site.

Real-life efficacy of generic sofosbuvir/ledipasvir for treatment of Iranian patients with chronic hepatitis C: A cohort study.

Background:Treatment of hepatitis C virus (HCV) infection with recently introduced direct-acting antiviral agents (DAA) is effective and safe, however there is little known regarding safety and efficacy of generic DAAs in the real-life clinical setting. This study aimed to evaluate the efficacy and safety of generic sofosbuvir/ledipasvir (SOF/LDV) in a real-life clinical experience.Methods:In this prospective cohort study, patients with chronic HCV infection who referred to Middle East Liver Diseases (MELD) Center were included. Based on the patients’ condition, they were treated with SOF/LDV fixed-dose combination with or without ribavirin (RBV) for 12 or 24 weeks.Results:A total of 30 (M/F: 19/11) patients with chronic HCV genotype 1 infection with a mean age of 49.8 years were treated with generic SOF/LDV with (9 patients) or without (11 patients) RBV for 12 (27 patients) or 24 (3 patients) weeks. Ten (33.3%) had cirrhosis and 13 (43.3%) with a previous history of treatment with interferon (IFN)-based regimens. Among the 30 patients, 26 (86.7%, 95% CI=70.3%-94.7%) achieved a rapid virologic response, 30 (100%, 95% CI=88.7%-100%) achieved the end of treatment response and 30 (100%, 95% CI=88.7%-100%) achieved a sustained virologic response. No severe treatment adverse event was observed however, 6 (20%) patients experienced mild to moderate adverse events.Conclusion:The treatment of HCV genotype 1 infection with generic SOF/LDV found to be safe and effective even in patients with cirrhosis and previous history of treatment with IFN-based treatments.

Effectiveness of Elbasvir/Grazoprevir in patients with hepatitis C virus genotype 1 infection and chronic kidney disease in the United States veterans population

Background & aimsRandomized controlled trials of EBR/GZR have reported high treatment efficacy, safety and tolerability in patients undergoing dialysis. However, real world effectiveness data for EBR/GZR in this population is lacking. We evaluated the effectiveness of EBR/GZR in an HCV-infected population with all stages of CKD including dialysis compared with control patients with estimated glomerular filtration rate (eGFR) ≥60 in the US Department of Veterans Affairs (VA). MethodsWe conducted a retrospective cohort study of patients with chronic HCV genotype 1 infection with EBR/GZR prescriptions dispensed during February 1, 2016–August 31, 2017 in 128 VA Medical Centers. We collected patient information regarding history of dialysis, end stage renal disease (ESRD), and/or eGFR values. We measured SVR based on undetectable HCV RNA at least 4 weeks after the completion of treatment. We examined SVR rates by CKD stage compared to control patients and within patient subgroups using logistic regression models. ResultsWe identified 5961 patients (42.5% genotype 1a, 55.0% genotype 1b) who met eligibility criteria and completed a EBR/GZR treatment course (≥11 weeks). Approximately 73.2% (n = 4361) had eGFR ≥60 who served as control patients, 14.4% (n = 860) had Stage 3 CKD, and 12.4% (n = 740) had Stage 4–5 CKD or ESRD. Of patients with Stage 4–5 CKD/ESRD, 76.1% underwent dialysis (n = 563). The overall SVR was 96.7% in all patients, 96.4% for eGFR≥60, 98.3% in Stage 3 CKD, and 96.5% in Stage 4–5 CKD/ESRD. No statistically significant differences were found in the SVR rates in patients with or without dialysis in the Stage 4–5 CKD/ESRD patients (adjusted OR 0.91; 95% CI 0.56–1.47 and OR 1.74; 95% CI 0.63–4.81) compared with those with eGFR≥60. ConclusionWe found EBR/GZR was effective in patients with HCV GT1 infection regardless of CKD severity or receipt of dialysis in the US VA population.

Effects of sofosbuvir/ledipasvir therapy on chronic hepatitis C virus genotype 4, infected children of 3-6 years of age.

Treatment of children aged 3-6 genotype 4 is still limited by the interferon side effects. We aimed in this study to evaluate the effectiveness and safety of sofosbuvir/ledipasvir in children (3-6years) genotype 4 chronic HCV-infected patients. In total, 22 consecutive chronic HCV-infected patients (mean age 4.8±0.9years, 19 males) were included in this prospective study. All patients received sofosbuvir 200mg/ledipasvir 45mg in a single oral daily dose. Patients were randomly subdivided into two groups according the duration of treatment into 8 and 12weeks. All the clinical and laboratory data were collected. All the side effects were recorded from the patients or their parents. Follow-up were made at Week 4, 8 and 12 and 12weeks after the end of treatment (SVR12). The overall SVR12 rate was 100%. At Week 4, 9/11 patients in the 12-week group (81.8%; 95% CI: 52.3%-94.7%) achieved virologic negativity, vs 10/11 (90.9%; 95% CI: 62.3%-98.4%) in the 8-week group. At Week 8, 10/11 (90.8%; 95% CI: 62.3%-98.4%) in the 12-week group vs 11/11 (100%; 95% CI: 74.1%-100%) in the 8-week group were virologically negative. The reported side effects were cough, abdominal pain, nausea, vomiting and diarrhoea especially early in the treatment. The main complaint was difficulty in swallowing the tablets in the youngest patient at the beginning of the course of treatment. All patients were compliant to treatment. Sofosbuvir/ledipasvir combination is safe and tolerable in the chronic infected HCV genotype 4 infected children (3-6years). The 8-week treatment duration is similarly effective as the 12-week duration.

Amino Acid Mutations in NS5B Protein among Treatment-naive Genotype 3A Infected Patients.

To determine the frequency of mutations at specific amino acid positions in full length NS5B gene among chronic HCV genotype 3a infected patients of Peshawar, who had not taken any previous treatment. Cross-sectional descriptive study. Institute of Basic Medical Sciences, Khyber Medical University, Peshawar (IBMS, KMU) and Comsats Institute of Information Technology (CIIT), Islamabad from September 2016 to December 2017. HCV genotype determination was carried out among 310 actively infected, treatment-naive patients, using type specific PCR-based genotyping assay. In a total of 162 (52%) HCV genotype 3a isolates, NS5B gene was amplified in 126 (78%) samples using qualitative PCR and sequencing. NS5B gene sequences were analysed for clinically relevant mutations against standard HCV 3a reference sequence (Isolate NZL1, BAA04609) using MEGA 6 software. Analysis of HCV NS5B amino acid sequences (aa.1-591), comprising essential motif A-F revealed four novel mutations: A67V, T131I, R374H and M425L in 27 (21%) viral isolates. Mutation D/N244S and D/N310K were found in 14 (11%) of the pre-treatment isolates. Mutations at positions 282 and 316 (S282T and C316N/Y) were not identified among studied isolates. This study reports mutations based on complete NS5B protein of HCV 3a genome that could help predict treatment response among the chronically infected with HCV genotype 3a patients of Peshawar.

Disentangling the lifespans of hepatitis C virus-infected cells and intracellular vRNA replication-complexes during direct-acting anti-viral therapy.

The decay rate of hepatitis C virus (HCV)-infected cells during therapy has been used to determine the duration of treatment needed to attain a sustained virologic response, but with direct-acting anti-virals (DAA), this rate has been difficult to estimate. Here, we show that it is possible to estimate it, by simultaneously analysing the viral load and alanine aminotransferase (ALT) kinetics during combination DAA therapy. We modelled the HCV RNA and ALT serum kinetics in 26 patients with chronic HCV genotype 1b infection, under four different sofosbuvir-based combination treatments. In all patients, ALT decayed exponentially to a set point in the normal range by 1-3weeks after initiation of therapy. The model indicates that the ALT decay rate during the first few weeks after initiation of therapy reflects the death rate of infected cells, with an estimated median half-life of 2.5days in this patient population. This information allows independent estimation of the rate of loss of intracellular replication complexes during therapy. Our model also predicts that the final ALT set point is not related to the release of ALT by dying HCV-infected cells. Using ALT data, one can separately obtain information about the rate of 'cure' of HCV-infected cells versus their rate of death, something not possible when analysing only HCV RNA data. This information can be used to compare the effects of different DAA combinations and to rationally evaluate their anti-viral effects.

Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1–6 and compensated cirrhosis: The EXPEDITION-8 trial

Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis. EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. ClinicalTrials.gov, NCT03089944. This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.

Efficacy and Safety of 8Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve, HCV-Infected Patients with APRI ≤ 1 in a Single-Arm, Open-Label, Multicenter Study.

IntroductionThe presence or absence of cirrhosis in patients with chronic hepatitis C virus (HCV) infection influences the type and duration of antiviral therapy. Non-invasive markers, like serum aspartate aminotransferase (AST) to platelet ratio index (APRI), may help identify appropriate HCV treatment-naive patients for 8-week treatment with the pangenotypic regimen of glecaprevir/pibrentasvir.MethodsThis single-arm, open-label, international, prospective study (NCT03212521) evaluated the efficacy and safety of 8-week glecaprevir/pibrentasvir regimen in HCV treatment-naïve adults with chronic HCV genotypes 1–6 infection, APRI ≤ 1, and no prior evidence of cirrhosis. The primary and secondary outcomes were sustained virologic response at 12 weeks post-treatment (SVR12) by modified intent-to-treat (mITT) and intent-to-treat (ITT) analyses, respectively. Additional endpoints included virologic failures, treatment adherence, and genotype-specific SVR12 rates.ResultsAmong the 230 patients enrolled, most were less than 65 years old (90%); 37% and 43% had a history of injection drug use or psychiatric disorders, respectively. SVR12 rates were 100% (222/222; 95% CI 98.3–100%) and 96.5% (222/230; 95% CI 94.2–98.9%) by mITT and ITT analyses, respectively. There were no virologic failures. ITT SVR12 rates were greater than 94% for all HCV genotypes. In patients with available data, treatment adherence was 99% (202/204). There were no grade 3 or higher laboratory abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and low rates of serious adverse events (2%).ConclusionsGlecaprevir/pibrentasvir was highly efficacious and well tolerated in HCV treatment-naïve patients with APRI ≤ 1 and no prior evidence of cirrhosis.Trial RegistrationClinicalTrials.gov number, NCT03212521.FundingAbbVie.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01123-0) contains supplementary material, which is available to authorized users.

The efficacy and safety of elbasvir/grazoprevir treatment in HCV genotype 1 patients in Taiwan.

BackgroundElbasvir/grazoprevir (EBR/GZR) is a new generation, fixed‐dose, combination antiviral drug used in chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection. Our study evaluates the clinical efficacy and safety of EBR/GZR after its launch in Taiwan.MethodsThis is a retrospective observational study. Patients who had received EBR/GZR for chronic HCV GT 1 between June 2017 and April 2018 were recruited. Patients’ age, sex, HCV GT, changes in HCV RNA level before and after treatment, sustained virologic response 12 weeks (SVR12) after the cessation of drug administration, side effects, and interaction effects were used to evaluate the clinical efficacy and safety.ResultsA total of 149 patients were recruited. Of them, 145 (97.3%) had HCV GT 1b, and the rest had HCV GT 1a; most of the EBR/GZR‐related side effects in this study were mild. Three participants were discontinued because their alanine transaminase levels were elevated to over 10 times the upper limit of normal. The therapeutic effect analyses revealed a rapid virologic response rate of 95.3% and an SVR12 rate of 98%. Subgroup analyses performed using SVR12 as the outcome variable revealed three demographic factors HCV GT 1, hepatocellular carcinoma medical history, and noncirrhosis plus HCV RNA level.ConclusionsThis study confirmed that EBR/GZR is safe and effective for treating patients with HCV GT 1 and exhibited excellent overall clinical efficacy in Taiwan. The therapeutic effects are unrelated to factors such as sex, HCV RNA level before treatment, and history of liver cirrhosis.

Effects of dual sofosbuvir/daclatasvir therapy on, chronic hepatitis C infected, survivors of childhood malignancy.

BACKGROUNDChildhood cancer survivors are potentially at a higher risk of infection with hepatitis C virus (HCV). The effects of all-oral direct-acting antiviral therapy (DAA) on both the HCV infection as well as the state of cancer remission have not been well investigated in this population.AIMTo test the effects of dual sofosbuvir/daclatasvir (SOF/DCV) therapy in the treatment of chronic HCV in survivors of hematologic malignancy in pediatric age group.METHODSWe conducted a prospective, uncontrolled, open-label multicenter study. A total of 20 eligible, chronic HCV, genotype-4, infected children who had been in continuous complete remission from hematologic cancer (leukemia/lymphoma) for at least one year were included in the study. All patients were treated with combined SOF/DCV for 12 wk. Patients were monitored throughout the study till 12 wk after end of treatment for safety and efficacy outcomes including the sustained virologic response 12 (SVR12) rate, hematological indices, liver and kidney functions.RESULTSThe intent-to-treat SVR12 rate was 20 of 20 (100%; 95%CI: 84%-100%). All patients showed normalized liver enzymes from week-4. All hematological indices, liver and kidney functions were kept normal throughout the study. No fatalities or treatment-emergent serious or severe adverse events were reported throughout the study.CONCLUSIONSOF/DCV combined therapy could be used safely and effectively in the treatment of chronic HCV genotype-4 infection in leukemia/lymphoma treated children. No relapses were detected during treatment and throughout the follow up period for either the original malignant disease or the HCV infection.

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to &lt;12 Years With Hepatitis C Virus Genotype 2 or 3 Infection

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open‐label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty‐four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%‐100%). The patient who did not achieve SVR12 was a 4‐year‐old who discontinued treatment after 3 days because of “abnormal drug taste.” The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3‐year‐old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection.

Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy

Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n= 78, group A) or 16 weeks (n= 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n= 21, group C) or G/P for 16 weeks (n= 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C.

AimsDrug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy.MethodsSubjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected.ResultsAmong the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2–4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023).ConclusionsCYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.