Chronic Hepatitis C Virus Genotype Research Articles

Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection.

Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h−1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

Effectiveness of directly acting oral antivirals in treatment of chronic HCV infection in children - experience from a tertiary care institute in southern India

Background: Worldwide, an estimated 71 million people are chronically infected with HCV, of which an estimated 2.1- 5.0 million are children aged ≤15 years. Children with chronic HCV infection have fewer treatment options than adults. Very few reports are available on HCV infection, treatment strategies and its outcome particularly in pediatric population. In this background, we evaluated the effectiveness and safety of Sofosbuvir/Ledipasvir in treating HCV infection in children.Methods: In this retrospective study, a total of 33 children with HCV positive status, 12 cases (children above 12 years of age) were selected for treatment. HCV-RNA quantitative assay, genotyping was carried out. Children above 12 years with HCV genotype 1 were treated with tablet ledipasvir-sofosbuvir (90/400 mg) orally once a day as morning dose for 12 weeks. Children with genotype 3 were treated with sofosbuvir 400 mg and weight based ribavirin for 24 weeks. Viral load was repeated after 12 weeks of completion of treatment with antivirals for sustained virological response (SVR 12).Results: Out of the 12 patients 11 patients had genotype 1 (5/11 had subtype-1a and 6/11 had subtype-1b) infection and only 1 patient has genotype 3 (subtype-3a). All of them attained SVR at the end of 12 weeks. The regimen was well tolerated and there were no side effects noted by the children and their caretakers. Drug compliance and the palatability of the drugs were good.Conclusions: Ledipasvir-sofosbuvir combination was highly effective at treating children with chronic HCV genotype 1 infection. The availability of an all oral, direct-acting antiviral regimen for paediatric population with chronic HCV would improve care for patients who currently have limited treatment options.

Real-world effectiveness and safety of glecaprevir/pibrentasvir therapy in patients with chronic hepatitis C virus infection in Switzerland.

In the era of pangenotypic treatment regimens against hepatitis C virus (HCV) infection, data from postmarketing observational studies are crucial to better understand the treatment patterns used in specific countries and treatment outcomes under real-life conditions. We report data from Switzerland from an ongoing, multinational postmarketing observational study on the pangenotypic treatment regimen of glecaprevir (GLE; NS3/4A protease inhibitor) and pibrentasvir (PIB; NS5A inhibitor), coformulated as GLE/PIB. Adults infected with chronic HCV genotypes 1&ndash;6 were eligible to participate in the postmarketing observational study if they started GLE/PIB at the treating physician&rsquo;s discretion. The primary objective was to evaluate the effectiveness of GLE/PIB based on sustained virological response 12 weeks after completion of treatment (SVR12); secondary outcomes included patient-reported outcomes (Fatigue Severity Scale, Work Productivity and Activity Impairment Questionnaire, Pictorial Representation of Illness and Self Measure tool) and safety data. In Switzerland, 109 patients were enrolled, and 107 patients received &ge;1 dose GLE/PIB (94.4% non-cirrhotic; 43.9%/14.0%/29.0%/13.1% GT1/GT2/GT3/GT4; 89.7% treatment-na&iuml;ve; 91.6% assigned to an 8-week GLE/PIB regimen). Overall, 95 of 98 patients with sufficient follow-up data (96.9%) achieved SVR12 (95% confidence interval [CI] 91.4% to 99.0%), and 91.6% in the safety population (including six non-virological failures). The three treatment failures were due to relapse. All three failures were GT3, without cirrhosis and treatment na&iuml;ve. Patient-reported outcomes improved as well. GLE/PIB was well tolerated with no serious adverse events and no adverse events leading to discontinuation or interruption of GLE/PIB treatment. These real-world effectiveness and safety data of GLE/PIB in patients from Switzerland were consistent with those seen in the multinational registration trials. (Trial registration number: Clinicaltrials.gov: NCT03303599.).

Changes in serum interferon-γ-inducible protein-10 levels and liver stiffness among chronic hepatitis C Egyptian patients in response to directly acting antiviral agents.

Interferon-γ inducible protein-10 (IP-10) is chemokine biomarker of liver inflammation, elevated in patients with chronic hepatitis C infection. Investigating if changes in serum IP-10 levels in response to directly acting antiviral agents (DAAs) treatment for chronic HCV patients are paralleled by changes in liver stiffness measurements (LSM), and assessing role of using serum IP-10 as a noninvasive accurate method to predict changes in hepatic necro-inflammation and fibrosis. A prospective observational study included 92 Egyptian chronic HCV patients, who received treatment with sofosbuvir with daclatasvir regimen. Patients were classified into two groups; group I (53 patients) with non to mild significant liver fibrosis (F0-F1), and group II (39 patients) with significant to advanced liver fibrosis (F2-F4). Fibroscan and serum IP-10 were assessed pretreatment and 3 months after end of treatment. All patients achieved SVR. Both IP-10 and LSM showed significant decline after treatment in both groups. No significant correlation was found between changes in LSM and IP-10. IP-10 detected liver cirrhosis at cut off level of 17.8 pg/ml, with 75% sensitivity and 73.86% specificity, with area under the curve = 0.66, however, IP-10 had no statistical significance in detecting advanced fibrosis. IP-10 might be of significance as a noninvasive predictor of liver cirrhosis. IP-10 significant decline post-DAAs treatment in chronic HCV genotype IV infected patients reflects significant improvement in fibrosis stage and hepatic necro-inflammation in response to treatment. No significant correlation was detected in the changes of both IP-10 and LSM.

Real-world Effectiveness and Safety of Direct-acting Antiviral Agents in Patients with Chronic Hepatitis C Genotype 2 Infection: Korean Multicenter Study.

BackgroundThe advancement of treatment with direct-acting antiviral (DAA) agents has improved the cure rate of hepatitis C virus (HCV) infection close to 100%. The aim of our study was to assess the real-world effectiveness and safety of DAA regimens for the treatment of patients with chronic HCV genotype 2.MethodsWe retrospectively analyzed the clinical data of patients treated with sofosbuvir plus ribavirin (SOF + RBV) or glecaprevir/pibrentasvir (G/P) for chronic HCV genotype 2 infection at seven university hospitals in the Korean southeast region.ResultsSOF + RBV therapy produced an 89% and 98.3% sustained virologic response 12 week (SVR12) after treatment completion in the full analysis set and per-protocol set, respectively, and the corresponding values for G/P therapy were 89.5% and 99.2%, respectively. The difference between the treatments was probably because 6.2% (59/953) of patients in the SOF + RBV group did not complete the treatment and 9.8% (14/143) in the G/P group did not test HCV RNA after treatment completion. Adverse events (A/Es) were reported in 59.7% (569/953) and 25.9% (37/143) of the SOF + RBV and G/P groups, respectively. In the SOF + RBV group, 12 (1.26%) patients discontinued treatment owing to A/Es, whereas no patients discontinued treatment because of A/Es in the G/P group.ConclusionIn both treatment groups, SVR was high when treatment was completed. However, there was a high dropout rate in the SOF + RBV group, and the dropout analysis showed that these were patients with liver cirrhosis (LC; 43/285, 15.1%), especially those with decompensated LC (12/32, 37.5%). Therefore, an early initiation of antiviral therapy is recommended for a successful outcome before liver function declines. Furthermore, patients with decompensated LC who are considered candidates for SOF + RBV treatment should be carefully monitored to ensure that their treatment is completed, especially those with low hemoglobin and high alanine transaminase.

Effectiveness of Retreatment with ombitasvir/paritaprevir/ ritonavir, dasabuvir+sofosbuvir+ribavirin in Patients with Chronic Hepatitis C, Subtype 1b and Cirrhosis, Who Failed Previous with First- and Second-generation NS5A Inhibitors

The use of Direct�Acting Antiviral agents (DAAs) in patients with chronic HCV GenoType (GT) 1 infection results in Sustained Virologic Response (SVR) rates of 95%-97%, but 3%-5% of patients experience virologic failure. We observed 41 patients infected with HCV subtype 1b who failed previous treatment with DAAs, including 37 subjects (90.2%) with liver cirrhosis. In total, 30(73.2%) subjects previously received NS5A inhibitors of the first generation (ledipasvir, daclatasvir, or ombitasvir) and 11 subjects (26.8%) received NS5A inhibitors of the second generation (velpatasvir). All patients received retreatment 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 mutation (L31M/V/I and/or Y93H), and the generation of previously used NS5A inhibitors. Observed SVR12 rates were as follows: 97.6% (40/41 patients) overall; 100% in patients without cirrhosis (n=4) versus 97.3% in those with cirrhosis (n=37); 100% with single L31M/V/I or Y93H mutation (n=22) versus 94.4% with double mutations (n=18); 100% in patients who failed previous treatment with first�generation (n=30) versus 90.9% in those who failed previous treatment with second�generation NS5A inhibitors (n=11).

PIN26 Choice of Recommended Treatment Options for Patients with Hepatitis C Genotype 1 in Moscow, Russian Federation

The possibilities of modern therapy for chronic hepatitis C include a large number of options that have marked differences in both effectiveness and cost. The aim of this study was to select optimal treatment regimens for chronic hepatitis C virus (HCV) genotype 1 for reimbursement in Moscow in 2020 based on their comparative efficacy and costs per course. Treatment regimens were ranked based on their comparative efficacy and costs per course. Comparative efficacy was evaluated based on published network meta-analyses, as well as our own indirect comparisons. Prices for drugs were provided by the Moscow Healthcare Department. When determining the target sub-groups of patients, the virus genotype, the presence or absence of treatment experience and liver cirrhosis were taken into account. List of comparators included pangenotypic and non-pangenotypic regimens, with the exception of regimens containing peginterferons. Based on the results of the analysis, several recommended schemes were selected for each of the target groups. Multilple regimens were recommended due to the fact that the cost of the course of treatment and the efficacy of all top regimens were comparable. In genotype 1a patients independent of subgroups top-3 regimens were: daclatasvir+sofosbuvir±ribavirin (€ 5938 per course), grasoprevir+elbasvir (€ 5964) and velpatasvir+sofosbuvir (€ 6223). The 4th and 5th positions in treatment-naïve and experienced patients without cirrhosis was dasabuvir+ombitasvir+paritaprevir+ritonavir+ribavirin (€ 6237) and glecaprevir+pibrentasvir (€ 6333). The 4th regimen for treatment-naïve cirrhotic patients was glecaprevir+pibrentasvir (€ 6333). In genotype 1b patients independent of subgroups top-4 regimens were: daclatasvir+sofosbuvir±ribavirin (€ 5938), grasoprevir+elbasvir (€ 5964), dasabuvir+ombitasvir+paritaprevir+ritonavir (€ 6219) and velpatasvir+sofosbuvir (€6223). The 5th regimen for all target groups, except treatment-experienced cirrhotic patients was glecaprevir+pibrentasvir (€ 6333). As a result of a transparent and scientific-based analysis were selected treatment regimens for patients with chronic HCV genotype 1 recommended for reimbursement in Moscow in 2020.

Interferon lambda 4 gene polymorphisms as a predicting tool of response to hepatitis C virus genotype 4 patients treated with Sofosbuvir and Ribavirin.

The relation between interferon lambda 4 gene (IFNL4) and direct acting antiviral (DAA) regimens in hepatitis C virus (HCV) infected patients is not clear. So, a single nucleotide polymorphisms (SNP) of IFNL4 gene genotypes and its relationship with Sofosbuvir (SOF) and Ribavirin (RBV) treatment response is under consideration. This study aims to investigate the relation between IFNL4 polymorphisms and clearance of HCV genotype 4 for HCV patients. Hence, the appropriate drug can be chosen for each patient. SNP genotyping assay for IFNL4 which formerly known as IL28B (rs368234815) was examined for genomic DNA. The DNA was extracted from whole blood of one hundred patients who documented to have infection with chronic HCV genotype 4 (positive PCR) and treated with SOF and RBV. Patients were diagnosed, previously, as HCV genotype 4 and classified according to drug response into two groups (responders, non-responders). All samples were compared with 50 of non-infected (negative PCR) people (control group). The TT/TT homozygous represents 48% of patients and 66% of non-infected people while the homozygous ∆G/∆G is 21% and 12%, respectively. There is significance to IFNL4 genotypes for the treatment response with the probability value p<0.001. The percentages of the appearance of genotypes TT/TT, TT/∆G and ∆G/∆G for responders were 60%, 28% and 12%, respectively. There is no significance for gender, age, ALT and PLC to treatment response to SOF and RBV, while INR has.

Body mass index (BMI) and alpha-fetoprotein (AFP) level correlate with the severity of HCV-induced fibrosis in a cohort of Egyptian patients with chronic HCV

BackgroundViral hepatitis is the seventh leading cause of mortality globally, and half of this mortality is attributed to hepatitis C virus (HCV). Egypt has the highest HCV prevalence worldwide, with an estimated 14.7% of the population being HCV-positive. HCV infection is the primary cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis varies in severity during chronic HCV infection, and 10–20% of chronic hepatitis C (CHC) patients with severe fibrosis develop cirrhosis. The goal of this work was to assess the clinico-demographic predictors of severity of HCV-induced fibrosis in a cohort of Egyptian patients.ResultsA cohort of Egyptian patients with chronic HCV genotype 4a infection showed significant association between severe fibrosis stages and obesity, represented by a higher body mass index (BMI), low albumin level, high alpha-fetoprotein (AFP) level, low thyroid-stimulating hormone (TSH) level, and high alkaline phosphatase (ALP) level. Multivariate analysis delineated BMI, TSH, and ALP as independent significant variables that could predict the risk of fibrosis severity in HCV infections.ConclusionThis study argues in favor of using the biomarker profile of CHC patients infected with HCV genotype 4a to identify patients at higher risk of developing severe fibrosis, which is a necessary first step towards precision medicine via patient stratification.

Treatment of Hepatitis C Cirrhotic Patients With Directly Acting Antivirals: A Multicenter Study.

With the introduction of sofosbuvir-based regimens, high cure rates and decreased duration has been achieved. Several studies showed variances in SVR rates between different genotypes, with lower rates of SVR among cirrhotic patients. The aim of our study was to assess the safety and effectiveness of sofosbuvir-based antiviral regimens for the treatment of HCVinfected Egyptian cirrhotic patients. This was a retrospective, observational, and comparative study. A total of nine hundred and forty-six cirrhotic patients with chronic HCV genotype 4 infection, who were eligible for direct acting drugs (DAAs) therapy, were enrolled. The primary outcome measures were the number of patients with successful eradication of the virus evidenced by SVR at 12 weeks after discontinuation of therapy (SVR12), and the secondary outcome measures were the incidence of adverse effects associated with the tested HCV therapy. Among the 946 patients enrolled in the study, 527 patients (55.7%) were males and 419 patients (44.3%) were females with a mean age of 54.00±8.88 years. 20.2% were diabetics and 19.1% were hypertensive. Patients were classified according to Child-Pugh classifications; 818 patients (86.46%) were Child-Pugh class A cirrhosis, while 28 patients (13.53%) were Child-Pugh class B cirrhosis. The SVR12 rate was 96.93% (917 /946). Treatment response in the Child-Pugh class A cirrhosis was 794 (97%) after 12 weeks, while treatment response in the Child-Pugh class B cirrhosis was 123 (96%). Mild side effects were observed in 76 patients. Sofosbuvir based regimens were effective and safe in the treatment of cirrhotic patients with chronic hepatitis C genotype 4.

S2713 Acute Kidney Injury Presenting as Hepatorenal Syndrome in the Setting of Glecaprevir/Pibrentasvir Treatment for Hepatitis C

INTRODUCTION: The regimen of glecaprevir and pibrentasvir is an effective treatment for hepatitis C (HCV), but FDA data suggests a risk of hepatobiliary toxicity. Here, we discuss the first description of hepatorenal syndrome secondary to hepatobiliary toxicity from glecaprevir/pibrentasvir. CASE DESCRIPTION/METHODS: A 65-year-old man with chronic HCV (genotype 1a), alcohol use disorder, and hepatocellular carcinoma (HCC), presented with abdominal distention and jaundice for one month. He was diagnosed with HCC in 2014 and treated with resection and adjuvant sorafenib without evidence of recurrence, and thus began HCV treatment with glecaprevir/pibrentasvir. At baseline he was Childs-Pugh class A with a total bilirubin of 0.9 mg/dL, INR of 0.95, and albumin of 3.2. Twenty-four days after initiation of glecaprevir/pibrentasvir he presented with fevers, fatigue, and dark urine. On exam he had jaundice, abdominal distension, and right upper quadrant tenderness. His labs showed a total bilirubin of 25.5 mg/dL, direct bilirubin of 16.1 mg/dL, INR of 1.64, and creatinine of 1.6 mg/dL (1.1 mg/dL two weeks prior). He was initially started on a three-day albumin challenge, but his renal function continued to decompensate, raising concern for a type 1 HRS, so he was transitioned to octreotide, midodrine, and albumin. Glecaprevir/pibrentasvir was also discontinued due to his acute liver decompensation after only 29 days of treatment. Eight days later, the patient’s creatinine had decreased from 2.0 to 1.3 mg/dL and his total bilirubin decreased from 25.6 to 16.4 mg/dL. Four months after discharge he has continued to improve with creatinine as low as 1.2mg/dL and a total bilirubin of 3.7 mg/dL. Notably, despite just four weeks of glecaprevir/pibrentasvir, his hepatitis C viral load has remained undetectable. DISCUSSION: In 2019, the FDA distributed a safety communication outlining liver injury in 46 individuals on glecaprevir/pibrentasvir and suggested avoidance in Child-Pugh class B and C patients. While research of the safety profile for glecaprevir/pibrentasvir in Child-Pugh class A is needed, this case reports highlights the importance of early and regular monitoring of liver and renal function in patients on this regimen. Current glecaprevir/pibrentasvir regimens are 12 weeks, yet a shortened four-week regimen still provided virus eradication in this case, raising the possibility of personalized treatment based on viral load. This could reduce potential side effects as well as the cost of antiviral therapy.

S2619 A Case of Happy Feet—Hepatitis C Necrolytic Acral Erythema in a Hispanic Patient

INTRODUCTION: Necrolytic acral erythema (NAE) was first described in 1996 in Egyptian patients with hepatitis C (HCV) infection. This entity has been strongly associated with HCV as a unique cutaneous marker. In the United States there are 23 cases reported, with a prevalence of 1.7% in 2012. There are rare reports in the literature of this cutaneous finding in the Hispanic population. CASE DESCRIPTION/METHODS: Fifty-four-year old Hispanic man with medical history of hypertension, alcohol abuse and chronic HCV (genotype 2) presented to the outpatient clinic with complaints of bilateral scaly plaques in his feet. The lesions appeared 5 years ago, initially in bilateral toes and then progressed to dorsum of the feet with associated pruritus and pain on light touch. He had tried over the counter topical agents and anti-fungal therapy without improvement. On exam had scleral icterus, with distended abdomen and fluid wave presence. Patient had bilateral hyperpigmented-violaceous scaly and lichenified well-demarcated plaques in dorsal area of feet. Pertinent labs included platelet count of 66th/uL, AST 80IU/L, ALT 83IU/L, Tbili 1.4mg/dL and HCV RNA PCR 2,950,000 copies. Given non-profit outpatient clinic supplies we were unable to obtain punch biopsy. Patient was referred to gastroenterology and was prescribed oral zinc sulfate 150 mg daily for suspected NAE. The patient demonstrated response to the treatment and had resolution of symptoms. DISCUSSION: NAE is a unique cutaneous marker of HCV infection. Pathogenesis remains unclear, HCV RNA peptides and zinc dysregulation may play a role. Most of cases are consistent with distinct acral distribution, HCV positive and zinc deficiency. Symptoms include pruritus in 93% of cases, burning and pain. These lesions present from erythematous-violaceous hyperpigmented plaques to vesicles and flaccid bullae. Differential diagnosis includes other necrolytic erythema such as psoriasis, eczema, pellagra and necrolytic migratory erythema. Skin biopsy shows hyperkeratosis, acanthosis, spongiosis and superficial perivascular lymphocytic infiltrate. Treatment usually involves therapy for underlying HCV infection. However oral zinc supplementation has reported resolution of lesions. From the 23 cases reported in the US, there is only 2 cases in a Hispanic patient. This case represents the third reported Hispanic patient from the US with HCV and necrolytic acral erythema treated successfully with oral zinc. Further cases are needed to define additional treatment options for this rare entity.Figure 1.: Patient's feet showing lesions in dorsal area.Figure 2Figure 3.: Left foot showing scaly violaceous plaques.

Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population: An observational study.

Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case–control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-β (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69–11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08–10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49–10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25–1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25–1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01–13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14–82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00–18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.

The relation of 25-hydroxy vitamin D concentrations to liver histopathology, seasonality and baseline characteristics in chronic hepatitis C virus genotype 2 or 3 infection.

Background and objectivesThe hydroxylation to 25-hydroxy vitamin D (25(OH)D) occurs in the liver and the impact of liver disease on vitamin D is unclear. This study evaluated the relationship between vitamin D concentrations and hepatic histopathology, seasonality and patient characteristics in well-characterized patients having undergone a liver biopsy.Method25(OH)D was measured post-hoc in pre-treatment serum from 331 North European patients with chronic HCV genotype 2 or 3 infection (NORDynamIC study). Liver biopsies were scored for fibrosis and inflammation according to the Ishak protocol, and graded for steatosis. Non-invasive markers of hepatic fibrosis as well as baseline viral and host characteristics, including genetic polymorphisms rs2228570, rs7975232, and rs10877012 were also evaluated.ResultsMean 25(OH)D concentration was 59 ±23 nmol/L, with 41% having values <50 nmol/L and 6% were <30 nmol/L. 25(OH)D correlated with fibrosis (r = -0.10, p ≤0.05) in univariate but not in multivariate analyses. No association was observed between 25(OH)D and hepatic inflammation, but with steatosis in HCV genotype 2 infected patients. None of the genetic polymorphisms impacted on 25(OH)D levels or fibrosis. 25(OH)D levels were significantly inversely correlated to BMI (r = -0.19, p = 0.001), and was also associated with season and non-Caucasian ethnicity.ConclusionFibrosis was not independently associated with 25(OH)D concentration and no association was seen with hepatic inflammation, but HCV genotype 2 infected patients with moderate-to-severe steatosis had lower 25(OH)D levels compared to those without steatosis. A high percentage had potential risk of 25(OH)D deficiency, and BMI, seasonality and ethnicity were independently associated with 25(OH)D as previously reported.

Glecaprevir–pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies—a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2)

Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2). We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised. Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event. Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations. AbbVie.

Efficacy and safety of elbasvir/grazoprevir in treatment-naive Chinese adults with hepatitis C virus infection: A randomized trial.

Background and AimIn China, clinical experience with direct‐acting antiviral treatments for hepatitis C virus (HCV) infection is still emerging. C‐CORAL is a phase 3, multinational, placebo‐controlled, double‐blind trial of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from the Asia‐Pacific region and Russia. Here, we report the data from participants enrolled in China.MethodsTreatment‐naive participants with chronic HCV genotype (GT) 1, GT4, or GT6 infection were randomly assigned to receive 50 mg EBR/100 mg GZR for 12 weeks (immediate‐treatment group, ITG) or placebo followed by deferred treatment with EBR/GZR (deferred‐treatment group, DTG). The primary efficacy end‐point was sustained virologic response at 12 weeks after completing treatment (SVR12), and the primary safety end‐point was a comparison of safety between participants receiving EBR/GZR and placebo (NCT02251990; Protocol PN‐5172‐067).ResultsA total of 152 participants in China were randomly assigned (ITG, n = 115; DTG, n = 37). SVR12 was achieved in 96.7% (146/151) participants overall and in 97.3% (142/146) of those with GT1b infection. Four participants relapsed (GT1b, n = 3; GT6a, n = 1). Drug‐related AEs were reported in 25 (21.7%) and 9 (24.3%) participants receiving EBR/GZR and placebo, respectively; no drug‐related serious adverse events (AEs) occurred. Two (1.7%) participants receiving EBR/GZR had late hepatic transaminase elevations. Patient‐reported outcomes indicate improved quality of life at follow‐up week 4 in participants receiving EBR/GZR compared to placebo.ConclusionEBR/GZR administered for 12 weeks represents a highly effective and safe treatment option for Chinese individuals with HCV GT1 infection.

Real-world effectiveness and safety of OBT/PTV/r and dasabuvir for patients with chronic HCV genotype 1b infection in China: A multicenter prospective observational study

Background and aimReal-world data on the effectiveness and safety of treatment with the direct-acting antiviral agent-based regimen are limited on the Chinese mainland. The aim of this study was to conduct a multicenter, prospective, real-world study of ombitasvir/paritaprevir/ritonavir (OBT/PTV/r) combined with dasabuvir (DSV) in hepatitis C virus (HCV) genotype 1b-infected non-cirrhotic or compensated cirrhotic Chinese adult patients. Materials and methodsGenotype 1b-infected patients were enrolled at eight sites in China. Patients received 25/150/100 mg of OBT/PTV/r once daily combined with 250 mg of DSV twice daily for 8 weeks or 12 weeks. Sustained virological response at 12 weeks post-treatment (SVR12) and the incidence of adverse events were assessed. We have also evaluated the effect of intensive questioning of patients who were overdue for SVR12 testing. Intention-to-treat (ITT) and modified ITT (mITT) populations were used in the analysis. ResultsOne hundred forty patients were included, among whom 90.0% (126/140) were newly diagnosed, 9.3% (13/140) had compensated cirrhosis, 92.9% (130/140) received 12 weeks of treatment, and 7.1% (10/140) received 8 weeks of treatment. In the mITT population, the virological response rate at week 4 was 96.4% (108/112), and at the end of treatment was 100% (102/102). Among these patients, 139 patients completed 12 weeks of treatment, and 73 patients were followed-up. All followed-up patients achieved SVR12. There was no adverse event-related discontinuation. Serious adverse events during treatment were reported in two (1.4%) patients, and none were considered to be drug-related. Sixty-six (47.1%) patients did not return to receive the HCV RNA test at 12 weeks post-treatment. ConclusionsThe rate of SVR12 was consistent with Phase III clinical studies. OBT/PTV/r combined with DSV showed effectiveness in Chinese adult patients, and both tolerability and safety profile were favorable. However, patient compliance should be further improved in the real world.

Effectiveness of sofosbuvir based direct-acting antiviral regimens for chronic hepatitis C virus genotype 6 patients: Real-world experience in Vietnam.

Hepatitis C virus (HCV) genotype 6 is the commonest cause of chronic hepatitis C infection in much of southeast Asia, but data on the effectiveness of direct-acting antiviral agents (DAAs) against this genotype are limited. We conducted a retrospective cohort study of patients attending the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam, to define the effectiveness of DAAs in the treatment of chronic HCV genotype 6 in actual practice. We included all patients with genotype 6 infections attending our hospital between March 2016 and October 2017 who received treatment with sofosbuvir-based DAA treatment regimens, and compared their responses with those with genotype 1 infections. 1758 patients (1148 genotype 6, 65.4%; 610 genotype 1, 34.6%) were analyzed. The majority of patients (1480, 84.2%) received sofosbuvir/ledipasvir (SOF/LDV) ± ribavirin (RBV); 278 (15.8%) received sofosbuvir/Daclatasvir (SOF/DCV) ± RBV. The median age of the patients was 57 years, (interquartile range (IQR) 46-64 years) The baseline HCV viral load (log IU/ml) was significantly higher in patients infected with genotype 6 compared with those infected with genotype 1 (6.8, 5.3-6.6 versus 6.3, 5.3-6.5 log10 IU/ml, p = <0.001, Mann Whitney U test). A sustained virological response (SVR), defined as an undetectable viral load measured between 12 and 24 weeks after completing treatment, and indicating cure, was seen in 97.3% (1711/1758) of patients. Treatment failure, defined as HCV viral load ≥15 IU/ml ≥12 weeks after completing treatment appeared to be more frequent in patients infected with genotype 6 virus (3.2%, 37/1148) than in those infected with genotype 1 (1.7%, 10/610), p = 0.050 chi-squared test). We found no evidence that patient's age, gender, liver cirrhosis, diabetes, HBV or HIV coinfection, prior treatment failure with pegylated interferon therapy, body mass index (BMI), aspartate aminotransferase to platelet ratio index (APRI), or fibrosis 4 (FIB-4) index were associated with treatment failure. Our study suggests that patients with HCV genotype 6 infection in Vietnam may respond less well to treatment with sofosbuvir based DAAs than patients with genotype 1 infections. Further studies are needed to confirm this observation and to define whether it is driven by genotype-specific mutations.

Effectiveness of Elbasvir/Grazoprevir in US Veterans with Chronic Hepatitis C Virus Genotype 1b Infection.

IntroductionReal-world treatment of hepatitis C virus (HCV) infection is complicated by many factors that are controlled for in the rigorous clinical trial setting. The aim of the present study was to assess the efficacy of elbasvir/grazoprevir in a Veterans Affairs population with chronic HCV genotype 1b infection.MethodsThis was a retrospective analysis of a cohort of patients aged ≥ 18 years with chronic HCV genotype 1b infection and ≥ 1 prescription of elbasvir/grazoprevir between February 1, 2016, and August 31, 2017. The primary analysis was conducted in the per-protocol population, which included all patients who had at least 11 weeks of treatment and had an available assessment for sustained virologic response (SVR) based on virologic data post–follow-up week 4.ResultsThe per-protocol population included 3371 patients. Overall, 97.3% of patients were male, 60.3% were black, and 85.5% were HCV treatment–experienced. Comorbidities in this population included hypertension (74.4%), history of alcohol use (55.7%), and depression (54.8%). In total, 97.5% of patients (3288/3371) achieved SVR. Among patient sub-groups, SVR was achieved by 96.0% (290/302) of those with chronic kidney disease stage 4/5, 97.8% (1527/1561) of those with a history of drug use, and 96.6% (831/860) of those with cirrhosis. No statistically significant differences were observed in the proportions of patients achieving SVR, regardless of age, race, HCV treatment history, viral load level, treatment regimen/duration, history of drug or alcohol use, HIV co-infection, or chronic kidney disease.ConclusionElbasvir/grazoprevir was highly effective in individuals with HCV genotype 1b infection in a large national Veterans Affairs clinical setting.

Effect of using Direct Acting Antivirals on the Synthetic Liver Functions in Treatment-Naïve Patients with Chronic Hepatitis C Virus Infection Genotype 4

Abstract Background and aim of the study Interferon-free direct-acting antivirals (DAAs) combination therapies, including sofosbuvir (SOF), daclatasvir (DCV) and paritaprevir -r/ombitasvir therapy with or without ribavirin, eradicate chronic hepatitis C virus (HCV) in a high percentage of patients, but its impact on improvement of synthetic liver function is unclear. The aim of this study was to evaluate the effect of DAAs on the synthetic functions of the liver in treatment- naïve chronic HCV genotype 4 patients who treated by different regimens of DAAs for 12 weeks and achieved a sustained virological response at 12 weeks after treatment completion (SVR 12). Patients and Methods From September 2017 to March 2018, 150 treatment- naïve chronic HCV genotype 4 Egyptian patients received different DAAs regimens for 12 weeks were enrolled for this prospective cohort study, to evaluate the effect of DAAs on serum albumin, total bilirubin, INR, prothrombin concentration and platelets count at the end of treatment (WK12) and at week 12 post treatment in comparison to baseline. Patients were categorized to three groups; Group 1 (easy to treat) included 60 patients treated by SOF/DAC regimen, Group 2 (Difficult to treat) included 60 patients treated by SOF/DAC + ribavirin regimen and Group 3 included 30 chronic HCV patients with chronic kidney disease (eGFR ≤ 30 ml/min and Haemoglobin level &amp;gt;10g/dl) treated by Qurevo (paritaprevir-r/ombitasvir) + ribavirin and all included patients were treated for 12 weeks and achieved a sustained virological response at week 12 post treatment (SVR 12). Results There was a statistically highly significant improvement of serum albumin, total bilirubin, PC and INR (P = 0.001) among groups 1 and 2 patients at both time points _the end of treatment and WK12 post treatment_ (except for s. total bilirubin; P value was 0.11 at the end of treatment as compared to baseline). Platelets count showed a statistically highly significant improvement (P = 0.001) at both time points among group 1 patients, however among groups 2 and 3, it showed a statistically highly significant decline at the end of treatment (P = 0.001) as compared to baseline then showed a statistically highly significant improvement at WK12 post treatment (P = 0.001) among group 2 patients and (P = 0.027) among group 3 patients as compared to baseline value. Among group 3 cases there was a statistically significant improvement of serum albumin (P = 0.001) and PC (P = 0.025) at WK12 post treatment as compared to baseline. Conclusion In conclusion, based on analysis of all laboratory parameters in this study, we can conclude that direct acting antiviral therapy (DAAs) is effective in improvement of synthetic liver functions in chronic hepatitis C genotype 4 patients who achieved a sustained virological response.