Chronic Hepatitis C Virus Genotype Research Articles

Improvement in Thrombocytopenia after Direct Acting Anti-Viral (DAA)Therapy in Patients with Hepatitis C Virus-Related Chronic Liver Disease in Pakistani Population-A Single Centered Study

Background: Hepatitis C Virus (HCV) infection remains a significant global health challenge, often leading to chronic liver diseases such as cirrhosis and associated complications like thrombocytopenia. Directly acting antivirals (DAAs) have revolutionized HCV treatment due to their high efficacy and favorable safety profiles but the impact on thrombocytopenia, particularly in the Pakistani population, has been less studied. Objective: This study aimed to evaluate the effects of DAA therapy on platelet count and other laboratory parameters in chronic HCV patients with thrombocytopenia in Pakistan and to establish correlations between treatment outcomes and baseline laboratory values. Methods: A retrospective observational study was conducted at the Sindh Institute of Urology and Transplantation from January 2018 to December 2022. Patients with chronic HCV genotype 3a infection, compensated cirrhosis, and a baseline platelet count of less than 150 × 10^9/L were included. Exclusion criteria encompassed decompensated liver disease, liver cancer, and other specific conditions. The treatment regimens were Sofosbuvir plus Daclatasvir or Velpatasvir plus Ribavirin over three months. Parameters such as complete blood counts, serum creatinine, liver enzymes, and Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores were recorded at baseline and post-treatment. Statistical analysis was performed using SPSS version 25, employing paired t-tests and Pearson correlation coefficients. Results: A total of 195 patients were studied, with a mean baseline platelet count of 100.7 × 10^9/L, which significantly increased to 122.2 × 10^9/L post-treatment (p < 0.001). Improvements were also noted in mean serum creatinine (0.96 mg/dL to 0.87 mg/dL; p = 0.009), total bilirubin (1.6 mg/dL to 1.2 mg/dL; p < 0.001), liver enzymes (ALT from 63.9 IU to 45.9 IU; p < 0.001 and AST from 86.8 IU to 59.5 IU; p < 0.001), and MELD scores (11.5 to 9.3; p < 0.001). Hemoglobin levels and total leukocyte counts also showed significant improvements. Conclusion: DAA therapy significantly improves platelet counts and other laboratory parameters in chronic HCV patients with thrombocytopenia, suggesting a positive impact on liver function and patient management. This study highlights the importance of DAAs in the therapeutic regimen for HCV in the Pakistani population, contributing to better clinical outcomes and healthcare practices.

Sex-related difference analyses of efficacy and safety in clinical trials of direct-acting antivirals to treat chronic HCV genotype 1 and 3 infections.

This study aims to identify clinically meaningful sex differences in efficacy and selected safety adverse events for the treatment of chronic hepatitis C virus infection (HCV) or HIV/HCV co-infection in those receiving combination direct-acting antiviral (DAA) regimens. Our assessment was based on adult trial participants treated at the approved DAA dosage and treatment duration from 40 phase 3 clinical trials submitted to the FDA. Female enrollment ranged from 11% to 54% (overall mean 38%). Females with HCV genotype (GT) 1 or 3 infection had statistically significant higher unadjusted or covariant-adjusted odds of achieving sustained virologic response at post-treatment Week 12 (SVR12) compared with males. Odds ratios favouring females were observed among Whites and those ≥40 years of age with HCV GT1 or 3 infections, and among those ≥50 years of age, non-cirrhotic and those with HCV GT3 infection who were treatment-experienced. These differences were not clinically relevant due to the high SVR12 rate achieved by females and males, overall or in subgroups. No differences were observed in SVR12 rates between HCV GT1 mono-infected and HCV GT1/ HIV-1 co-infected participants. Numerically, more females reported headache, fatigue and nausea compared to males, but the differences were small and predominately Grade 1 or 2 severity. Discontinuation rates for any reason or due to an adverse event were low and similar between the sexes. Our study demonstrated females successfully complete DAA regimens and achieve high SVR12 rates despite numerically higher adverse events for certain commonly reported events.

Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to liver steatosis, fibrosis, and hepatocellular carcinoma (HCC). Despite the accumulation of clinical data showing the impact of amino acid substitutions at positions 70 (R70Q/H) and/or 91 (L91M) in the HCV core protein in progressive liver diseases, including HCC, the underlying mechanisms have not been elucidated.We analyzed 72 liver biopsy specimens from patients with chronic HCV genotype 1b (HCV-1b) infection prior to antiviral treatment. Levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nuclear factor erythroid 2-related factor 2 (NRF2) in the nucleus were quantified using liver tissue immunohistochemistry. The effects of amino acid substitutions in the HCV core region on hepatocellular oxidative stress were investigated using wild-type or double-mutant (R70Q/H+L91M) HCV-1b core transfection and stable expression in human hepatoma HuH-7 cells.Overall, 24, 19, 11, and 18 patients had the wild-type, R70Q/H, L91M, and R70Q/H+L91M genotypes, respectively, in the HCV core. A significantly higher accumulation of hepatocellular 8-OHdG and a lower NRF2/8-OHdG ratio were observed in patients with R70Q/H+L91M than in those with the wild-type disease. Increased levels of intracellular superoxide and hydrogen peroxide in the cytoplasm and mitochondria, mRNA expression of enzymes generating oxidative stress, and nuclear expression of nicotinamide adenine dinucleotide phosphate oxidase 4 were augmented in cells treated with R70Q+L91M.HCV core proteins harboring either or both substitutions of R70Q/H or L91M enhanced hepatocellular oxidative stress in vivo and in vitro. These amino acid substitutions may affect HCC development by enhancing hepatic oxidative stress in patients with chronic HCV-1b infection.

A therapeutic dose and its pharmacokinetics of ropeginterferon Alfa-2b for hepatitis C treatment

Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. Its biweekly dosing schema has demonstrated tolerability and clinical efficacy for treating chronic hepatitis in previous clinical studies. This trial evaluates the pharmacokinetics of 400μg ropeginterferon alfa-2b in patients with chronic hepatitis C virus (HCV) and provides the data to support the clinical utility of ropeginterferon alfa-2b at 400 μg. Seventeen patients with chronic HCV genotype 2 were enrolled to receive a single injection of 400μg ropeginterferon alfa-2b plus 14-day treatment of ribavirin. Pharmacokinetics, safety, and HCV RNA reduction/clearance were assessed. Tmax was 154.003h and T1/2 was 114.273h. The Cmax was 29.823ngmL-1. AUClast was 9364.292h∗ng mL-1 and AUCinf was 11084.317h∗ng mL-1. All adverse events were mild or moderate, and there were no serious adverse events. A 1000-fold reduction in the geometric mean of HCV RNA was observed 14d after the single injection of ropeginterferon alfa-2b. Two patients achieved clearance of HCV RNA, and the other five patients had HCV RNA levels lower than 200 IU mL-1. Ropeginterferon alfa-2b at 400μg led to PK exposures associated with safety and notable clinical activity in patients with chronic HCV. This study suggests that ropeginterferon alfa-2b at 400μg is an acceptable dosing regimen for treating chronic HCV and also provides supporting data for the clinical use of ropeginterferon alfa-2b at a higher starting dose for other indications.

Retreatment of patients with chronic hepatitis C, subtype 3a, and cirrhosis, who previously failed a regimen containing NS5A inhibitors with sofosbuvir/velpatasvir plus ribavirin for 24 weeks

Background & Aims The use of direct acting antiviral agents (DAAs) in patients with chronic HCV genotype (GT) 3a infection results in sustained virologic response (SVR) rates of 93–98%, but 5–8% of patients experience virologic failure. Methods. We observed 48 patients infected with HCV subtype 3a who failed previous treatment with DAAs, including 43 subjects (89.6%) with liver cirrhosis. Thirty-seven (77%) subjects previously received NS5A inhibitors of the first generation (daclatasvir) and 11 subjects (23%) – of the second generation (velpatasvir). All patients received retreatment with sofosbuvir (SOF)/ velpatasvir (VEL) and ribavirin (RBV) for 24 weeks. We compared SVR12 rates depending on fibrosis stage, presence of NS5A mutation (L31M or A30K and Y93H), and on the generation of previously used NS5A inhibitors. Results. Observed SVR12 rate were: 83,3% (40/48 patients) overall; 100% in patients without cirrhosis (n=5) vs 81,4% (n=35) in those with cirrhosis (n=43) (P=0,01); 86,7% (n=13) with single L31M or A30K(n=15) vs 77,8% (n=21) with Y93H mutation (n=27) (P=0,46), 86,5% (n=32) in patients who previously failed first generation (n=37) vs 72,7% (n=8) in those who failed second generation NS5A inhibitors (n=11) (P=0,35). Conclusions. Retreatment with SOF/VEL+RBV was highly effective and safe in patients with chronic HCV GT3a infection, including those with liver cirrhosis, who previously failed DAA containing NS5A inhibitors. Presence of NS5A RASs L31M, A30K, and Y93H at the baseline, as well as the generation of previously used NS5A inhibitors did not impact SVR12 rates.

S3264 A Hepatitis C (HCV) Infection Treatment Dilemma

Introduction: HIV/HCV coinfection increases liver-related morbidity and mortality. This special population should be prioritized for treatment. Currently available direct-acting antivirals (DAAs) are safe and effective, but there are many drug interactions (DIs) to consider. Carbamazepine (CBZ) is contraindicated with all available DAAs. Patients that require treatment for HCV but cannot stop CBZ do not have a clear treatment option. Patients may be transitioned to newer antiepileptics that do not have the same contraindications, but some patients are unwilling or unable to change medications. Case Description/Methods: Patient is a 59-year-old man with well-controlled HIV on HAART, well-controlled trigeminal neuralgia on CBZ, anemia, and non-cirrhotic (FibroScan 12 kPa), treatment naïve, chronic HCV genotype 1a. Due to DIs between DAAs and CBZ, multiple attempts were made to discontinue CBZ but were unsuccessful. Neurosurgery offered surgical gamma knife management, but up to 40% of patients still require CBZ post-procedure. An initial plan for daclatasvir (DAC)-sofosbuvir (SOF)-ribavirin (RBV) was proposed, but DAC is no longer available in the US. Patient was followed conservatively but developed thrombocytopenia and progression of fibrosis (FibroScan 14.7kPa). Given worsening liver condition, shared decision-making was performed, and patient completed 16 weeks of Glecaprevir (GLE)/pibrentasvir (PIB) + SOF 400mg with 4 weeks of ezetimibe 10mg stopping when the viral load was undetectable. Patient was instructed to start the ezetimibe with the GLE/PIB + SOF but was hesitant to take it due to adverse reaction to statins in the past. At 4 weeks of treatment, HCV viral load was still detectable. Patient was re-educated on the purpose of the ezetimibe and reassured it was not a statin. He took it from week 4-8 of treatment. At week 8, HCV viral load was undetectable. Patient achieved SVR 12 and showed improvement of his FibroScan score to 9.6 kPa. Discussion: GLE/PIB is pangenotypic, has a high barrier to resistance, and has been proven safe and effective in combination with SOF + RBV in MAGELLAN 3 for 16 weeks duration. Patient has history of anemia, making RBV undesirable. Ezetimibe blocks the NPC1L receptor which potentially inhibits HCV entry into the hepatocyte. HCV relies on cell-to-cell transmission, so we chose to add ezetimibe 10mg daily until HCV not detected. There is a need for larger studies to determine the applicability of this case study to other patients.

CD8+ T-Cell Exhaustion Phenotype in Chronic Hepatitis C Virus Infection Is Associated With Epitope Sequence Variation.

Background and AimsDuring chronic hepatitis C virus (HCV) infection, CD8+ T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of “inhibitory” molecules such as PD-1 (programmed cell death protein 1) and/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes.MethodsThe study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8+ T-cells expressing PD-1/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb.ResultsThere was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8+ T-cells. A predominance of NS31406 epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8+PD-1+Tim-3+ T-cells, P=0.0102. Variability (at least two variants) of NS31406 epitope sequence was associated with increased frequencies of global CD8+PD-1+Tim-3+ T-cells (P=0.0197) and lower frequencies of CD8+PD-1−Tim-3− T-cells (P=0.0079). In contrast, infection with NS31073 dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8+PD-1+Tim-3+ T-cells (P=0.0054).ConclusionsOur results indicate that PD-1/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8+ T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8+ T-cell exhaustion in HCV infection.

Safety and efficacy of sofosbuvir-velpatasvir to treat chronic hepatitis C virus infection in treatment-naive patients in Rwanda (SHARED-3): a single-arm trial

Hepatitis C virus (HCV) genotype 4 is the predominant type of HCV found in sub-Saharan Africa. Various genotype 4 subtypes, such as 4r, frequently have resistance-associated substitutions that can increase rates of treatment failure with common direct-acting antiviral regimens. In-vitro studies suggest that the NS5A inhibitor velpatasvir is effective against viral isolates containing such resistance-associated substitutions, but its clinical efficacy against genotype 4 non-a/d subtypes in sub-Saharan Africa remains to be confirmed. We aimed to evaluate the safety and efficacy of sofosbuvir-velpatasvir among adults chronically infected with HCV and naive to direct-acting antiviral treatment in Rwanda, where genotype 4 non-a/d subtypes predominate. In this single-arm prospective trial, we enrolled adults (age ≥18 years) in Rwanda who had chronic HCV infection and a plasma HCV RNA titre of at least 1000 IU/mL. Patients were referred from hospitals with HCV treatment programmes throughout Rwanda and were sequentially enrolled and assessed for eligibility at a single study site. Individuals with decompensated liver disease or hepatitis B virus co-infection were excluded. Participants were given an oral fixed-dose combination tablet of sofosbuvir (400 mg) and velpatasvir (100 mg) once-daily for 12 weeks. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after completion of treatment (SVR12) in the intention-to-treat population. Viral sequencing of the NS5A and NS5B genes was done at baseline for all participants and end of follow-up (week 24) for participants who did not have SVR12. This study is registered with ClinicalTrials.gov (NCT03888729) and is completed. Between Sept 23, 2019, and Jan 10, 2020, 73 individuals were screened for eligibility, of whom 12 (16%) were excluded and 61 (84%) were enrolled. 40 (66%) participants were female, 21 (34%) were male, median age was 64 years (IQR 51-74), and median baseline HCV viral load was 5·7 log10 IU/mL (5·2-6·2). The genotypes identified among the participants were 4k (28 [46%] participants), 4r (11 [18%]), 4v (eight [13%]), 4q (five [8%]), 4l (three [5%]), 4b (one [2%]), 4c (one [2%]), and one undetermined genotype 4 subtype. Three isolates could not be sequenced and were of indeterminate genotype. Of the 55 HCV isolates that were successfully sequenced, all had at least two NS5A resistance-associated substitutions. 59 (97% [95% CI 89-99]) participants had SVR12. 18 (30%) participants had grade 3 adverse events (including 12 [20%] with hypertension), and none had grade 4 adverse events. Four (7%) participants had serious adverse events, including one asthma exacerbation, one abscess, one uterine myoma, and one pelvic fracture related to a motor vehicle accident. No serious adverse events were attributed to the study drug and no adverse event resulted in discontinuation of the study drug. A 12-week regimen of sofosbuvir-velpatasvir is safe and efficacious in treating chronic HCV genotype 4 infection in patients in Rwanda. This regimen could be an effective treatment option in regions known to have a high prevalence of HCV genotype 4 of diverse non-a/d subtypes. Gilead Sciences.

Sero-reactivity to three distinct regions within the hepatitis C virus alternative reading frame protein (ARFP/core+1) in patients with chronic HCV genotype-3 infection.

Hepatitis C virus (HCV) infection affects more than 71 million people worldwide. The disease slowly progresses to chronic, long-term liver injury which leads to hepatocellular carcinoma (HCC) in 5 % of infections. The alternative reading frame protein (ARFP/core+1) is encoded by a sequence overlapping the HCV core gene in the +1 reading frame. Its role in hepatitis C pathogenesis and the viral life cycle is unclear, although some observers have related its production to disease progression and the development of HCC. The aim of this study was to determine whether ARFP is immunogenic in patients with chronic HCV genotype 3 infection and to assess whether sero-reactivity is associated with disease progression, particularly to HCC. Immunogenic epitopes within the protein were predicted by a bioinformatics tool, and three −20 aa length-peptides (ARFP-P1, ARFP-P2 and ARFP-P3) were synthesized and used in an avidin-biotin ARFP/core+1 peptide ELISA. Serum samples from 50 patients with chronic HCV genotype 3 infection, 50 genotype-1 patients, 50 HBV patients and 110 healthy controls were tested. Sero-reactivity to the ARFP peptides was also tested and compared in 114 chronic HCV genotype-3 patients subdivided on the basis of disease severity into non-cirrhotic, cirrhotic and HCC groups. Chronic HCV genotype-3 patients showed noticeable rates of reactivity to ARFP and core peptides. Seropositivity rates were 58% for ARFP-P1, 47 % for ARFP-P2, 5.9 % for ARFP-P3 and 100 % for C22 peptides. There was no significant difference between these seroreactivities between HCV genotype-3 patients with HCC, and HCV genotype-3 patients with and without liver cirrhosis. Patients with chronic HCV genotype-3 infection frequently produce antibodies against ARFP/core+1 protein. ARFP peptide reactivity was not associated with disease severity in patients with HCV genotype-3. These results support the conclusion that ARFP/core+1 is produced during HCV infection, but they do not confirm that antibodies to ARFP can indicate HCV disease progression.

Cost-Effectiveness Analysis of Pan-Genotypic Sofosbuvir-Based Regimens for Treatment of Chronic Hepatitis C Genotype 1 Infection in China.

Background: Hepatitis C virus (HCV) genotype 1 is the most prevalent HCV infection in China. Sofosbuvir-based direct antiviral agent (DAA) regimens are the current mainstays of treatment. Sofosbuvir/velpatasvir (SOF/VEL) and sofosbuvir/ledipasvir (SOF/LDV) regimens became reimbursable in China in 2020. Thus, this study aimed to identify the optimal SOF-based regimen and to inform efficient use of healthcare resources by optimizing DAA use in treating HCV genotype 1.Methods and Models: A modeling-based cost-utility analysis was conducted from the payer's perspective targeting adult Chinese patients with chronic HCV genotype 1 infection. Direct medical costs and health utilities were inputted into a Markov model to simulate lifetime experiences of chronically infected HCV patients after receiving SOF/LDV, SOF/VEL or the traditional strategy of pegylated interferon (pegIFN) + ribavirin (RBV). Discounted lifetime cost and quality adjusted life years (QALYs) were computed and compared to generate the incremental cost utility ratio (ICUR). An ICUR below the threshold of 31,500 $/QALY suggests cost-effectiveness. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of model findings.Results: Both SOF/LDV and SOF/VEL regimens were dominant to the pegIFN + RBV regimen by creating more QALYs and incurring less cost. SOF/LDV produced 0.542 more QALYs but cost $10,390 less than pegIFN + RBV. Relative to SOF/LDV, SOF/VEL had an ICUR of 168,239 $/QALY which did not meet the cost-effectiveness standard. Therefore SOF/LDV was the optimal strategy. These findings were robust to linear and random variations of model parameters. However, reducing the SOF/VEL price by 40% would make this regimen the most cost-effective option.Conclusions: SOF/LDV was found to be the most cost-effective treatment, and SOF/VEL was also economically dominant to pegIFN + RBV. These findings indicated that replacing pegIFN + RBV with DAA regimens could be a promising strategy.

The Impact of IL28B Gene Polymorphisms on Drug Responses

To achieve high therapeutic efficacy in the patient, information on pharmacokinetics, pharmacodynamics, and pharmacogenetics is required. With the development of science and technology, especially genetic sequencing technology, more and more research on pharmacogenomics has been conducted. The relationship between the genome and the response of a person to drugs is being explored to support personalized medicine, which shows efficacy in clinical treatment. In particular, the IL28B gene polymorphisms have been studied and shown to have impacts on drug responses in the treatment of many diseases, such as chronic hepatitis C, chronic hepatitis B, and myeloproliferative neoplasms. However, pharmacogenetic studies of the IL28B gene have not given exact recommendations for dose adjustment in treatment; they only show the impact tendency that individuals with an unfavorable genotype (usually the genotype of the mutant allele) show poor response to treatment compared to those with a favorable genotype. The frequency of mutant alleles varies among different ethnic groups and between different viral genotypes. Identifying and predicting the possibility of successful treatment helps both clinicians and patients make better choices of treatment decisions to optimize treatment possibilities, and reduce side effects and treatment costs.
 Keywords
 IL28B polymorphism, drug response, hepatitis C, hepatitis B, myeloproliferative disorders.
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Susser et al., Predictive Value of Interferon-Lambda Gene Polymorphisms for Treatment Response in Chronic Hepatitis C, Plos One, Vol. 9, No. 11, 2014, pp. e112592, https://doi.org/10.1371/journal.pone.0112592.[42] A. Tsubota et al., Impact of IL28B Polymorphisms on 24‐Week Telaprevir‐Based Combination Therapy for A Sian Chronic Hepatitis C Patients with Hepatitis C Virus Genotype 1b, Journal of Gastroenterology Hepatology, Vol. 29, No. 1, 2014, pp. 144-150, https://doi.org/10.1111/jgh.12402.[43] M. Manns et al., Simeprevir with Pegylated Interferon Alfa 2a or 2b Plus Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C Virus Genotype 1 Infection (QUEST-2): A Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial, The Lancet, Vol. 384, No. 9941, 2014, pp. 414-426, https://doi.org/10.1016/S0140-6736(14)60538-9.[44] M. Nakayama, H. Kobayashi, K. Fukushima, M. Ishido, Y. Komada, K. Yoshizawa, Predictive Factors for 24 Weeks Sustained Virologic Response (SVR24) and Viral Relapse in Patients Treated with Simeprevir Plus Peginterferon and Ribavirin, Hepatology International, Vol. 10, No. 1, 2016, pp. 158-168, https://doi.org 10.1007/s12072-015-9654-9.[45] F. Poordad et al., Factors that Predict Response of Patients with Hepatitis C Virus Infection to Boceprevir, Gastroenterology, Vol. 143, No. 3, 2012, pp. 608-618, https://doi.org/10.1053/j.gastro.2012.05.011.[46] C. Hézode et al., Daclatasvir Plus Peginterferon Alfa and Ribavirin for Treatment-Naive Chronic Hepatitis C Genotype 1 or 4 Infection: A Randomised Study, Gut, Vol. 64, No. 6, 2015, pp. 948-956, http://dx.doi.org/10.1136/gutjnl-2014-307498.[47] A Thompson et al., GS-5885 + GS-9451 + Peginterferon and Ribavrin (Pr) for Six or 12 Weeks Achieves A High SVR12 in Treatment Naïve Genotype 1 IL28B CC Patients, Journal of Hepatology, Vol. 58, No. Suppl 1, 2013, pp. S29, https://doi.org/10.1016/S0168-8278(13)60066-5.[48] S. Zeuzem et al., Pegylated Interferon-Lambda (Pegifn-Λ) Shows Superior Viral Response with Improved Safety and Tolerability Versus Pegifn-Α-2a In HCV Patients (G1/2/3/4): EMERGE Phase Iib Through Week 12, Journalof Hepatology, Vol. 54, No. Suppl 1, 2011, pp. S538, https://doi.org/10.1016/S0168-8278(11)61362-7.[49] S. Zeuzem et al., Faldaprevir and Deleobuvir for HCV Genotype 1 Infection, The New England Journal of Medicine, Vol. 369, No. 7, 2013, pp. 630-639, https://doi.org/10.1056/NEJMoa1213557.[50] T. R. O'Brien, S. Kottilil, J. J. Feld, T. R. Morgan, R. M. Pfeiffer, Race or Genetic Makeup for Hepatitis C Virus Treatment Decisions?, Hepatology, Vol. 65, No. 6, 2017, pp. 2124-2125, https://doi.org/10.1002/hep.29057.[51] R. M. Pfeiffer et al, Subgroup Differences in Response to 8 Weeks of Ledipasvir/Sofosbuvir for Chronic Hepatitis C, Open Forum Infectious Diseases, Vol. 1, No. 3, 2014, pp.1-4 ofu110, https://doi.org/10.1093/ofid/ofu110.[52] N. Akuta et al., Retreatment Efficacy and Predictors of Ledipasvir Plus Sofosbuvir to HCV Genotype 1 in Japan, Journal of Medical Virology, Vol. 89, No. 2, 2017, pp. 284-290, https://doi.org/10.1002/jmv.24617.[53] T. R. O’Brien, S. Kottilil, R. M. Pfeiffer, IFNL4 Genotype is Associated with Virologic Relapse After 8-Week Treatment with Sofosbuvir, Velpatasvir, and Voxilaprevir, Gastroenterology, Vol. 153, No. 6, 2017, pp. 1694-1695, https://doi.org/10.1053/j.gastro.2017.06.069.[54] A. J. Khan, V. A. Saraswat, P. Ranjan, D. Parmar, T. S. Negi, S. Mohindra, Polymorphism in Interferon Λ3/Interleukin‐28B Gene and Risk to Noncirrhotic Chronic Hepatitis C Genotype 3 Virus Infection and Its Effect on the Response to Combined Daclatasvir and Sofosbuvir Therapy, Journal of Medical Virology, Vol. 91, No. 4, 2019, pp. 659-667, https://doi.org/10.1002/jmv.25359.[55] A. Vasanthakumar et al., Reduced Itpase Activity and Favorable Il28b Genetic Variant Protect Against Ribavirin-Induced Anemia in Interferon-Free Regimens, Plos One, Vol. 13, No. 5, 2018, pp. e0198296, https://doi.org/10.1371/journal.pone.0198296.[56] H. 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Lau et al., Peginterferon Alfa-2a, Lamivudine, and The Combination for Hbeag-Positive Chronic Hepatitis B, New England Journal of Medicine, Vol. 352, No. 26, 2005, pp. 2682-2695, https://doi.org/10.1056/NEJMoa043470.[65] Z. Zhao et al., The Impact Of IFNL3 Genotype on Interferon Treatment Outcome in Patients Chronically Infected with Hepatitis B Virus: A Meta-Analysis, Microbial Pathogenesis, Vol. 134, 2019, pp. 103598, https://doi.org/10.1016/j.micpath.2019.103598.[66] M. Lindgren et al., Genetic Variation in IL 28B (IFNL 3) and Response to Interferon‐Alpha Treatment in Myeloproliferative Neoplasms, European Journal of Haematology, Vol. 100, No. 5, 2018, pp. 419-425, https://doi.org/10.1111/ejh.13034.[67] P. J. Campbell, A. R. Green, The Myeloproliferative Disorders, New England Journal of Medicine, Vol. 355, No. 23, 2006, pp. 2452-2466, https://doi.org/10.1056/NEJMra063728.[68] R. T. Silver, J. J. Kiladjian, H. C. 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Cost-effectiveness analysis of glecaprevir/pibrentasvir regimen for treating Chinese patients with chronic hepatitis C genotype 1 and genotype 2 infection.

Hepatitis C virus (HCV) infection is an important health threat in China to which direct acting antivirals (DAAs) are very effective. In 2019, another novel DAA glecaprevir/pibrentasvir (GLE/PIB) was officially approved. Knowledge of its cost-effectiveness would be informative for clinical decision-making but has not been evaluated. This study aims to evaluate the cost-effectiveness of GLE/PIB to inform policy-making on drug reimbursement and HCV eradication. Markov models were developed from the payers' perspective and simulated the lifetime experience of adult patients chronically infected with HCV genotype 1 or genotype 2. Two regimens, GLE/PIB and pegylated interferon (pegIFN) plus ribavirin (RBV), were compared in cost and quality adjusted life years (QALY) with both outcomes being discounted to 2020 values. The incremental cost-effectiveness ratio (ICER) was computed to reflect the incremental benefit of GLE/PIB versus pegIFN + RBV. The robustness of the model outcomes was examined using deterministic and probabilistic sensitivity analysis (PSA) to identify influential parameters and to assess the probability of GLE/PIB being cost-effective. The GDP per capita in China in 2019 ($10,275) was used as the threshold for cost-effectiveness. For the entire target population, GLE/PIB was the dominant regimen attaining a cost-saving of $255 and 1.17 more QALYs relative to pegIFN + RBV. The finding was more pronounced for HCV genotype 1 infection by saving $1,656 and creating 1.37 more QALYs. At the $10,275 threshold, the probability of GLE/PIB being cost-effective was 99.32% overall and 99.85% for HCV genotype 1 infection. The age of starting DAA treatment, price of pegIFN + RBV, cost of cirrhosis treatment and duration of the GLE/PIB regimen were the five most influential factors. For the patients with HCV genotype 2 infection, the ICER of GLE/PIB was $12,914/QALY with 95% confidence interval of $4,047/QALY to $37,640/QALY. The GLE/PIB regimen statistically cannot be ruled out as a cost-effective option for HCV genotype 2 infection. GLE/PIB is a cost-effective strategy to treat chronic HCV genotype 1 and HCV genotype 2 infection in China. This regimen should be initiated at a younger age to maximize its value. To achieve national eradication, it may be timely to consider replacing pegIFN + RBV with DAAs, such as GLE/PIB, as the first-line treatment.

The distribution of hepatitis C virus infection in Shanghai, China: a time-spatial study

BackgroundShanghai, as a pilot city of China to achieve the goal of eliminating hepatitis C, its strategy of allocating medical resources is a pressing problem to be solved. This study aims to infer the time-spatial clustering patterns of HCV-infected cases, and grasp the dynamic genotype distribution of HCV, thereby inform elimination strategies of HCV with efficacy and efficiency.MethodsReported HCV cases including their demographic information in Shanghai city from 2005 to 2018 were released from the National Infectious Disease Reporting Information System, population data at community scale, geographical layers of hospitals, communities and districts were gathered from former research. Blood samples of HCV-infected individuals were collected during 2014–2018 from 24 sentinel hospitals, HCV-antibody test, qualitative nucleic acid test and NS5B/5’UTR gene amplification were performed accordingly to determine the genotypes of the specimen. Furthermore, global and local spatial self-correlation analysis of both acute and chronic HCV infections were conducted at community scale year by year, then time-spatial clusters of acute and chronic HCV infections and HCV genotype distribution of specimen collected from sentinel hospitals by districts were mapped by using Arcmap10.1.ResultsA total of 2631 acute HCV cases and 15,063 chronic HCV cases were reported in Shanghai from 2005 to 2018, with a peak in 2010 and 2017, respectively. The mean age of chronic HCV patients was 49.70 ± 14.55 years, 3.34 ± 0.32 years older than the acute (t = 10.55, P-value < 0.01). The spatial distribution of acute HCV infection formed one primary cluster (Relative Risk = 2.71), and the chronic formed one primary cluster and three secondary clusters with Relative Risk ranged from 1.94 to 14.42, meanwhile, an overlap of 34 communities between acute and chronic HCV clusters were found with time period spans varied from 6 to 12 years. Genotype 1 (N = 257, 49.71%) was the most prevalent HCV genotype in Shanghai, genotype 3 infections have increased in recent years. Baoshan district presented cluster of acute HCV and the highest proportion of genotype 2, Pudong new area was the cluster of chronic HCV and occupied the highest proportion of genotype 3.ConclusionsDespite the low prevalence of HCV infection, it is still needed to push forward the elimination process in Shanghai, as there is a certain amount of HCV infected people waiting to be treated. The time-spatial clustering patterns and the dynamic of HCV genotype distribution together indicated a changing constitution of different transmission routes of HCV infection, thus, a focused strategy may be needed for high-risk population related to genotype 3 infection like drug users, in addition to an enforcement of the existing measures of preventing the iatrogenic and hematogenic transmission of HCV.

Direct-acting antiviral regimens in Egyptian patients with chronic hepatitis C virus infection: A real-world single-center experience

Background and study aims:Chronic hepatitis C virus (HCV) infection has always been identified as a major health threat and a potential cause of liver cirrhosis, portal hypertension, and other associated problems. The introduction of direct-acting antiviral agents (DAAs) has represented a paradigm shift in HCV management. In this study, we aim to observe the rate of sustained virologic response (SVR12) in a large scale of patients at a single center as well as record the post-treatment changes in the hematologic, hepatic, and renal biochemical profiles. Patients and methodsIn total, 1933 chronic HCV genotype 4 mono-infected non-HCC patients who completed the treatment with six different DAA regimens in the Faculty of Medicine, Ain Shams University Research Institute (MASRI), were retrospectively enrolled in this study. The rate of sustained virologic response after 12 weeks off-therapy (SVR12) was assessed. The baseline characteristics to predict the SVR12 were then analyzed. The post-treatment changes in many profiles were recorded and analyzed. ResultsThe overall SVR12 rate was 96.2% (after excluding 84 cases who were lost to follow-up). It was achieved in 346/375 patients (92.3%), 466/477 patients (97.7%), 60/62 patients (96.8%), 11/11 patients (100%), 532/545 patients (97.6%), and 445/463 patients (96.1%) who received sofosbuvir/daclatasvir (SOF/DCV), sofosbuvir/daclatasvir/ribavirin (SOF/DCV/RBV), sofosbuvir/ledipasvir (SOF/LDV), sofosbuvir/ledipasvir/ribavirin (SOF/LDV/RBV), sofosbuvir/simeprevir (SOF/SMV), and ombitasvir/paritaprevir/ritonavir/ribavirin (OBV/PTV/r + RBV), respectively. In total, 73 patients (3.8%) failed to achieve SVR12. The baseline aspartate aminotransferase (AST), cirrhotic status, and treatment regimen were determined to have a significant impact on SVR12. In the overall treated population, the levels of serum AST, alanine aminotransferase, albumin, creatinine, bilirubin, and hemoglobin and platelet count improved significantly after treatment. Furthermore, sustained virologic response was strongly related to cirrhosis and its degree. ConclusionThe interferon-free DAA regimens offered high SVR12 rates in Egyptian patients with chronic HCV infection. They were associated with a significant improvement in the hematologic, hepatic, and renal biochemical profiles. The baseline AST, liver cirrhosis, and treatment regimen might have an impact on achieving SVR.

The effect of direct acting antiviral agents on vascular endothelial function in Egyptian patients with chronic hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is correlated with cerebrovascular and cardiovascular disease (CVD). This study aimed to assess the effect of treatment with DAAs on vascular endothelial function in cirrhotic and non-cirrhotic HCV infected patients without any CVD risk factors. Fifty chronic HCV genotype 4 infected patients, without cardiovascular risks who have been listed to receive sofosbuvir/daclatasvir with ribavirin combination as triple therapy for 3 months were prospectively recruited. Endothelial dysfunction markers as soluble vascular cell adhesion molecule-1 (sVCAM-1) and Von willebrand factor (vWf) and inflammation marker (IL6) were estimated at baseline and 3 months post the end of therapy (SVR). All patients achieved SVR. VCAM1 level was significantly improved after HCV clearance with DAA in cirrhotic HCV patients (P = 0.002) compared to patients with mild liver fibrosis (P = 0.006). Levels of vWF also decreased significantly in cirrhosis and non-cirrhosis groups after SVR (P < 0.001 and P = 0.011, respectively). Systemic inflammatory marker (IL6) showed significant decrease in cirrhotic patients (P = 0.001). While, IL6 level did not change significantly in non-cirrhotic group (P = 0.061). Also at SVR, noninvasive liver fibrosis indices have been reduced significantly in the two groups (P < 0.001). HCV clearance by new DAA treatment improves the vascular endothelial dysfunction in Egyptian HCV infected patients with different levels of liver fibrosis and with no risk factors for endothelial dysfunction or CVD.

Primary hyperoxaluria as an indication of liver and kidney transplantation: Case report and literature review

Primary Hyperoxaluria (PH) is a metabolic liver disease that results in oxalate overproduction that cannot be metabolized by the liver [1]. PH is caused by mutations in one of three genes that encode enzymes involved in glyoxylate metabolism. As oxalate is primarily excreted in the urine, the kidney is the prime target for oxalate deposition, which leads to end-stage kidney disease [2]. A patient named MN with Nephrocalcinosis (NC) was referred to the Children`s Memorial Health Institute of Warsaw in early childhood. The patient was diagnosed with PH type 1. PH type 1 is caused by mutations in a gene called AGXT that encodes alanine-glyoxylate aminotransferase. This enzyme is found in hepatic peroxisomes. It converts a compound called glyoxylate to the amino acid glycine [3]. In 02.12.1996, at the age of 13 the patient received a first kidney transplant from family member. In 16/09/1998 graftectomy was performed due to rapidly progressive kidney failure, nephrocalcinosis and infections. The patient had to return to hemodialysis after renal allograft loss. Also the patient was diagnosed with chronic HCV genotype 4 infection in 1998. In 08.11.2002, at the age of 19, the patient was qualified for a simultaneous liver and second kidney transplantation due to primary hyperoxaluria. The patient was treated with combination of: Daclizumab, steroid, tacrolimus, mycophenolate mofetil. Since October, 2015 the patient had been treating with combination of ombitasvir, paritaprevir, ribavirin and ritonavir. Hepatitis C Virus (HCV) was successfully eliminated. Patients with kidney failure from primary hyperoxaluria type 1 should not undergo kidney transplantation alone due to the very high risk of recurrence. Combined liver and kidney transplantation is the treatment of choice [4]. Keywords: Primary hyperoxaluria; kidney insufficiency; kidney transplantation; combined liver; kidney transplantation.

Presence of interferon-λ 4, male gender, absent/mild steatosis and low viral load augment antibody levels to hepatitis C virus

Objectives Despite recombinant interferon-λ 4 (IFN-λ4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-λ4 may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). Materials and methods Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. Results Patients producing IFN-λ4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-λ4 (IFNL4 rs12979860 CT/TT versus CC, p<.0001, Mann–Whitney U-test). Additionally, in univariate analyses S/CO was significantly higher in men than women (p<.001), as well as in patients with absent/mild interface hepatitis (Ishak grade 0–2 versus 3–4, p = .009), and absent/mild steatosis (grade 0–1 versus 2–3, p = .0005). Also, an inverse correlation with HCV RNA level (rs = −0.14, p = .02) was noted. In multivariate analysis IFN-λ4, gender, steatosis and viral load remained independently associated. Conclusions To our knowledge, this is the first report that demonstrates that the ability to produce IFN-λ4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-λ4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection. ClinicalTrials.gov Identifier: NCT00143000

Efficacy and Safety of Ombitasvir plus Paritaprevir, Ritonavir and Ribavirin in Non-cirrhotic Treatment-naïve and Treatment-experienced Egyptians with Chronic HCV Genotype-4 Infection.

Hepatitis C virus genotype 4 (HCV-GT4) is a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. A combination of three new direct-acting antivirals ombitasvir, paritaprevir, and ritonavir has been recommended for treatment of HCV-GT4 infection. The current study was aimed to assess the efficacy and safety of this combination plus ribavirin in non-cirrhotic, treatment-naïve and -experienced Egyptians with HCV-GT4 infection in a real-world setting. A total of 255 Egyptians with HCV-GT4 infection were enrolled, including 82 treatment-experienced and 173 treatment-naïve patients. All of them completed 12-week treatment protocol of ombitasvir, paritaprevir and ritonavir as an oral dose combination with ribavirin. Virological response (VR) was measured, as well as the biochemical parameters related to treatment efficacy and adverse events at baseline and after treatment, at 4 (VR4) and 12 (VR12) weeks post-treatment. The results showed that the VR4 rates were 98.8% in both groups, and VR12 rates were 97.7% and 96.3% in treatment-naïve and -experienced patients, respectively, with no significant differences found between the groups concerning VR4 (P=0.9) and VR12 (P=0.3). The most common adverse events were headache and fatigue, which were significantly more common (P=0.001 and 0.003, respectively) in treatment-experienced than in treatment-naïve group. The quadruple regimen was well-tolerated, and the reported adverse events were generally mild to moderate. This real-world setting study confirms that the combination of ombitasvir, paritaprevir, ritonavir, and ribavirin is highly effective in the treatment of HCV- GT4 infection with a good safety and tolerability profile.

Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial

In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

Effectiveness of retreatment with ombitasvir/paritaprevir/ritonavir anddasabuvir+sofosbuvir+ribavirin in patients with chronic hepatitis C, subtype 1b, and cirrhosis, who failed previoustreatment 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 failedprevious treatment with second-generation NS5A inhibitors (n = 11). Retreatment with 3D + SOF + RBV was highly effective and safe in patients with chronic HCV GT1b infection, including those with liver cirrhosis, who failedprevious treatment withDAA containing NS5A inhibitors. Fibrosis stage and single or simultaneous presence of NS5A RASs L31M/V/I and Y93H at the baseline, as well as the generation of previously used NS5A inhibitors, did not impact SVR12 rates.