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Bovine herpesvirus 4 (BoHV-4) is an indigenous virus in cattle prevalent mainly in North and South American countries and European countries, but the genomic sequences and genetic characteristics of Japanese strains have not been reported. BoHV-4 is suspected, but not proven, to be associated with various diseases. In the present study, we isolated BoHV-4 from a 10-month-old Japanese Black calf with respiratory symptoms in Japan. To identify the genetic characteristics of the isolate named strain SG20, complete genome sequencing was performed using a combination of next-generation and Sanger sequencing technologies. The complete long unique coding region (LUR) of SG20 was found to comprise 108,819 nucleotides with 41.4% GC content and contain at least 78 open reading frames. It shares 83.4 to 99.3% overall nucleotide identity with six BoHV-4 strains available in the database. The deduced amino acid sequence alignment revealed that SG20 contains genotype 1-specific features of BoHV-4, such as amino acid substitutions and insertions within the glycoprotein B region. Phylogenetic analyzes based on the nucleotide sequences of ORF20 indicated that the virus belonged to genotype 1 (Movar 33/63-like group). The strain was also analyzed using the complete LUR and placed in the same clade as a strain recently isolated from China, but it was distinct from American and European BoHV-4 strains of genotype 1. Although further genomic and epidemiologic information is needed, our results help elucidate the molecular epidemiology of BoHV-4 and provide a foundation for future studies. [ABSTRACT FROM AUTHOR]

The hepatitis E virus (HEV) is infecting over 20 million people annually with a high morbidity especially in pregnant women and immune-suppressed individuals. While HEV genotype 1 (HEV-1) infects only humans, genotype 3 (HEV-3) is zoonotic and commonly transmitted from infected animals to humans. Whereas a few reverse genetics systems enabling targeted genome manipulations exist for HEV-3, those for HEV-1 are still very limited, mainly because of inefficient cell culture replication. Here, the generation of HEV-1 strain Sar55 and HEV-3 strain 47832mc by transfecting in vitro-transcribed and capped virus genomes into different cell lines was attempted. Culture supernatants of colon-derived colorectal adenocarcinoma cell line Caco-2 contained HEV-1 and HEV-3 capable of infecting Caco-2 cells. Density gradient centrifugation analyses of culture supernatants confirmed that HEV-1 particles were quasi-enveloped in analogy to HEV-3 and that non-virion-associated capsid protein was secreted from cells. Following transfection or infection of Caco-2 cells, HEV-1 consistently reached higher titers than HEV-3 in culture supernatants, but HEV-1 generated by transfection of Caco-2 cells was unable to efficiently infect hepatoma cell lines PLC/PRF/5 or HuH7-Lunet BLR. Taken together, our results indicate that HEV-1 is able to exert a complete replication cycle in Caco-2 cells. An efficient cell culture system for this genotype will be useful for studying species tropism, but further research is required to determine the significance of HEV-1 replication in colon-derived cells.

Japanese encephalitis virus (JEV) is a pathogen responsible for high mortality and morbidity rates among children with encephalitis. Since JEV genotype 1 (GI) is the most prevalent strain in South Korea these days, corresponding research and vaccine development is urgently required. Molecular genetic studies on JEV vaccines can be boosted by obtaining genetically stable full-length infectious JEV complementary DNA (cDNA) clones. Furthermore, the significance of the reverse genetics system in facilitating molecular biological analyses of JEV properties has been demonstrated. This study constructed a recombinant JEV-GI strain using a reverse genetics system based on a Korean wild-type GI isolate (K05GS). RNA extracted from JEV-GI was used to synthesize cDNA, a recombinant full-length JEV clone, pTRE-JEVGI, was generated from the DNA fragment, and the virus was rescued. We performed in vitro and in vivo experiments to analyze the rescued JEV-GI virus. The rescued JEV-GI exhibited similar characteristics to wild-type JEV. These results suggest that our reverse genetics system can generate full-length infectious clones that can be used to analyze molecular biological factors that influence viral properties and immunogenicity. Additionally, it may be useful as a heterologous gene expression vector and help develop new strains for JEV vaccines.

Background: At the moment, there is no vaccine for the hepatitis C virus (HCV), despite it being more infectious than the hepatitis B virus (HBV) and the human immunodeficiency virus (HIV). Existing drugs based on protease and polymerase inhibitors present adverse clinical outcomes, sparking the search for alternatives. Medicinal plants contain bioactive compounds that hold great promise. Thus, the present study was aimed at evaluating the druggability of bioactive compounds implicated in folk medicine in the management of HCV against RNA-directed RNA polymerase (RdRp). Methods: Traditional healers involved in the management of hepatitis were consulted, and they suggested the use of leaves of Vernonia amygdalina, Jatropha tanjorensis, Annona muricata, and Solanum nigrum (berries too) in the management of hepatitis. The collection of plant parts and phytochemical screening via gas chromatography-mass spectrophotometer (GC–MS) were carried out. Resulting bioactive compounds and a control HCV drug, remdesivir, were screened for ADMET properties using the pkCSM online prediction tool, while molecular docking was performed using AutoDockTool 1.5.6 and the resulting interactions visualised in 2-Dimension using Discovery Studio 2022 Client. Results: GC–MS analysis of the medicinal plants revealed 60 bioactive compounds, of which 15 did not violate Lipinski's rule of five and 2 returned only one violation, while the control drug returned two violations. All the ligands were not inhibitors of CYP1A2, CYP2C19, CYPCC9, CYPAD6, and CYP3A4, except for 1,3-dihydrobenzo-[c]thiophen, docosahexaenoic acid, and benzonitrile N-oxide, which were inhibitors of CYP1A2. The intestinal absorption rates of the various ligands (73.56–100 %) were better than those of remdesivir, with an intestinal absorption rate of 67.15 %. Docking analysis revealed scores that ranged from -4.3 to -8.0 k/cal for the ligands, while the score for remdesivir was -9.0 k/cal. Eight ligands and remdesivir interacted with both the finger and palm regions, while one ligand interacted with the finger and thumb regions. Others interacted either with the finger (n = 5) or palm (n = 3) regions. These various interactions have the potential to alter the structural integrity and conformation of the RdRp protein and, in the process, interfere with its role in replication. Conclusion: The findings indicate that the selected medicinal plants possess bioactive compounds that hold great promise for the development of newer and safer nucleoside inhibitors against HCV. Given the high diversity of the virus, there may be a need to expand the scope of genotype-specific treatment regimens using bioactive compounds from medicinal plants. List of Abbreviations and Units: AA, Amino Acid; HCV, Hepatitis C Virus; HBV, Hepatitis B Virus; GC–MS, Gas chromatograph-mass spectrophotometer; MD, Molecular docking; PDB, Protein Data Bank; RdRp, RNA directed RNA polymerase; RNA, Ribonucleic Acid; HIV, Human Immunodeficiency virus; NIST, National Institute of Standards and Technology; WHO, World Health Organization

Impaired renal functions have been reported with Hepatitis E virus (HEV) infections, especially with genotypes 3 and 4. These complications were reported during the acute and chronic phases of infection. HEV genotype 1 causes acute infection, and the effect of HEV-1 infections on renal functions is not known. We examined the kidney function parameters in the serum of HEV-1 patients (AHE, n = 31) during the acute phase of infection. All of the included patients developed an acute self-limiting course of infection, without progression to fulminant hepatic failure. We compared the demographic, laboratory, and clinical data between AHE patients with normal kidney function parameters and those with abnormal renal parameters. Out of 31 AHE patients, 5 (16%) had abnormal kidney function tests (KFTs) during the acute phase of infection. Three patients had abnormal serum urea and creatinine, and two patients had either abnormal urea or creatinine. Four out of five patients had an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2. AHE patients with abnormal KFTs were older and had a lower level of albumin, but a slightly elevated alanine transaminase (ALT) compared to AHE patients with normal KFTs. There were no significant differences between the two groups in terms of age, sex, liver transaminase levels, and the viral load. Similarly, the clinical presentations were comparable in both groups. Interestingly, these KFTs in patients with abnormal renal parameters returned to normal levels at the recovery. The serum creatinine level was not correlated with patients' age or liver transaminase levels, but it was significantly negatively correlated with albumin level. In conclusion, this study is the first report that evaluated KFTs in patients during the acute phase of HEV-1 infections. Impaired KFTs in some AHE patients resolved at convalescence. KFTs and renal complications should be monitored during HEV-1 infections. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis globally. Genotype 1 HEV (HEV-1) is responsible for multiple outbreaks in developing countries, causing high mortality rates in pregnant women. However, studies on HEV-1 have been hindered by its poor replication in cultured cells. The JE04-1601S strain recovered from a Japanese patient with fulminant hepatitis E who contracted HEV-1 while traveling to India was serially passaged 12 times in human cell lines. The cell-culture-generated viruses (passage 12; p12) grew efficiently in human cell lines, but the replication was not fully supported in porcine cells. A full-length cDNA clone was constructed using JE04-1601S_p12 as a template. It was able to produce an infectious virus, and viral protein expression was detectable in the transfected PLC/PRF/5 cells and culture supernatants. Consistently, HEV-1 growth was also not fully supported in the cell culture of cDNA-derived JE04-1601S_p12 progenies, potentially recapitulating the narrow tropism of HEV-1 observed in vivo. The availability of an efficient cell culture system for HEV-1 and its infectious cDNA clone will be useful for studying HEV species tropism and mechanisms underlying severe hepatitis in HEV-1-infected pregnant women as well as for discovering and developing safer treatment options for this condition. [ABSTRACT FROM AUTHOR]

Genotype 1 hepatitis E virus (HEV-1), unlike other genotypes of HEV, has a unique small open reading frame known as ORF4 whose function is not yet known. ORF4 is located in an out-framed manner in the middle of ORF1, which encodes putative 90 to 158 amino acids depending on the strains. To explore the role of ORF4 in HEV-1 replication and infection, we cloned the complete genome of wild-type HEV-1 downstream of a T7 RNA polymerase promoter, and the following ORF4 mutant constructs were prepared: the first construct had TTG instead of the initiation codon ATG (A2836T), introducing an M→L mutation in ORF4 and a D→V mutation in ORF1. The second construct had ACG instead of the ATG codon (T2837C), introducing an M→T mutation in ORF4. The third construct had ACG instead of the second in-frame ATG codon (T2885C), introducing an M→T mutation in ORF4. The fourth construct contained two mutations (T2837C and T2885C) accompanying two M→T mutations in ORF4. For the latter three constructs, the accompanied mutations introduced in ORF1 were all synonymous changes. The capped entire genomic RNAs were generated by in vitro transcription and used to transfect PLC/PRF/5 cells. Three mRNAs containing synonymous mutations in ORF1, i.e., T2837CRNA, T2885CRNA, and T2837C/T2885CRNA, replicated normally in PLC/PRF/5 cells and generated infectious viruses that successfully infected Mongolian gerbils as the wild-type HEV-1 did. In contrast, the mutant RNA, i.e., A2836TRNA, accompanying an amino acid change (D937V) in ORF1 generated infectious viruses upon transfection, but they replicated slower than the wild-type HEV-1 and failed to infect Mongolian gerbils. No putative viral protein(s) derived from ORF4 were detected in the wild-type HEV-1- as well as the mutant virus-infected PLC/PRF/5 cells by Western blot analysis using a high-titer anti-HEV-1 IgG antibody. These results demonstrated that the ORF4-defective HEV-1s had the ability to replicate in the cultured cells, and that these defective viruses had the ability to infect Mongolian gerbils unless the overlapping ORF1 was accompanied by non-synonymous mutation(s), confirming that ORF4 is not essential in the replication and infection of HEV-1. [ABSTRACT FROM AUTHOR]

• Lack of efficient HEV-1 cell culture systems hinders research. • Comparison of revere genetics approaches for the generation of HEV-1 and HEV-3. • HEV-1 strain Sar55 replicates efficiently in colon-derived Caco-2 cells. • Robust reverse genetics system enables investigation of many aspects of HEV-1. The hepatitis E virus (HEV) is infecting over 20 million people annually with a high morbidity especially in pregnant women and immune-suppressed individuals. While HEV genotype 1 (HEV-1) infects only humans, genotype 3 (HEV-3) is zoonotic and commonly transmitted from infected animals to humans. Whereas a few reverse genetics systems enabling targeted genome manipulations exist for HEV-3, those for HEV-1 are still very limited, mainly because of inefficient cell culture replication. Here, the generation of HEV-1 strain Sar55 and HEV-3 strain 47832mc by transfecting in vitro -transcribed and capped virus genomes into different cell lines was attempted. Culture supernatants of colon-derived colorectal adenocarcinoma cell line Caco-2 contained HEV-1 and HEV-3 capable of infecting Caco-2 cells. Density gradient centrifugation analyses of culture supernatants confirmed that HEV-1 particles were quasi-enveloped in analogy to HEV-3 and that non-virion-associated capsid protein was secreted from cells. Following transfection or infection of Caco-2 cells, HEV-1 consistently reached higher titers than HEV-3 in culture supernatants, but HEV-1 generated by transfection of Caco-2 cells was unable to efficiently infect hepatoma cell lines PLC/PRF/5 or HuH7-Lunet BLR. Taken together, our results indicate that HEV-1 is able to exert a complete replication cycle in Caco-2 cells. An efficient cell culture system for this genotype will be useful for studying species tropism, but further research is required to determine the significance of HEV-1 replication in colon-derived cells. [ABSTRACT FROM AUTHOR]

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA-positive donor organs are typically not given to patients who have cleared HCV. A 64-year-old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA

Introduction: Non-cirrhotic treatment-naive hepatitis C patients infected with genotype 1 can be treated with ledipasvir/sofosbuvir (LDV/SOF) for 8 weeks, but in practice this regimen is frequently extended up to 12 weeks at least in part due to insufficient real-world data supporting shortening of treatment. The aim of our study was to compare 8- and 12-week regimens’ efficacy in patients eligible for 8-week therapy in a real-world setting. Material and methods: Data of HCV genotype 1 infected patients treated with LDV/SOF between 2015 and 2018 included in the EpiTer-2 database were analyzed with respect to patients’ characteristics and length of treatment. Results: Among a total of 1718 patients treated with LDV/SOF, 679 were included in the analysis, 238 (35%) received 8-week regimen, whereas 441 were treated for 12 weeks although they fulfilled the criteria for a shorter course. The majority of patients were infected with genotype 1b (89%) and demonstrated minimal fibrosis (55%). The 12-week regimen was assigned significantly more frequently to patients with comorbidities, concomitant medications and advanced liver fibrosis. The sustained virologic response rate was similar after 8 (98%) and 12 (97%) weeks of therapy according to intent-to-treat analysis and reached 99% in both groups after exclusion of patients lost to follow-up. Conclusions: We confirmed high effectiveness regardless of treatment duration with LDV/SOF in non-cirrhotics infected with HCV genotype 1 eligible for the 8-week regimen according to the current label. This real-world study also demonstrated no need for addition of ribavirin (RBV) in this population and showed that shortening of treatment significantly improves the safety profile of LDV/SOF medication. [ABSTRACT FROM AUTHOR]

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ABSTRACT Background and Aim Ropeginterferon alfa‐2b (P1101) is a novel long‐acting mono‐PEGylated recombinant proline interferon (IFN) conjugated to a 40 kDa branched polyethylene glycol (PEG) chain at its N‐terminus, allowing every‐two‐week injection. It received European Medicines Agency and Taiwan marketing authorization for the treatment of polycythemia vera in 2019 and 2020, respectively. This phase 2 study aimed to evaluate the pharmacokinetics, safety, and preliminary efficacy of ropeginterferon alfa‐2b as compared with PEG‐IFN‐α2a in patients with chronic hepatitis C virus genotype 1 infection. Methods One hundred six treatment naive patients were enrolled in this phase 2 study and randomized to four treatment groups: subcutaneous weekly PEG‐IFN‐α2a 180 μg (group 1), weekly ropeginterferon alfa‐2b 180 μg (group 2), weekly ropeginterferon alfa‐2b 270 μg (group 3), or biweekly ropeginterferon alfa‐2b 450 μg (group 4) plus ribavirin for 48 weeks. Results After multiple weekly administration, serum exposure (AUC0‐τ) in ropeginterferon alfa‐2b 180 μg was approximately 41% greater and the accumulation ratio of 2‐fold greater than PEG‐IFN‐α2a 180 μg. The incidences of flu‐like symptoms were 66.7% (18/27), 53.3% (16/30), 55.0% (11/20), and 48.3% (14/29), anxiety were 14.8% (4/27), 6.7% (2/30), 0%, and 0%, and depression were 25.9% (7/27), 13.3% (4/30), 0%, and 3.4% (1/29), for groups 1–4, respectively. Two grade 2 of 3 depression were noted in PEG‐IFN‐α2a arm, but none in ropeginterferon arms. The SVR24 rates were 77.8% (21/27), 66.7% (20/30), 80% (16/20), and 69% (20/29), respectively. Conclusions Ropeginterferon alfa‐2b showed longer effective half‐life and superior safety profile than PEG‐IFN‐α2a. Biweekly injection of ropeginterferon alfa‐2b will be studied in larger viral hepatitis patient population.

Background & aims: Treatment of hepatitis C virus (HCV) by elbasvir/grazoprevir (EBR/GZR) was found to be efficacious and well tolerated in clinical trials. This study aimed to evaluate the effectiveness and tolerability of EBR/GZR in the treatment of HCV genotype 1-infected Taiwanese patients. Methods: Chronic hepatitis C patients infected with GT1b or 1a without resistance-associated substitution, and treated with 12-week EBR/GZR were enrolled from 10 hospitals in Taiwan between August 2017 and December 2018. All clinical and virologic data were collected at each participating center. Primary efficacy endpoint was sustained virologic response at week 12 (SVR12) after end of the EBR/GZR therapy, assessed in the per-protocol population, which excluded patients with important deviations from the protocol. Analysis was also performed based on the modified full analysis set, which included all allocated patients receiving at least 4-week medication. Virologic failure was recorded as breakthrough, nonresponse, or relapse. Safety was assessed through collection of adverse events, physical examination, vital signs, and standard laboratory evaluations. Results: Per protocol SVR12 rates were 99.5% (1169/1175) for all HCV genotype 1 patients. Among patients with stage 4 or 5 chronic kidney diseases, 100% (107/107) achieved SVR12. In univariate analyses, variables associated with SVR12 were treatment termination (P

Impaired renal functions have been reported with Hepatitis E virus (HEV) infections, especially with genotypes 3 and 4. These complications were reported during the acute and chronic phases of infection. HEV genotype 1 causes acute infection, and the effect of HEV-1 infections on renal functions is not known. We examined the kidney function parameters in the serum of HEV-1 patients (AHE, n = 31) during the acute phase of infection. All of the included patients developed an acute self-limiting course of infection, without progression to fulminant hepatic failure. We compared the demographic, laboratory, and clinical data between AHE patients with normal kidney function parameters and those with abnormal renal parameters. Out of 31 AHE patients, 5 (16%) had abnormal kidney function tests (KFTs) during the acute phase of infection. Three patients had abnormal serum urea and creatinine, and two patients had either abnormal urea or creatinine. Four out of five patients had an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2. AHE patients with abnormal KFTs were older and had a lower level of albumin, but a slightly elevated alanine transaminase (ALT) compared to AHE patients with normal KFTs. There were no significant differences between the two groups in terms of age, sex, liver transaminase levels, and the viral load. Similarly, the clinical presentations were comparable in both groups. Interestingly, these KFTs in patients with abnormal renal parameters returned to normal levels at the recovery. The serum creatinine level was not correlated with patients’ age or liver transaminase levels, but it was significantly negatively correlated with albumin level. In conclusion, this study is the first report that evaluated KFTs in patients during the acute phase of HEV-1 infections. Impaired KFTs in some AHE patients resolved at convalescence. KFTs and renal complications should be monitored during HEV-1 infections.

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis globally. Genotype 1 HEV (HEV-1) is responsible for multiple outbreaks in developing countries, causing high mortality rates in pregnant women. However, studies on HEV-1 have been hindered by its poor replication in cultured cells. The JE04-1601S strain recovered from a Japanese patient with fulminant hepatitis E who contracted HEV-1 while traveling to India was serially passaged 12 times in human cell lines. The cell-culture-generated viruses (passage 12; p12) grew efficiently in human cell lines, but the replication was not fully supported in porcine cells. A full-length cDNA clone was constructed using JE04-1601S_p12 as a template. It was able to produce an infectious virus, and viral protein expression was detectable in the transfected PLC/PRF/5 cells and culture supernatants. Consistently, HEV-1 growth was also not fully supported in the cell culture of cDNA-derived JE04-1601S_p12 progenies, potentially recapitulating the narrow tropism of HEV-1 observed in vivo. The availability of an efficient cell culture system for HEV-1 and its infectious cDNA clone will be useful for studying HEV species tropism and mechanisms underlying severe hepatitis in HEV-1-infected pregnant women as well as for discovering and developing safer treatment options for this condition.

Genotype 1 hepatitis E virus (HEV-1), unlike other genotypes of HEV, has a unique small open reading frame known as ORF4 whose function is not yet known. ORF4 is located in an out-framed manner in the middle of ORF1, which encodes putative 90 to 158 amino acids depending on the strains. To explore the role of ORF4 in HEV-1 replication and infection, we cloned the complete genome of wild-type HEV-1 downstream of a T7 RNA polymerase promoter, and the following ORF4 mutant constructs were prepared: the first construct had TTG instead of the initiation codon ATG (A2836T), introducing an M→L mutation in ORF4 and a D→V mutation in ORF1. The second construct had ACG instead of the ATG codon (T2837C), introducing an M→T mutation in ORF4. The third construct had ACG instead of the second in-frame ATG codon (T2885C), introducing an M→T mutation in ORF4. The fourth construct contained two mutations (T2837C and T2885C) accompanying two M→T mutations in ORF4. For the latter three constructs, the accompanied mutations introduced in ORF1 were all synonymous changes. The capped entire genomic RNAs were generated by in vitro transcription and used to transfect PLC/PRF/5 cells. Three mRNAs containing synonymous mutations in ORF1, i.e., T2837CRNA, T2885CRNA, and T2837C/T2885CRNA, replicated normally in PLC/PRF/5 cells and generated infectious viruses that successfully infected Mongolian gerbils as the wild-type HEV-1 did. In contrast, the mutant RNA, i.e., A2836TRNA, accompanying an amino acid change (D937V) in ORF1 generated infectious viruses upon transfection, but they replicated slower than the wild-type HEV-1 and failed to infect Mongolian gerbils. No putative viral protein(s) derived from ORF4 were detected in the wild-type HEV-1- as well as the mutant virus-infected PLC/PRF/5 cells by Western blot analysis using a high-titer anti-HEV-1 IgG antibody. These results demonstrated that the ORF4-defective HEV-1s had the ability to replicate in the cultured cells, and that these defective viruses had the ability to infect Mongolian gerbils unless the overlapping ORF1 was accompanied by non-synonymous mutation(s), confirming that ORF4 is not essential in the replication and infection of HEV-1.

The Hepatitis C virus (HCV) infection is a public health problem. The high level of HCV replication and its lack of post-transcriptional correction mechanisms results in the emergence of viral variants and the difficulty in determining polymorphisms and variants that contain the substitutions associated with resistance towards new antivirals. The main focus of this study was to map the NS5A and NS5B polymorphisms and resistance mutations to new antiviral drugs in HCV strains genotype 1 from patients with chronic hepatitis C infection. Serum samples were collected from patients who underwent routine viral load tests at the Instituto Adolfo Lutz, Sao Paulo city, Brazil. A total of 698 and 853 samples were used for the characterization of NS5A and NS5B regions, respectively, which comprise the HCV genotypes 1a and 1b. The prevalence of resistance mutations found in the NS5A region was 6.4%, with Y93H, L31M, Q30R, and Y93N as the main resistance-associated substitutions (RAS). No NS5B-associated RAS was observed for any of the analyzed drugs. These findings support that the RAS test should be offered to individuals with poor response to double combination regimens prior to treatment initiation, thereby assisting strain vigilance and selection of effective treatment or retreatment options using DAA regimens. [ABSTRACT FROM AUTHOR]

Japanese encephalitis virus (JEV) is a pathogen responsible for high mortality and morbidity rates among children with encephalitis. Since JEV genotype 1 (GI) is the most prevalent strain in South Korea these days, corresponding research and vaccine development is urgently required. Molecular genetic studies on JEV vaccines can be boosted by obtaining genetically stable full-length infectious JEV complementary DNA (cDNA) clones. Furthermore, the significance of the reverse genetics system in facilitating molecular biological analyses of JEV properties has been demonstrated. This study constructed a recombinant JEV-GI strain using a reverse genetics system based on a Korean wild-type GI isolate (K05GS). RNA extracted from JEV-GI was used to synthesize cDNA, a recombinant full-length JEV clone, pTRE-JEVGI, was generated from the DNA fragment, and the virus was rescued. We performed in vitro and in vivo experiments to analyze the rescued JEV-GI virus. The rescued JEV-GI exhibited similar characteristics to wild-type JEV. These results suggest that our reverse genetics system can generate full-length infectious clones that can be used to analyze molecular biological factors that influence viral properties and immunogenicity. Additionally, it may be useful as a heterologous gene expression vector and help develop new strains for JEV vaccines., Competing Interests: The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (© 2024 The Authors.)

Bovine herpesvirus 4 (BoHV-4) is an indigenous virus in cattle prevalent mainly in North and South American countries and European countries, but the genomic sequences and genetic characteristics of Japanese strains have not been reported. BoHV-4 is suspected, but not proven, to be associated with various diseases. In the present study, we isolated BoHV-4 from a 10-month-old Japanese Black calf with respiratory symptoms in Japan. To identify the genetic characteristics of the isolate named strain SG20, complete genome sequencing was performed using a combination of next-generation and Sanger sequencing technologies. The complete long unique coding region (LUR) of SG20 was found to comprise 108,819 nucleotides with 41.4% GC content and contain at least 78 open reading frames. It shares 83.4 to 99.3% overall nucleotide identity with six BoHV-4 strains available in the database. The deduced amino acid sequence alignment revealed that SG20 contains genotype 1-specific features of BoHV-4, such as amino acid substitutions and insertions within the glycoprotein B region. Phylogenetic analyzes based on the nucleotide sequences of ORF20 indicated that the virus belonged to genotype 1 (Movar 33/63-like group). The strain was also analyzed using the complete LUR and placed in the same clade as a strain recently isolated from China, but it was distinct from American and European BoHV-4 strains of genotype 1. Although further genomic and epidemiologic information is needed, our results help elucidate the molecular epidemiology of BoHV-4 and provide a foundation for future studies.

Hepatitis E, a significant global public health issue in China, is caused by sporadic infections with regional hepatitis E virus (HEV) genotypes 1, 3, and 4. To date, most immunoassays currently used to test human sera for the presence of anti-HEV antibodies cannot identify HEV at the genotype level. However, such information would be useful for identifying the source of infecting virus. Therefore, here we describe the development of a competitive enzyme-linked immunosorbent assay (ELISA) for detecting anti-genotype 1 HEV antibodies in human sera. Using recombinant genotype 1 HEV ORF3 protein as immunogen, traditional hybridoma technology was employed to generate seven monoclonal antibodies (mAbs), of which two mAbs specifically reacted with the immunogen. One of these two mAbs, 1D2, was labeled with horseradish peroxidase (HRP) for use in competitive ELISA (cELISA). After cELISA optimization using a checkerboard assay design, the amount of ORF3SAR−55 as coating antigen (100 ng/well), HRP-1D2 mAb concentration (1 μg/mL), and test serum dilution (1:10) were selected and a result ≥ 19.5 was used as the cutoff for a positive result. Importantly, cross-genotype cELISA results indicated that the cELISA could not detect anti-genotype 3 rabbit and 4 swine HEV antibodies. Moreover, human sera confirmed as negative for anti-HEV antibodies using the commercial ELISA kit were all negative via cELISA. However, because the commercial ELISA kit detects anti-all genotypes HEV antibodies and the cELISA only detects anti-genotype 1 HEV antibodies, the consistence rate of two assays detecting positive sera is low. In summary, here a cELISA for detecting anti-genotype 1 HEV antibodies was developed for use in epidemiological investigations of genotype 1 HEV infections in humans. Key points: • Seven mAbs were produced using genotype 1 HEV ORF3 protein as immunogen. • One mAb that specifically bound to genotype 1 HEV ORF3 protein was selected and labeled for use in a cELISA to detect anti-genotype 1 HEV antibodies. • The competitive ELISA developed here will aid clinical diagnosis of HEV infections and will be useful for large-scale serological testing of genotype 1 HEV infections in humans. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the dynamics and evolution of porcine reproductive and respiratory syndrome virus (PRRSV) genotype 1 following its introduction into a herd concurrently infected with both PRRSV genotypes. The results demonstrated that 2 novel genotype 1 groups emerged, termed clusters II and III. The emergence of cluster II suggested that this cluster of genotype 1 virus potentially correlated with the outbreak. Then, cluster III was detected with the disappearance of cluster II. The evolution of the genotype 1 virus from cluster II to cluster III is likely to be associated with immune evasion induced by amino acid substitutions at N-linked glycosylation sites. In contrast, evolution of the genotype 2 isolates was not observed. This result suggests that genotype 2 viruses were not affected by the emergence of the genotype 1 virus and each genotype developed independently. [ABSTRACT FROM AUTHOR]

Background and Aim: Ropeginterferon alfa‐2b (P1101) is a novel long‐acting mono‐PEGylated recombinant proline interferon (IFN) conjugated to a 40 kDa branched polyethylene glycol (PEG) chain at its N‐terminus, allowing every‐two‐week injection. It received European Medicines Agency and Taiwan marketing authorization for the treatment of polycythemia vera in 2019 and 2020, respectively. This phase 2 study aimed to evaluate the pharmacokinetics, safety, and preliminary efficacy of ropeginterferon alfa‐2b as compared with PEG‐IFN‐α2a in patients with chronic hepatitis C virus genotype 1 infection. Methods: One hundred six treatment naive patients were enrolled in this phase 2 study and randomized to four treatment groups: subcutaneous weekly PEG‐IFN‐α2a 180 μg (group 1), weekly ropeginterferon alfa‐2b 180 μg (group 2), weekly ropeginterferon alfa‐2b 270 μg (group 3), or biweekly ropeginterferon alfa‐2b 450 μg (group 4) plus ribavirin for 48 weeks. Results: After multiple weekly administration, serum exposure (AUC0‐τ) in ropeginterferon alfa‐2b 180 μg was approximately 41% greater and the accumulation ratio of 2‐fold greater than PEG‐IFN‐α2a 180 μg. The incidences of flu‐like symptoms were 66.7% (18/27), 53.3% (16/30), 55.0% (11/20), and 48.3% (14/29), anxiety were 14.8% (4/27), 6.7% (2/30), 0%, and 0%, and depression were 25.9% (7/27), 13.3% (4/30), 0%, and 3.4% (1/29), for groups 1–4, respectively. Two grade 2 of 3 depression were noted in PEG‐IFN‐α2a arm, but none in ropeginterferon arms. The SVR24 rates were 77.8% (21/27), 66.7% (20/30), 80% (16/20), and 69% (20/29), respectively. Conclusions: Ropeginterferon alfa‐2b showed longer effective half‐life and superior safety profile than PEG‐IFN‐α2a. Biweekly injection of ropeginterferon alfa‐2b will be studied in larger viral hepatitis patient population. [ABSTRACT FROM AUTHOR]

Introduction Non-cirrhotic treatment-naive hepatitis C patients infected with genotype 1 can be treated with ledipasvir/sofosbuvir (LDV/SOF) for 8 weeks, but in practice this regimen is frequently extended up to 12 weeks at least in part due to insufficient real-world data supporting shortening of treatment. The aim of our study was to compare 8- and 12-week regimens’ efficacy in patients eligible for 8-week therapy in a real-world setting. Material and methods Data of HCV genotype 1 infected patients treated with LDV/SOF between 2015 and 2018 included in the EpiTer-2 database were analyzed with respect to patients’ characteristics and length of treatment. Results Among a total of 1718 patients treated with LDV/SOF, 679 were included in the analysis, 238 (35%) received 8-week regimen, whereas 441 were treated for 12 weeks although they fulfilled the criteria for a shorter course. The majority of patients were infected with genotype 1b (89%) and demonstrated minimal fibrosis (55%). The 12-week regimen was assigned significantly more frequently to patients with comorbidities, concomitant medications and advanced liver fibrosis. The sustained virologic response rate was similar after 8 (98%) and 12 (97%) weeks of therapy according to intent-to-treat analysis and reached 99% in both groups after exclusion of patients lost to follow-up. Conclusions We confirmed high effectiveness regardless of treatment duration with LDV/SOF in non-cirrhotics infected with HCV genotype 1 eligible for the 8-week regimen according to the current label. This real-world study also demonstrated no need for addition of ribavirin (RBV) in this population and showed that shortening of treatment significantly improves the safety profile of LDV/SOF medication.

Georg von Massow,1 Damir Garcia-Cehic,1,2 Josep Gregori,1–3 Francisco Rodriguez-Frias,2,4 María Dolores Macià,5 Ana Escarda,6 Juan Ignacio Esteban,1–2,7 Josep Quer1–2,71Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut of Research (VHIR) – Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; 3Roche Diagnostics S.L., Sant Cugat del Vallès, Barcelona, Spain; 4Biochemistry and Microbiology Department, VHIR-HUVH, Barcelona, Spain; 5Unidad de Microbiología Molecular, Servicio de Microbiología, Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), Hospital Universitario Son Espases, Mallorca, Spain; 6Digestive Department, Hospital Universitario Son Espases, Mallorca, Spain; 7Medicine Department, Universitat Autònoma de Barcelona, Barcelona, SpainAbstract: Hepatitis C virus (HCV) is a highly variable infectious agent, classified into 8 genotypes and 86 subtypes. Our laboratory has implemented an in-house developed high-resolution HCV subtyping method based on next-generation sequencing (NGS) for error-free classification of the virus using phylogenetic analysis and analysis of genetic distances in sequences from patient samples compared to reference sequences. During routine diagnostic, a sample from an Equatorial Guinea patient could not be classified into any of the existing subtypes. The whole genome was analyzed to confirm that the new isolate could be classified as a new HCV subtype. In addition, naturally occurring resistance-associated substitutions (RAS) were analyzed by NGS. Whole-genome analysis based on p-distances suggests that the sample belongs to a new HCV genotype 1 subtype. Several RAS in the NS3 (S122T, D168E and I170V) and NS5A protein (Q(1b)24K, R(1b)30Q and Y93L+Y93F) were found, which could limit the use of some inhibitors for treating this subtype. RAS studies of new subtypes are of great interest for tailoring treatment, as no data on treatment efficacy are reported. In our case, the patient has not yet been treated, and the RAS report will be used to design the most effective treatment.Keywords: subtype, direct-acting antivirals, HCV, genotype 1

BackgroundWe hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons.MethodsProspective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR).ResultsAmong 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated.ConclusionWhereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.

Hepatitis E is one of the leading causes of acute viral hepatitis worldwide. Chronic infection with hepatitis E is less common and limited to immunosuppressed patients and is usually due to genotype 3 of the virus. Genotype 1, the most prevalent strain in the South Asian region, is seldom known to be associated with chronic hepatitis. Here we describe a case of chronic hepatitis E with genotype 1 in a post-liver transplant setting. In the index case, previously compensated cryptogenic cirrhosis was decompensated by an acute hepatitis E infection, which necessitated liver transplantation because of acute chronic liver failure. This later progressed to chronicity. This case may have significant implications in management, especially in the post-liver transplant setting. [ABSTRACT FROM AUTHOR]

Extrahepatic disorders are recorded with hepatitis E virus (HEV) infection. The impact of HEV infection on the male reproductive system is a query. In this study, we retrospectively analyzed semen from infertile men and prospectively examined the semen from acute hepatitis E patients (AHE) for HEV markers. HEV RNA and HEV Ag were not detectable in the semen of infertile men nor the semen of AHE patients. Although HEV markers were detectable in the urine of patients infected with HEV-1, these markers were absent in their semen. There is no significant difference in the level of reproductive hormones between AHE patients and healthy controls. Semen analysis of AHE patients did not show a notable abnormality and there was no significant difference in the semen quality and sperm characteristics between AHE and healthy controls. • HEV RNA was not detectable in the semen of infertile men. • The levels of sex hormones were comparable in acute HEV patients and healthy controls. • HEV markers were absent in the semen of acute HEV genotype 1 infected patients. • No abnormality was recorded in the semen of HEV infected patients. [ABSTRACT FROM AUTHOR]

Introduction and aim. Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an open-label multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection.Material and methods. All patients received coformulated OBV/ PTV/r daily + DSV twice daily (3-DAA). GTIa-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/ RBV nonresponders with cirrhosis who were treated for 24 weeks. GTIb-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12).Results. The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event.Discussion. The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

Background/Aims: Chronic hepatitis C (HCV) virus infection reactivates under immunosuppressive drugs and therefore has a negative impact on long-term survival of kidney transplant recipients. Treatment-induced clearance of hepatitis C virus (HCV) in kidney transplant candidates prevents virus reactivation after transplantation. Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (PrOD) represents a highly effective treatment regimen for HCV genotype 1 (GT1), also suitable for patients with end-stage renal disease (ESRD). Serious drug-drug interactions may represent a limiting factor of this regimen. The aim of this retrospective study was to evaluate safety, efficacy and drug-drug interactions management associated with PrOD treatment in the Czech real-world cohort. Methods: Emphasizing concomitant medication adjustment, we described the treatment course with PrOD regimen in 23 patients (4 with CKD4 and 19 on maintenance haemodialysis) infected with HCV GT1 (21 GT1b, 2 GT1a), 18 males and 5 females with an average age of 53.7 years. Six patients had compensated liver cirrhosis and 3 of them were liver transplant recipients. Results: All 23 patients completed the 12-week treatment and achieved sustained virological response 12 weeks after the treatment (SVR12 rate 100%). None of the patients presented with a significant decrease in haemoglobin level, white blood cell and platelet count during the treatment period. The most frequent adverse events were nausea, hypotension, diarrhoea, and hyperkalemia. Four patients presented with a serious adverse event unrelated to the antiviral drugs (salmonellosis, non-functional kidney graft rejection, early gastric cancer, renal cyst infection, initiation of haemodialysis). Concomitant medication had to be modified with the treatment initiation in 10 out of 23 (43.5%) patients (calcium channel blockers, ACE inhibitors, statins, diuretics, tacrolimus); four patients required further adjustment of antihypertensive drugs or tacrolimus dosage on-treatment. Conclusion: PrOD regimen demonstrated an excellent efficacy and good tolerability. Both prospective adjustment of concomitant medication and further on-treatment adjustment allowed for a safe treatment course.

Interferon-free therapy for genotype 1 hepatitis C is highly effective at any severity of liver fibrosis. The purpose of work was to assess cost-effectiveness and the budget impact of paritaprevir/ombitasvir/dasabuvir/ ritonavir (PTV/OBV/DSV/r) ± ribavirin therapy depending on time treatment initiation at different stages of liver fibrosis. Materials and methods. The cost-effectiveness analysis was performed from the payer perspective using a Markov model with a lifetime and 10-year time horizon for male patients at the age of 45 years. The budget impact analysis was performed with the horizon of 10 years. In base case the analysis of PTV/OBV/DSV/r costs was carried out on the basis of estimated price of registration including VAT and the average wholesaler extra charge taking into account population of the Russian Federation. During cost-effectiveness assessment life expectancy and costs have been discounted for 3,5% a year. The budget impact analysis was performed without discounting. Results. In the analysis with a lifetime horizon the costeffectiveness of PTV/OBV/DSV/RTV + ribavirin for patients with genotype 1a is 66,71–392,02 thousand rubles/QALY. For HCV genotype 1b therapy with PTV/OBV/DSV/RTV can dominate over lack of antiviral therapy (i.e. to lead to cost saving at increase in life expectancy) (at F2) or to be up to 204,22 thousand rubles/QALY (at F0). The cost-effectiveness of PTV/OBV/DSV/RTV ± ribavirin at the 10-year horizon for HCV patients with genotype 1a varies within 575,68-1424,15 thousand rubles/QALY, and for HCV patients with genotype 1b – within 350,05–871,46 thousand rubles/QALY. The budget impact of PTV/OBV/DSV/RTV ± ribavirin decreases in some cases at earlier purpose of antiviral therapy. So, PTV/OBV/DSV/RTV + ribavirin therapy for patients with HCV with fibrosis 3 stage (genotype 1a), decreases budget impact by 27,5% in comparison with its prescription only after development of the compensated cirrhosis. Conclusions. PTV/OBV/DSV/RTV ± ribavirin therapy of HCV (genotype 1) may be considered as economically highly effective therapy for patients with any severity of liver fibrosis

The combination of pegylated-interferon and ribavirin (PegIFN+RBV) is currently the gold standard in treating chronic hepatitis C virus (HCV) patients in Malaysia and is reimbursed by the Malaysian authorities. This analysis evaluated the cost-effectiveness (CE) of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (OBT/PTV/r+DSB±RBV) regimen as compared with the PegIFN+RBV or no treatment in chronic HCV Genotype 1 (GT1) treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia. A Markov model based on previously published CE models of HCV was adapted for the Malaysian public healthcare payer perspective, based on good modeling practices. Treatment attributes included efficacy, regimen duration, and EQ-5D treatment-related health utility. Transitional probabilities and health state health utilities were derived from previous studies. Costs were derived from Malaysian data sources. Costs and outcomes were discounted at 3.0% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties around key variables. Based on the analysis, patients treated with the OBT/PTV/r+DSB±RBV showed less frequent progression to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths when compared with standard care (ie, PegIFN+RBV or no treatment). At a price of MYR 1846/day, the OBT/PTV/r+DSB±RBV regimen is cost-effective over PegIFN+RBV and yields better outcomes in terms of life-years (LYs) gained and quality-adjusted life-years (QALYs) at a higher cost, which is still well below the implied willingness to pay threshold of MYR 384 503/QALY. The OBT/PTV/r+DSB±RBV regimen is cost-effective for treatment naïve, treatment experienced, cirrhotic, and noncirrhotic GT1 chronic HCV patients in Malaysia. • In Malaysia, only the combination of Pegylated-interferon and ribavirin (PegIFN+RBV) is reimbursed by the Malaysian authorities as the gold standard in treating chronic hepatitis C virus (HCV) patients. Although the favorable cost-effectiveness (CE) profile of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavarin (OBT/PTV/r+DSB±RBV) regimen compared with multiple standards of care has been documented worldwide, evidence from Malaysia is limited. • This analysis evaluated the CE of the OBT/PTV/r+DSB±RBV regimen compared with PegIFN+RBV or no treatment for chronic HCV genotype 1 for treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia. • This CE analysis reveals that the OBT/PTV/r+DSB±RBV regimen provides superior clinical outcomes versus the current standard of care in Malaysia (ie, PegIFN+RBV and no treatment) with fewer patients treated with the OBT/PTV/r+DSB±RBV regimen experiencing HCV-related complications of CC, DCC, HCC, and liver-related deaths. In turn, patients treated with the OBT/PTV/r+DSB± RBV regimen have a favorable CE profile with higher numbers of life-years (Lys) gained and quality-adjusted life-years (QALYs) than patients treated with standard of care. [ABSTRACT FROM AUTHOR]

Dientamoeba fragilis (D. fragilis) represents a common protozoan in both high and low income countries. Despite this, epidemiological data on dientamoebiasis are still limited, and it is possible that the actual prevalence rates of D. fragilis have been underestimated due to the challenges in its detection and identification. In the present study, symptomatic patients from Rome (Central Italy) were surveyed for two years to determine D. fragilis percentage of infection and genotypes. Stool samples collection was performed over 864 patients, DNA extracted, and RT-PCR performed by the SeeGene Allplex™ Gastrointestinal Parasite Panel Assays. Seventy-nine resulted positive for D. fragilis (9.1%). Co-infections were detected in 22 isolates: 21 displayed Blastocystis sp. + D. fragilis (27.8%). Based on the sequence of a central fragment of the SSU rRNA gene, only genotype 1 was identified. These findings are among the few available data regarding genetic diversity of D. fragilis in Italy. Large-scale human and animal research are required to enhance our knowledge of prevalence, host range, genetic variability and zoonotic transmission of this little-known intestinal protozoan. [Display omitted] • Application of a GI Parasite Panel Assays for detecting Dientamoeba fragilis. • A 9.1% percentage of infection was detected. • Only Dientamoeba fragilis genotype 1 was detected in humans. [ABSTRACT FROM AUTHOR]

The main reason for the ineffectiveness of antiviral therapy in patients with chronic hepatitis C that impedes full and adequate treatment of IFN-α and ribavirin is the development of neutropenia and thrombocytopenia. The present study included 63 patients (59% men and 41% women) with chronic hepatitis C that did not previously receive antiviral therapy. All patients had HCV genotype-1 (15 patients with genotype 1a; 42 people, with genotype 1b; 6 patients, with genotypes (1a + 1b)). The patients’ age was 33.8 ± 0.7 years, with term of infection 6,1 ± 0,8 years. It was shown that in the case of treatment with Peg-IFN-alpha in combination with ribavirin, a significant decrease in the number of white blood cells, neutrophils and platelets prevailed in patients with HCV-monoinfected genotype 1b in the F0-F2 stages (2,8-8,6 kPa) at METAVIR. With the development of moderate “early” (less than 12 weeks of antiviral therapy) and for the prevention of “late” (more than 12 weeks of treatment) neutropenia, appointment of immune medicine likopid (glucosaminylmuramyldipeptide) at a dosage of 1 mg, 2 times a day for 20 days, in patients with chronic hepatitis C (genotype 1b ) with

Interferon-free therapy for genotype 1 hepatitis C are preferable from the point of view of clinical effectiveness and safety.The purpose of work was the assessment of costs and costeffectiveness of regimens for the treatment of HCV (1 genotype) at the treatment-naive patients.Methods. The assessment was carried out from the payer perspective. In base case the analysis of costs of the drugs included and recommended for inclusion in the List of VED was carried out on the basis of a median of the registered prices including VAT and the average wholesale extra charge taking into account population in the Russian Federation.Besides, the scenario with the assessment on the basis of the prices of all drugs (which both are included, and not included in the List by VED) revealed in auctions for 2016 is analysed.Results. In the base case cost of paritaprevir/ombitasvir/ dasabuvir/ritonavir (PTV/OBV/DSV/r) therapy in patients without cirrhose is 12,2-26,6% less compared with simeprevir with pegylated interferon alfa and ribavirin (PegIFN/RBV/ SMV) at a full course of the last (12 weeks) at all patients. In scenario with refusal of inefficient therapy with PegIFN/ RBV/SMV after 4 weeks, PTV/OBV/DSV/r is characterized by the comparable volume of expenses – from decrease by 15,5% to increase by 3,2%.The analysis on the basis of the prices of auctions has shown that in comparison with the PegIFN/RBV/SMV (without refusal of inefficient therapy with PegIFN/RBV/SMV after 4 weeks) and daclatasvir and asunaprevir, economy at therapy by a PTV/OBV/DSV/r will make 4,1-19,8% and 28,3%, respectively. In comparison with PegIFN/RBV/SMV (with refusal of therapy in the absence of effect in 4 weeks) PTV/OBV/DSV/r is characterized by the comparable volume of expenses (from decrease by 7,5% to increase by 12,8%). In genotype 1b costs of PTV/OBV/DSV/r are 24,6% higher compared with narlaprevir in a combination with ritonavir, peginterferon and ribavirin.Cost-effectiveness of PTV/OBV/DSV/r is higher at patients without cirrhosis in comparison with all analysed alternatives, except for a narlaprevir in a combination with ritonavir, peginterferon and ribavirin (genotype 1b).At patients with cirrhosis the analysis on the basis of the registered prices has shown that at a full cycle of therapy decrease in costs of a PTV/OBV/DSV/r ± RBV will make 8,4% in comparison with the PegIFN/RBV/SMV, but at refusal of PegIFN/RBV/SMV in 4 weeks in the absence of the response, additional expenses on PTV/OBV/DSV/r ± RBV will make 5,6%.In the analysis on the basis of the prices of auctions PTV/ OBV/DSV/r ± RBV will allow to lower expenses at patients with cirrhosis on average by 11,9% in comparison with the daclatasvir and asunaprevir. In comparison with PegIFN/ RBV/SMV PTV/OBV/DSV/r ± RBV or it doesn’t influence expenses (at a full course of a simeprevir at all patients), or it increases them by 15,2% (at refusal of therapy in the absence of the response in 4 weeks). The cost-effectiveness of PTV/ OBV/DSV/r ± RBV surpasses all comparators at patients with cirrhosis, as well as at patients without cirrhosis. The sensitivity analysis has shown high reliability of the received results.Conclusions. Costs of PTV/OBV/DSV/r ± RBV at treatment-naive patients with HCV (1 genotype) without cirrhosis and with the compensated cirrhosis, are comparable to costs of a PegIFN/RBV/SMV at higher clinical and economic effectiveness.Taking into account the need for repeated courses of therapy to treatment-naive patients with the compensated cirrhosis, now purpose of a PTV/OBV/DSV/r ± RBV in the first line of therapy is the most preferable economically.

Abstract Background In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. Methods HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates. Results The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. Conclusions Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. Trial registration number NCT01724086 (date of registration: September 26, 2012)

Direct‐acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C virus (HCV) infection. We describe UK real‐world DAA experience. Individuals commencing HCV treatment containing a DAA regimen (Mar 2014‐Nov 2016), participating in the National HCV Research UK (HCVRUK) Cohort Study were recruited from 33 UK HCV centers. The data were prospectively entered at sites onto a centralised database. The data were reported as median (Q1‐Q3). Of the 1448 treated patients, 1054 (73%) were males, the median age being 54 years (47‐60), 900 (62%) being genotype 1 and 455 (31%) genotype 3. The majority, 887 (61%) had cirrhosis, and 590 (41%) were treatment‐experienced. DAA regimens utilised: genotype1 sofosbuvir (SOF)/Ledipasvir/±Ribavirin (625/900, 69%) and Ombitasvir/Paritaprevir/Dasabuvir/±RBV (220/900, 24%), and in genotype 3 SOF/Daclatasvir + RBV (256/455, 56%) and SOF/pegylated interferon/RBV (157/455, 35%). Overall, 1321 (91%) achieved sustained virological response (SVR12), genotype 1 vs 3, 93% vs 87%, P < .001. Prior treatment, presence of cirrhosis and treatment regimen did not impact SVR12. Predictors of treatment failure were genotype 3 infection, OR, 2.015 (95% CI: 1.279‐3.176, P = .003), and male sex, OR, 1.878 (95% CI: 1.071‐3.291, P = .028). Of those with hepatic decompensation at baseline (n = 39), 51% (n = 20) recompensated post‐treatment, lower baseline serum creatinine being associated with recompensation (P = .029). There were two liver‐related deaths, both having decompensated disease. This real‐world UK data, comprising of a predominantly cirrhotic HCV genotype 1/3 cohort, confirms DAA efficacy with an overall 91% SVR12, with 51% recompensating post‐treatment. Genotype 3 infection was a predictor of treatment failure. Highlight: HCVRUK is one of the largest real world HCV databases.This study reports on real world outcomes of 1448 patients registered with HCVRUK (62% genotype 1 and 31% genotype 3), of whom about two‐thirds had cirrhosis and 40% were treatment experienced.Majority received a sofosbuvir‐based regimen.Overall 91% achieved SVR12. Genotype 3 infection and male gender were predictors of treatment failure. [ABSTRACT FROM AUTHOR]

Aim: The present study aimed to determine the real‐world efficacy and safety of the non‐structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. Methods: This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post‐treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. Results: Treatment outcomes for EBR/GZR were good in direct‐acting antiviral (DAA)‐naïve patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A‐L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A‐L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A‐Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91–16 940; P < 0.0001) was identified as an independent predictor of treatment failure. No serious adverse events were observed with EBR/GZR therapy. Conclusions: The SVR rate of EBR/GZR would have been 100% in patients without either a history of DAA therapy or double mutation. This combination of drugs could be safely given and is, thus, considered a highly useful first‐line treatment for DAA‐naïve patients with HCV. [ABSTRACT FROM AUTHOR]

Background: Secondary spread of hepatitis E virus (HEV) infection occurs often in endemic settings in developing countries. The host immune signatures contributing to protection against subsequent HEV reinfection are unknown.Methods: Twelve seroconverted rhesus macaques were reinoculated with homologous HEV genotype 1 (gt1, Sar-55) and followed for 115 days. HEV RNA, HEV-specific T-cell responses, IgG anti-HEV antibody, and the IgG anti-HEV avidity index were tested.Results: Four animals with baseline IgG anti-HEV levels from 1.5 to 13.4 World Health Organization (WHO) U/mL evidenced reinfection as determined by HEV RNA in stool, and increase in IgG anti-HEV levels between 63- and 285-fold (P = .003). Eight animals with baseline IgG anti-HEV levels from 2.8 to 90.7 WHO U/mL did not develop infection or shed virus in feces, and IgG anti-HEV antibody levels were unchanged (P = .017). The 4 reinfected animals showed a lower HEV-IgG avidity index (average 35.5%) than the 8 protected animals (average 62.1%). HEV-specific interferon-gamma-producing T cells were 2-fold higher in reinfected animals (P = .018).Conclusions: Preexisting antibody and high IgG avidity index (>50%) are important factors for protection against HEV reinfection. HEV-specific T-cell responses were elevated in reinfected animals after subsequent exposure to HEV. [ABSTRACT FROM AUTHOR]

Aim: Although the development of new direct‐acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. Methods: This large‐scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b‐infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety‐two patients (4.3%) previously received DAA‐based treatment. Seven hundred and forty‐five patients (34.9%) had cirrhosis. Results: Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 × 10–7). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 × 10–3), no previous DAA‐based treatment (P = 2.54 × 10–14), low HCV‐RNA levels (P = 1.64 × 10–6), wild‐type non‐structural protein 5A L31/Y93 (P = 7.33 × 10–13), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 × 10–14) were independent factors contributing to SVR. Except for patients with DAA‐based treatment history, absence of cirrhosis (P = 2.15 × 10–3; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA‐naïve patients. Conclusion: This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment. [ABSTRACT FROM AUTHOR]

Background: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1.Methods: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics.Results: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment.Conclusions: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen. [ABSTRACT FROM AUTHOR]

Background and Aim: In September 2015, sofosbuvir and ledipasvir were approved for clinical use in Japan for patients infected with genotype 1 hepatitis C virus. We conducted a postmarketing prospective cohort study to elucidate the safety and efficacy of this therapy in a real‐world setting. Methods: We treated 509 patients using standard doses of sofosbuvir and ledipasvir for 12 weeks. As sustained virological response (SVR) in 2 patients could not be evaluated, 507 patients were finally analyzed. Patients with daclatasvir plus asunaprevir failure were excluded. Results: Four patients (0.8%) discontinued treatment due to adverse events. SVR rates for the overall cohort, patients <65 years old, ≥65 and <75 years old, and ≥75 years old were 98% (495/507), 98% (161/163), 96% (179/186), and 98% (155/158), respectively. SVR rates among cirrhotic patients, patients with moderate chronic kidney disease (CKD), patients with a history of hepatocellular carcinoma (HCC) treatment, patients with protease inhibitor (PI) triple therapy failure, and patients with resistance‐associated substitutions (RASs) to nonstructural protein 5A (NS5A) were 97% (228/235), 98% (117/119), 95% (95/100), 94% (46/49), and 92% (44/48), respectively. In the comparison of factors between patients with and without SVR, high body weight, discontinuation of therapy, and NS5A RASs were significantly associated with non‐SVR. Conclusions: In this real‐world setting, sofosbuvir and ledipasvir were a safe treatment even in patients ≥75 years old. When patients without pre‐existing NS5A RASs and daclatasvir plus asunaprevir failure are selected, extremely high SVR rates can be achieved irrespective of age. Sofosbuvir and ledipasvir was a safe treatment even in a real‐world setting. When patients without pre‐existing nonstructural protein 5A (NS5A) resistance‐associated substitutions (RASs) and daclatasvir plus asunaprevir failure are selected, extremely high sustained virological response (SVR) rates can be achieved. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV) can account for up to a 30% mortality rate in pregnant women, with highest incidences reported for genotype 1 (gt1) HEV. Reasons contributing to adverse maternal-fetal outcome during pregnancy in HEV-infected pregnant women remain elusive in part due to the lack of a robust tissue culture model for some strains. Open reading frame (ORF4) was discovered overlapping ORF1 in gt1 HEV whose protein expression is regulated via an IRES-like RNA element. To experimentally determine whether gt3 HEV contains an ORF4-like gt1, gt1 and gt3 sequence comparisons were performed between the gt1 and the homologous gt3 sequence. To assess whether ORF4 protein could enhance gt3 replication, Huh7 cell lines constitutively expressing ORF4 were created and used to assess the replication of the Kernow-C1 gt3 and sar55 gt1 HEV. Virus stocks from transfected Huh7 cells with or without ORF4 were harvested and infectivity assessed via infection of HepG2/C3A cells. We also studied the replication of gt1 HEV in the ORF4-expressing tunicamycin-treated cell line. To directly show that HEV transcripts have productively replicated in the target cells, we assessed events at the single-cell level using indirect immunofluorescence and flow cytometry. Despite not naturally encoding ORF4, replication of gt3 HEV was enhanced by the presence of gt1 ORF4 protein. These results suggest that the function of ORF4 protein from gt1 HEV is transferrable, enhancing the replication of gt3 HEV. ORF4 may be utilized to enhance replication of difficult to propagate HEV genotypes in cell culture. IMPORTANCE: HEV is a leading cause of acute viral hepatitis (AVH) around the world. The virus is a threat to pregnant women, particularly during the second and third trimester of pregnancy. The factors enhancing virulence to pregnant populations are understudied. Additionally, field strains of HEV remain difficult to culture in vitro. ORF4 was recently discovered in gt1 HEV and is purported to play a role in pregnancy related pathology and enhanced replication. We present evidence that ORF4 protein provided in trans enhances the viral replication of gt3 HEV even though it does not encode ORF4 naturally in its genome. These data will aid in the development of cell lines capable of supporting replication of non-cell culture adapted HEV field strains, allowing viral titers sufficient for studying these strains in vitro. Furthermore, development of gt1/gt3 ORF4 chimeric virus may shed light on the role that ORF4 plays during pregnancy.

Currently in the Russian Federation or chronic hepatitis C (CHC) are still relevant Interferon-based regimens. The purpose of this study is to investigate the influence of baseline characteristics and prognosis of the patient HCV genotype 1 for the development of leukopenia (LP) and neutropenia (NP). We investigated factors such as sex, age, body mass index (BMI), viral load, genotype of Interleukin-28 B (IL-28B), the initial level of leukocytes and neutrophils, alanine aminotransferase (ALT), fibrosis, duration of infection, presence of previous therapy. Absolute values of leukocytes and neutrophils were analyzed on 4, 12, 24, 48 weeks of therapy, and at 4, 12, 24 weeks after antiviral treatment with protease inhibitors (PI) 1 and 2 generation. Prognostic criteria were identified, indicating the possible development of the LP and NP expressed during treatment with interferon: female gender, low initial load, TT-genotype of IL-28B, the initial level of white blood cells and neutrophils below 5,7×109/L and 3,4×109/L, respectively. Mathematical models predicting the onset of LP and NP, formalized in the form of decision trees were also constructed. These models have shown the greatest potential for practical use in view of highest accuracy and reliability.

An attack of a brown bear (Ursus arctos) on human was detected in November, 2014 in the Barabash village (Khasan region of the Primorski krai) located in close proximity to the national park Land of the Leopard. The bear was shot. The deviant behavior of the bear indicated the possibility of rabies. The diagnosis was confirmed by means of laboratory methods. The strain RABV/Ursus arctos/Russia/Primorye/PO 01/2014 (further PO 01) was isolated from the brain of the bear. PO 01 is the first completely sequenced Far Eastern strain of RABV. It can be considered as topotypic. PO 01 considerably differs from the vaccine strain RV 97 (GenBank EF542830) that is the basis of attenuated vaccine applied in the Land of the Leopard. At the same time, the immunodominant sites in PO 01 and RV 97 proteins differ slightly. It can be recommended to continue application of the vaccine. The analysis of the PO 01 genome (GenBank KP997032) revealed its belonging to the Eurasian genetic subgroup of the genotype 1 (street rage). Thus, this genetic subgroup stretches to the East. Expansion of the cross-border protected territories of Russia and China in the Far East demands the correct statistics of circulation of the lyssaviruses to be kept.

Vinay Sundaram,1 Kris V Kowdley21Department of Medicine and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, 2Liver Care Network, Swedish Medical Center, Seattle, WA, USAAbstract: Chronic hepatitis C virus (HCV) infection is one of the most common etiologies of liver-related mortality throughout the world. Among the six HCV genotypes, genotype 1 was significantly more aggressive when utilizing the combination of pegylated interferon and ribavirin, as genotype 1-infected patients had the lowest likelihood of achieving cure (40%–50%) and required twice as long duration of treatment, as compared to genotypes 2 and 3. Recently, however, significant advances have been made with the advent of all-oral direct-acting antiviral agents, which have significantly improved the safety, efficacy, and tolerability of the treatment of HCV genotype 1. Among the available treatments for HCV genotype 1, the combination therapy of ledipasvir/sofosbuvir provides several advantages compared to other regimens, including use of a single-pill regimen, possibility to shorten the duration of treatment to 8 weeks, efficacy in patients exposed to protease inhibitors, safety in decompensated cirrhosis, and potential to avoid ribavirin. In this review, we discuss the pharmacotherapy of the combination of ledipasvir/sofosbuvir therapy and summarize the results of the Phase III clinical trials for this treatment in HCV genotype 1 patients. We will also discuss the data for special populations, including decompensated cirrhosis, human immunodeficiency virus (HIV) coinfected patients, African-Americans, the elderly, and those who failed sofosbuvir-containing regimens.Keywords: pegylated interferon, ribavirin, cirrhosis, liver transplantation, direct-acting antiviral

Purpose: We aimed to evaluate retrospectively the results of treatment of patients with chronic hepatitis C in our clinic. Material and Methods: We evaluated the treatment results of 109 patients who treated with the diagnosis of chronic hepatitis C between the years of 2003-2015 in our clinic. Results: The 52.3% of the patients were male, the mean age was 52.3, mean ALT value 58.3 IU/ml and average HCV-RNA levels was 3,7x106 IU/ml. Previous treatment history in 47 patients (43%) was available. Eigthy-one patients (74.3%) received treatment of pegylated interferon and ribavirin and 28 patients(25.7%) received combination of pegylated interferon, ribavirin and telaprevir. Early virologic response were obtained in 99(90.8%) of 109 patients. Sustained virologic response was more higher in patients who achieved early virologic response. Sustained viralogic response in group of PegIFN/R was %74.1 and in group of PegIFN/R/T was 76.9%. At least one of complaints as rash, itching, taste disorder and anorectal pain were observed in PegIFN/R/T group. All patients had anemia as the most common hematologic side-effect. Depressive symptoms was observed in 19% of patients. Conclusion: With available treatment options in our country, patients who can not be achieved to SVR rates are available. There is a need for new antiviral drugs that used in the world for the patients infected with genotype 1 who had unsuccessful treatment. [Cukurova Med J 2016; 41(2.000): 342-346]

While new direct-acting antiviral therapies for hepatitis C virus (HCV) are the standard of care, interferon-α (IFN-α) remains a standard therapy in Taiwan based on its low cost and high response rate to IFN-α-based therapy. IFN-α exerts antiviral activity by inducing the expression of hundreds of genes that establish an antiviral state via Jak kinase (JAK)/signal transducers and activators of transcription (STAT) signaling. We quantified the transcript levels of JAK/STAT signaling genes in peripheral blood mononuclear cells of HCV genotype 1 patients and estimated the correlation between transcript levels and patient responses to IFN-α-based therapy. Methods: A total of 100 HCV genotype 1 naïve patients were enrolled. All patients received response-guided therapy for 24–48 weeks with pegylated IFN-α and ribavirin. Peripheral blood mononuclear cells were collected before treatment. Twenty patients with sustained virological responses (SVR) and 20 patients without SVR were selected for a JAK/STAT signaling genes transcript analysis using multiplex reverse transcription-polymerase chain reaction. Transcripts that were upregulated or downregulated were further validated in 100 patients. Results: Suppressor of cytokine signaling 1 (SOCS1) expression was upregulated in SVR patients compared with non-SVR patients (relative quantification = 2.14) based on a multiplex reverse transcription-polymerase chain reaction analysis. We further analyzed SOCS1 expression in 100 patients. We found that SOCS1 expression did not differ significantly between SVR and non-SVR patients. Conclusion: Peripheral blood SOCS1 expression before treatment was not associated with SVR in HCV genotype 1 patients treated with pegylated IFN-α and ribavirin.

The introduction of direct-acting antiviral agents (DAAs) has markedly improved the sustained virological response (SVR) rates in patients with chronic hepatitis C. Currently, four classes of DAAs targeting three HCV proteins (NS3, NS5A, and NS5B) have been approved for treatment in many countries. Since drugs show advantages and disadvantages, use of a combination of two or more DAAs with different targets or addition of ribavirin in a difficult-to-treat patient shows an SVR rate of ∼90% after 12 weeks of treatment or expanded treatment for 24 weeks. Various types of DAA are awaiting approval which will improve the treatment of chronic hepatitis C virus genotype 1 infection. However, high costs, drug resistance and interactions between various drugs remain to be overcome. With further advances in the development of antiviral agents, it could be expected that in the near future, there will be DAAs that are affordable and cost effective, require shorter treatment duration, effective in a broad range of patients, and have less side effects and drug-drug interactions. (Korean J Gastroenterol 2016;67:127-131)

Updated HCV clinical guidelines placed direct acting agents (DAAs) as the preferable the first line regimens.The objective of the study was PE assessment of HCV therapy among G1 naïve patientsMethods: Analysis is based on data of randomized clinical trials and average price of HCV medicines from state auctions placed in state procurement system in 2015.Results: PTV/OBV/DSV/r cost is 30,5% lower vs PegIFN/RBV/SMV. In comparison with PegIFN/RBV/BCV combination PTV/OBV/DSV/r is cost saving by 10,6% at patients without cirrhosis and 36,2% at patients with cirrhosis. DCV/ASV combination is chipper PTV/OBV/DSV/r and it would be used for G1 naïve patient (cost saving is 9,4-10,4%). DCV/ASV and PTV/OBV/DSV/r SVR12 costs are comparable and significantly lower than PegIFN-based regimen: PegIFN/RBV/SMV and PegIFN/RBV/BCV. 4 weeks stop rules due to therapy inefficiency for PegIFN/RBV/SMV regimen could cut cost by 12,6% и 28,0% among patients without and cirrhosis accordingly. By way PTV/OBV/DSV/r is the most cost effective versus PegIFN/RBV/SMV. PTV/OBV/DSV/r as the first line therapy for PegIFN experienced patients provides budget saving 118,2 thousand RUB or 12,2% of budget.Conclusion: Right now PTV/OBV/DSV/r regimen is the most cost effective the first line therapy for naïve patients.