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SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure-activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 μM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure-activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing antiviral agents against SARS and COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

β-l-5-(( E )-2-Bromovinyl)-1-((2 S ,4 S )-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17 ) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU ( 17 ) has demonstrated excellent anti -VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24 ) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP ( 24 ), in vivo , effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP ( 24 ) is needed. In this article, an efficient approach for the synthesis of l-BHDU ( 17 ) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU ( 17 ) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24 ). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.

A structural and spectroscopic study of 5-chloroorotic acid (5-ClOA) biomolecule was carried out by IR and FT-Raman and the results obtained were compared to those achieved in 5-fluoroorotic acid and 5-aminoorotic acid compounds. The structures of all possible tautomeric forms were determined using DFT and MP2 methods. To know the tautomer form present in the solid state, the crystal unit cell was optimized through dimer and tetramer forms in several tautomeric forms. The keto form was confirmed through an accurate assignment of all the bands. For this purpose, an additional improvement in the theoretical spectra was carried out using linear scaling equations (LSE) and polynomic equations (PSE) deduced from uracil molecule. Base pairs with uracil, thymine and cytosine nucleobases were optimized and compared to the natural Watson-Crick (WC) pairs. The counterpoise (CP) corrected interaction energies of the base pairs were also calculated. Three nucleosides were optimized based on 5-ClOA as nucleobase, and their corresponding WC pairs with adenosine. These modified nucleosides were inserted in DNA:DNA and RNA:RNA microhelices, which were optimized. The position of the -COOH group in the uracil ring of these microhelices interrupts the DNA/RNA helix formation. Because of the special characteristic of these molecules they can be used as antiviral drugs.Communicated by Ramaswamy H. Sarma.

Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human noroviruses (HuNoVs) are acute viral gastroenteritis pathogens that affect all age groups, yet no approved vaccines and drugs to treat HuNoV infection are available. In this study, we screened an antiviral compound library to identify compound(s) showing anti-HuNoV activity using a human intestinal enteroid (HIE) culture system in which HuNoVs are able to replicate reproducibly. Dasabuvir (DSB), which has been developed as an anti-hepatitis C virus agent, was found to inhibit HuNoV infection in HIEs at micromolar concentrations. Dasabuvir also inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human rotavirus A (RVA) infection in HIEs. To our knowledge, this is the first study to screen an antiviral compound library for HuNoV using HIEs, and we successfully identified dasabuvir as a novel anti-HuNoV inhibitor that warrants further investigation. IMPORTANCE Although there is an urgent need to develop effective antiviral therapy directed against HuNoV infection, compound screening to identify anti-HuNoV drug candidates has not been reported so far. Using a human HIE culture system, our compound screening successfully identified dasabuvir as a novel anti-HuNoV inhibitor. Dasabuvir's inhibitory effect was also demonstrated in the cases of SARS-CoV-2 and RVA infection, highlighting the usefulness of the HIE platform for screening antiviral agents against various viruses that target the intestines.

Background and Aims: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable., Approach and Results: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12., Conclusions: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Introductions and Objectives: The introduction of direct-acting antiviral (DAA) agents promises to change dramatically the management of hepatitis C in kidney transplant recipients, a patient group where the treatment of hepatitis C is historically challenging. The purpose of the current study was to assess (in a 'real-life' setting) the safety and efficacy of all-oral, interferon-free, direct-acting antiviral agents in kidney transplant recipients with HCV., Material and Methods: We performed a single-arm, multi-center study in a cohort (n = 95) of kidney transplant recipients who underwent antiviral therapy with DAAs. The primary end-point was sustained virologic response (SVR) (serum HCV RNA < 15 IU/mL, 12 weeks after treatment ended; SVR12). We recorded data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities., Results: Various regimens were adopted at the discretion of the treating physician: elbasvir/grazoprevir (n = 11), paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens ± ribavirin (n = 23), and sofosbuvir-based regimens ± ribavirin (n = 61). The SVR12 rate was 93.7% (89/95) (95% CI, 88%; 98%), according to intention-to-treat analysis; three patients without viral response (n = 3) were found. Ribavirin was administered in 8 (8.4%) allograft recipients. The frequency of drop-outs was 4.2% (4/95) (95% CI, 0.2%; 8.2%); these were related to arthralgia/myalgia (n = 2), fatigue (n = 1), and lowered estimated glomerular filtration rate (eGFR) (n = 1). There were no differences with regard to serum creatinine and eGFR before and after antiviral therapy and during follow-up in the whole cohort. The patient who interrupted antiviral treatment due to raised serum creatinine was on sofosbuvir/daclatasvir regimen; one of the four drop-outs obtained SVR., Conclusions: All-oral, interferon-free therapy with DAAs for chronic HCV after kidney transplantation was effective and well-tolerated in a 'real-life' clinical setting. Identical results have been observed in patients with intact kidneys or advanced chronic kidney disease. Careful evaluation of kidney function over follow-up in kidney transplant recipients who received DAAs regimens is recommended. Clinical trials aimed to assess whether sustained viral response translates into improved patient/graft survival are under way., (Copyright © 2021 AEDV. Published by Elsevier España, S.L.U. All rights reserved.)

Replication of peste des petits ruminants virus (PPRV) strongly depends on the cellular environment and resources of host cells including nucleoside pool. Thus, enzymes involved in nucleoside biosynthesis (such as pyrimidine biosynthesis pathway) are regarded as attractive targets for antiviral drug development. Here, we demonstrate that brequinar (BQR) and leflunomide (LFM) which are two specific inhibitors of DHODH enzyme and 6-azauracil (6-AU) which is an ODase enzyme inhibitor robustly inhibit PPRV replication in HEK293T cell line as well as in peripheral blood mononuclear cells isolated from goat. We further demonstrate that these agents exert anti-PPRV activity via the depletion of purimidine nucleotide. Interestingly, these inhibitors can trigger the transcription of antiviral interferon-stimulated genes (ISGs). However, the induction of ISGs is largely independent of the classical JAK-STAT pathway. Combination of BQR with interferons (IFNs) exerts enhanced ISG induction and anti-PPRV activity. Taken together, this study reveals an unconventional novel mechanism of crosstalk between nucleotide biosynthesis pathways and cellular antiviral immunity in inhibiting PPRV replication. In conclusion, targeting pyrimidine biosynthesis represents a potential strategy for developing antiviral strategies against PPRV., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The use of direct-acting antiviral agents (DAAs) in patients with chronic HCV genotype (GT) 1 infection results in sustained virologic response (SVR) rates of 95%-97%, but 3%-5% of patients experience virologic failure. We observed 41 patients infected with HCV subtype 1b who failed previous treatment with DAAs, including 37 subjects (90.2%) with liver cirrhosis. In total, 30 (73.2%) subjects previously received NS5A inhibitors of the first generation (ledipasvir, daclatasvir, or ombitasvir) and 11 subjects (26.8%) received NS5A inhibitors of the second generation (velpatasvir). All patients received retreatment with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) with sofosbuvir (SOF) and ribavirin (RBV). We compared SVR12 rates depending on fibrosis stage, presence of just single or double NS5A mutation (L31M/V/I and/or Y93H), and the generation of previously used NS5A inhibitors. Observed SVR12 rates were as follows: 97.6% (40/41 patients) overall; 100% in patients without cirrhosis (n = 4) versus 97.3% in those with cirrhosis (n = 37); 100% with single L31M/V/I or Y93H mutation (n = 22) versus 94.4% with double mutations (n = 18); 100% in patients who failed previous treatment with first-generation (n = 30) versus 90.9% in those who failed previous treatment with second-generation NS5A inhibitors (n = 11). Retreatment with 3D + SOF + RBV was highly effective and safe in patients with chronic HCV GT1b infection, including those with liver cirrhosis, who failed previous treatment with DAA 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., (© 2021 Wiley Periodicals LLC.)

Background and Aims: The 12-week regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (OPrD) has shown high efficacy and tolerability in clinical trials for the treatment of chronic hepatitis C virus (HCV). The shorter 8-week regimen has been recently incorporated into clinical guidelines and on-label indications, but real-world evidence on its use is limited. Given this knowledge gap, the AMETHYST study aimed to evaluate the effectiveness of the 8- and 12-week regimens of OPrD in treatment-naive patients with HCV with mild to moderate liver fibrosis in Romanian clinical practice., Methods: This was a secondary data collection study analyzing data from a 1-year Patient Support Program in HCV in Romania. Patients received OPrD treatment for 8 or 12 weeks. The effectiveness endpoint was sustained virologic response 12 weeks post-treatment (SVR12)., Results: A total of 1,835 treatment-naive patients with HCV with mild or moderate fibrosis were included in the study. Of these, 426 and 1,375 completed the 8-week and 12-week regimens, respectively. SVR12 was 98.1% in the 8-week treatment group and 98.7% in the 12-week treatment group., Conclusion: The study provides real-world evidence that 8-week and 12-week treatment regimens of OPrD are highly effective in treatment-naive patients with HCV with mild to moderate liver fibrosis.

Hepatitis C virus (HCV) infections are more common among US veterans receiving care through Veterans Affairs (VA) Medical Centers than among the general population. Historically, HCV therapies had lower efficacy rates in VA patients, possibly due to common comorbidities such as psychiatric disorders and substance abuse. The direct-acting antivirals ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV)±ribavirin (RBV) are approved in the US for HCV genotype 1 (GT1)-infected adults with or without cirrhosis. This study prospectively evaluated the safety and efficacy of OBV/PTV/r+DSV±RBV in VA patients with HCV GT1 infection. TOPAZ-VA was a phase 3b, open-label trial. Adult US veterans with HCV GT1 infection, without cirrhosis or with compensated cirrhosis, were eligible for enrollment. Patients with GT1a infection received OBV/PTV/r +DSV+RBV for 12 weeks or 24 weeks (for those with cirrhosis); GT1b-infected patients without cirrhosis received OBV/PTV/r +DSV for 12 weeks; those with cirrhosis received OBV/PTV/r +DSV with RBV. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12); safety was also assessed. Ninety-nine patients were enrolled at 10 sites from May through November 2015. The majority were male (96%), white (60%), and with GT1a infection (68%); 49% reported ongoing psychiatric disorders. Overall, 94% (93/99) achieved SVR12; three patients had a virologic failure. The most common AEs were fatigue (28%), headache (20%), and nausea (15%); six patients discontinued treatment due to AEs. In US veterans with HCV GT1 infection, OBV/PTV/r +DSV±RBV yielded a 94% overall SVR12 rate and was well tolerated. The presence of psychiatric disorders and/or injection drug use did not impact efficacy., (© 2019 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.)

Background: Hepatic decompensation is a fatal on-treatment side effect during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Prompt bilirubin testing can reveal hepatic failure in susceptible patients, and clinical parameters precipitating early elevation of bilirubin can warn clinicians to avoid PrOD prescription., Methods: This retrospective study included 169 Hepatitis C virus (HCV)-genotype 1b patients who underwent a 12-week course of PrOD with or without ribavirin. Laboratory data underwent χ analysis with Fisher's exact test to determine the precipitating factors causing hyperbilirubinemia in patients who had received 1 week of treatment., Results: Sustained viral response was achieved in 164 patients (97.0%). Total bilirubin was ≥2 mg/dL (21.3%) in 36 patients after 1 week of treatment. Pretreatment white blood cell (WBC) <4500/µL and platelet <100,000/µL correlated with total bilirubin ≥2 mg/dL (relative risk [RR]: 21.64, 95% CI: 5.23-89.64, p < 0.001) after 1 week of treatment. Pretreatment platelet ≥100 000/µL and WBC <4500/µL correlated with direct bilirubin ≥0.45 mg/dL (RR: 6.56, 95% CI: 1.42-30.38, p = 0.016) and indirect bilirubin ≥0.6 mg/dL (RR: 4.77, 95% CI: 1.03-22.15, p = 0.046). Pretreatment platelet <100,000/µL with F3/F4 fibrosis correlated with first week total bilirubin ≥2 mg/dL (RR: 3.57, 95% CI: 1.35-9.09, p = 0.010)., Conclusion: PrOD is an effective antiviral regimen for HCV genotype 1b patients. Total bilirubin ≥2 mg/dL after 1 week of treatment serves as an early warning of irreversible progression toward hepatic decompensation, and the current study provides a guide by which to monitor chronic hepatitis C patients undergoing PrOD treatment.

Background: Hepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved., Methods: We conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy. Plasma HCV, soluble CD14 (sCD14), interferon-inducible protein 10, soluble CD163 (sCD163), interleukin 6 (IL-6), interleukin 18, monocyte chemoattractant protein (MCP-1), autotaxin (ATX), and Mac2-binding protein (Mac2BP) were measured over 48 weeks., Results: Participants were treated with PrOD for 12 (n = 9) or 24 (n = 36) weeks; the SVR rate at 12 weeks was 93%. At baseline, cirrhosis was associated with higher ATX and MCP-1, female sex with higher ATX and IL-6, older age with higher Mac2BP, higher body mass index with higher ATX, and HIV-1 protease inhibitor use with higher sCD14 levels. In those with SVR, interferon-inducible protein 10, ATX, and Mac2BP levels declined by week 2, interleukin 18 levels declined by the end of treatment, sCD14 levels did not change, and sCD163, MCP-1, and IL-6 levels changed at a single time point., Conclusions: During HIV/HCV coinfection, plasma immune activation marker heterogeneity is in part attributable to age, sex, cirrhosis, body mass index, and/or type of antiretroviral therapy. HCV treatment with paritaprevir-ritonavir-ombitasvir plus dasabuvir is highly effective and is associated with variable rate and magnitude of decline in markers of immune activation., Clinical Trials Registration: NCT02194998., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection., Methods: We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S., Results: Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4., Conclusions: We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: To assess the safety, efficacy, and pharmacokinetics of mini-tablet formulations of ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) with or without ribavirin for 12 weeks in children infected with chronic hepatitis C virus (HCV) genotype (GT) 1., Methods: This is an ongoing, open-label, Phase 2/3 study in children 3-11 years old infected with HCV GT1 who were HCV treatment-naïve and non-cirrhotic. Pediatric mini-tablet formulations of OBV, PTV, ritonavir, and DSV plus ribavirin oral solution were administered for 12 weeks based on body weight. Endpoints included SVR12, adverse events (AEs), and pharmacokinetic parameters., Results: Overall, 26 children received OBV, PTV, ritonavir, and DSV plus ribavirin; 14 were 3-8 years old and 12 were 9-11 years old; 35% were male; and all had chronic HCV GT1a infection. The SVR12 rate was 96% (25/26; 95% CI 81.1-99.3), with 1 child failing to achieve SVR12 due to non-adherence and treatment discontinuation. Treatment-emergent AEs of Grade ≥ 3 occurred in 3 children; 2 events in 1 child were considered serious; and none were considered treatment-related. No AEs led to discontinuation of study treatment. The most common AEs were headache (27%), fatigue (23%), pyrexia (19%), and vomiting (19%). Pharmacokinetic results showed mini-tablet formulations of OBV, PTV, DSV, and ritonavir drug exposures were comparable to the adult formulation., Conclusion: The mini-tablet combination of OBV, PTV, ritonavir, and DSV plus ribavirin to treat HCV GT1a infection for 12 weeks was highly effective and suitable in children 3-11 years of age., Trial Registration: ClinicalTrials.gov identifier, NCT02486406.

The World Health Organization has called for the elimination of hepatitis C virus (HCV) as a public health threat by 2030. Highly effective direct-acting antiviral agents provide the therapeutic tools required for elimination. In the absence of a vaccine, HCV elimination will require enhanced primary prevention and an increase in the proportions of people diagnosed and treated. Given that globally only 20% of people with chronic HCV are diagnosed, and around 5% have initiated HCV treatment, the task ahead is enormous. But, global public health needs optimism, and countries currently on track for HCV elimination provide a pathway forward., Competing Interests: Competing Interests No conflicts (M. Martinello, S. Bajis). G.J. Dore is an advisory board member and has received honoraria from Abbvie, Gilead, and Merck; has received research grant funding from Abbvie, Gilead, and Merck; and travel sponsorship from Gilead, Abbvie, and Merck., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The 3-DAA regimen consisting of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) has shown high sustained virologic response rates (~95%) in phase 3 clinical trials including >2300 HCV genotype 1-infected patients. Real-world evidence studies have confirmed the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic HCV genotype 1 infection and are consistent with clinical trial results. TOPAZ-I and TOPAZ-II are ongoing phase 3b trials, assessing safety, efficacy and long-term progression of liver disease and clinical outcomes for up to 5 years post-treatment in patients treated with OBV/PTV/r + DSV ± RBV. High rates of sustained virologic response (SVR) were achieved regardless of presence or absence of cirrhosis.In this report, we assessed the long-term progression of liver disease and incidence of clinical outcomes up to 3 years of post-treatment follow-up in patients with chronic HCV GT1 infection who were treated with (OBV/PTV/r + DSV) ± RBV in the TOPAZ-I and TOPAZ-II studies. Improvements were observed in liver disease markers including FIB-4, METAVIR and Child-Pugh scores as well as platelet counts. Clinical outcomes related to long-term progression of liver disease such as liver decompensation were infrequent (<1%). Hepatocellular carcinoma (HCC) occurred in 1.4% of cirrhotic patients., (© 2020 John Wiley & Sons Ltd.)

The use of direct-acting antiviral agents (DAAs) in patients with chronic HCV genotype 1 infection results in sustained virologic response (SVR) rates of 95%-97%, but 3%-5% of patients experience virologic failure. We observed 17 patients infected with HCV subtype 1b who failed previous treatment with DAA, including 13 subjects (76.5%) with liver cirrhosis. Twelve subjects (70.6%) previously received NS5A inhibitors of the first generation (ledipasvir or daclatasvir) and five subjects (29.4%) - the second generation (velpatasvir). All patients were retreated with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) with sofosbuvir (SOF) and ribavirin (RBV). We compared SVR 12 rates depending on fibrosis stage, presence of just single or double NS5A mutations (L31M/V/I and/or Y93H), and on the generation of previously used NS5A inhibitor. Observed SVR 12 rates were as follows: 94.1% (16/17 patients) overall; 100% in patients without cirrhosis (n = 4) vs 92.3% in those with cirrhosis (n = 13); 100% with single L31M/V/I or Y93H mutation (n = 7) vs 88.9% with double mutations (n = 9); 100% in patients who previously failed first generation (n = 12) vs 80.0% in those failed second-generation NS5A inhibitors (n = 5). Retreatment with 3D + 0SOF + RBV was highly effective and safe in patients with chronic HCV GT1b infection who failed previous use of NS5A inhibitors. Fibrosis stage, baseline presence of NS5A RAS mutations and the generation of previously used NS5A inhibitors may impact the probability of achieving SVR 12 , but statistical significance was not demonstrated in our small retrospective cohort. Further studies in a larger population are needed to confirm or not the predictive value of these baseline factors., (© 2020 John Wiley & Sons Ltd.)

Background: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs., Methods: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants., Results: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m 2 ). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness., Conclusion: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment., Trial Registration: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Background/aims: mbitasvir/paritaprevir/ritonavir (OMV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) combination has demonstrated excellent rates of sustained virologic response (SVR) and a very good safety profile in patients with the chronic hepatitis C virus (HCV) genotype 1 or 4 infections. We aimed to investigate the effectiveness and safety of OMV/PTV/r ± DSV ± RBV combination regimen in a real-world clinical practice., Materials and Methods: Data from HCV genotype 1 and 4 patients treated with OMV/PTV/r ± DSV ± RBV (n=862) in 34 centers across Turkey between April 1, 2017 and August 31, 2018 were recorded in a large national database. Demographic, clinical, and virologic data were analyzed., Results: The mean age of the patients was 55.63, and 430 patients (49.9%) were male. The majority had HCV genotype 1b infection (77.3%), and 66.2% were treatment-naïve. Non-cirrhosis was present at baseline in 789 patients (91.5%). SVR12 rate was 99.1% in all patients. Seven patients had virologic failure. No significant differences were observed in SVR12 according to HCV genotypes. HCV RNA was undetectable at treatment week 4 in 90.9%, at treatment week 8 in 98.5%, and at the end of treatment (EOT) in 98.9%. SVR12 ratio was significantly higher in the non-cirrhotic patients compared to that in the compensated cirrhotic patients. Rates of adverse events (AEs) in the patients was 59.7%., Conclusion: The present real-life data of Turkey for the OBV/PTV/r ± DSV ± RBV treatment of patients with HCV genotype 1b, 1a, or 4 infection from 862 patients demonstrated high efficacy and a safety profile.

Purpose: Since 2017 treatment-naïve patients infected with genotype 1b of hepatitis C virus and minimal or moderate fibrosis can be treated with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (OPrD) for 8 weeks according to updated Summary of Product Characteristics. The aim of our study was to assess the comparative efficacy of 8 and 12-weeks therapy with OPrD in large cohort of patients eligible for 8 weeks regimen treated in real-world setting., Materials and Methods: We analysed data of 3067 HCV genotype 1b infected patients treated with OPrD between 2015 and 2017. Final analysis included patients with none, minimal or moderate fibrosis (F0-F2)., Results: A total of 771 patients were enrolled in the study, including 197 (26%) treated for 8-weeks and 574 patients fulfilling criteria for 8-weeks but assigned to 12-weeks regimen. Majority of patients had no or minimal fibrosis (F0-F1). Longer treatment duration was more often administered in patients with moderate fibrosis, comorbidities, concomitant medications. SVR was achieved in 186 (94%) patients treated for 8 weeks and 558 (97%) for 12 weeks (p = 0.07). After exclusion of lost to follow-up patients, sustained virological response (SVR) rate reached 95% and 99%, respectively (p = 0.01). We were not able to identify factors associated with non-response., Conclusions: This real-word experience study confirmed similar, high effectiveness of 8 and 12-weeks regimens of OPrD in genotype 1b HCV infected patients with non-advanced fibrosis. Despite of reduced SVR rate after 8-weeks regimen, there is no need to extend therapy to 12-weeks in vast majority of such patients and no need to add ribavirin., Competing Interests: Declaration of competing interest Dorota Zarębska-Michaluk – Sponsored Lectures: AbbVie, Gilead, Merck; Anna Piekarska – Consultancy: AbbVie, Gilead, Merck, Roche; Jerzy Jaroszewicz – Consultancy: AbbVie, BMS, Gilead; Research funding: Merz, Roche; Jakub Klapaczyński – Sponsored Lectures Gilead; Włodzimierz Mazur – Consultancy: AbbVie, BMS, Gilead, Janssen, Merck, Roche; Research funding: AbbVie, Gilead, Merck, Roche; Rafał Krygier – Consultancy - AbbVie, Gilead, Promed; Teresa Belica-Wdowik – Consultancy: AbbVie, Gilead; Research funding: AbbVie; Barbara Baka-Ćwierz – Consultancy: AbbVie, Gilead, Roche; Research funding: AbbVie, Roche; Ewa Janczewska – Consultancy: AbbVie, BMS, Gilead, Janssen, Roche; Research funding: AbbVie, Allergan, BMS, Gilead, Janssen, Merck, Roche, Vertex, Tobira; Krzysztof Tomasiewicz – Consultancy: AbbVie, Alfa Wasserman, BMS, Gilead, Janssen, Merck, Roche; Research funding: AbbVie, BMS, Gilead, Janssen, Merck, Roche; Aleksander Garlicki – Consultancy: AbbVie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Roche, Sanofi Pasteur; Research funding: Amgen, Janssen, Pfizer; Agnieszka Czauż-Andrzejuk – Research funding: AbbVie, Merck; Dorota Dybowska – Sponsored Lectures: Abbvie. Waldemar Halota – Consultancy: AbbVie, BMS, Gilead, Janssen, Merck, Roche; Research funding: AbbVie, Gilead, Roche; Małgorzata Pawłowska – Consultancy: AbbVie, BMS, Gilead, Janssen, Merck, Roche; Research funding: AbbVie, Gilead, Roche; Krzysztof Simon – Consultancy: AbbVie, Gilead, BMS, Merck, Janssen, Alfa-Wassermann, Baxter, Bayer, Roche; Research funding: AbbVie, Allergan, Bayer, EISAI, Gilead, Intercept, Janssen, Tobira, Pfizer; Olga Tronina – Consultancy: AbbVie; Research funding: Janssen; Robert Flisiak—Consultancy: AbbVie, Alfa Wasserman, BMS, Gilead, Janssen, Merck, Roche; Research funding: AbbVie, Gilead, Janssen, Merck, Roche; Paweł Pabjan, Beata Dobracka, Beata Lorenc, Magdalena Tudrujek-Zdunek, Marek Sitko, Jolanta Citko, Łukasz Laurans, Zbigniew Deroń, Iwona Buczyńska, Jolanta Białkowska – none declared., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aims: Hepatitis C virus (HCV) infection is a common disease that causes liver cirrhosis, hepatocellular carcinoma, and extra hepatic manifestations with high mortality and morbidity rates. This study aimed to present real-life experiences and results of treatment of HCV infection with direct-acting antiviral agents (DAAs) from the Euro-Asian region, including Turkey and Azerbaijan., Materials and Methods: A total of 1224 patients with chronic HCV infection were treated with DAAs in accordance with the international guidelines for the management of HCV infection. The mean age was 58.74±14.75 years, with 713 (58.25%) females. The genotypes of the patients were as follows: genotype 1b, 83.36% (n=1024); genotype 1a, 8.08% (n=99); genotype 2, 2.85% (n=35); genotype 3, 3.34% (n=41); genotype 4, 1.71% (n=21); and combined genotypes, 0.32% (n=4). Approximately 808 patients were treated with sofosbuvir-based DAAs with or without Ribavirin for 12 or 24 weeks, whereas 416 patients were treated with the Paritaprevir, Ombitasvir, Ritonavir.Dasabuvir (PROD) regimen with or without Ribavirin for 12 weeks or 24 weeks., Results: At the end of follow-up examinations, 1183 patients (97.93%) had sustained virological response (SVR), 17 (1.40%) died of reasons unrelated to the treatment regimen, 12 had recurrence after treatment, and 129 (10.67%) had adverse events like anemia, itching, and weakness., Conclusion: In this large cohort of HCV-infected patients, treatment with DAAs yielded a high overall SVR rate of 97.93%. DAAs were safe and well-tolerated. Thus, the elimination of HCV infection is no longer a dream worldwide.

Background: This is a real-world evidence study that aims to analyze the efficacy, tolerability and safety profile of paritaprevir/ombitasvir/ritonavir and dasabuvir, in patients with renal impairment., Methods: We conducted an observational prospective study, on 232 patients with chronic kidney disease, undergoing treatment with paritaprevir/ombitasvir/ritonavir and dasabuvir, for chronic hepatitis C infection - genotype 1b. Renal and liver function were assessed at the beginning of therapy, monthly during treatment and three months after therapy completion., Results: All patients achieved sustained virologic response. Common side effects were nausea, fatigue and headache. Close monitoring of tacrolimus blood levels and dose reduction was required in kidney transplant recipients., Conclusions: HCV therapy in the setting of renal dysfunction has always been a challenging topic. Direct-acting antivirals have shown promising effects, demonstrating good tolerance and efficacy in patients with HCV infection and renal impairment. Sustained virologic response within our study population was 100%.

Background and Aims: The advent of direct-acting antiviral agents promises to change the management of hepatitis C virus infection (HCV) in patients with chronic kidney disease (CKD), a patient group in which the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' cohort of patients with CKD., Methods: We performed an observational single-arm multi-centre study in a large (n=198) cohort of patients with stage 1-3 CKD who underwent antiviral therapy with DAAs for the treatment of HCV. The primary end-point was sustained virologic response (serum HCV RNA <15IU/mL, 12 weeks after treatment ended) (SVR12). We collected data on on-treatment adverse events (AEs), severe AEs, and laboratory abnormalities., Results: The average baseline eGFR (CKD-EPI equation) was 70.06±20.1mL/min/1.72m 2 ; the most common genotype was HCV 1b (n=93, 51%). Advanced liver scarring was found in 58 (46%) patients by transient elastography. Five regimens were adopted: elbasvir/grazoprevir (n=5), glecaprevir/pibrentasvir (n=4), ritonavir-boosted paritaprevir/ombitasvir/dasabuvir (PrOD) regimen (n=40), simeprevir±daclatasvir (n=2), and sofosbuvir-based combinations (n=147). The SVR12 rate was 95.4% (95% CI, 93.8%; 96.8%). There were nine virological failures - eight being relapsers. Adverse events occurred in 30% (51/168) of patients, and were managed clinically without discontinuation of therapy or hospitalization. One of the most common AEs was anaemia (n=12), which required discontinuation or dose reduction of ribavirin in some cases (n=6); deterioration of kidney function occurred in three (1.7%)., Conclusions: All-oral, interferon-free therapy with DAAs for chronic HCV in mild-to-moderate CKD was effective and well-tolerated in a 'real-world' clinical setting. Studies are in progress to address whether sustained viral response translates into better survival in this population., (Copyright © 2019. Published by Elsevier España, S.L.U.)

Objective: The recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-based regimes have become a poor treatment choice in clinical practice. Today DAAs offer shorter, well-tolerated, highly effective curative therapies. This study aimed to evaluate the effectiveness and safety of DAAs in patients with end-stage renal disease and HCV genotype 1 infection in real clinical practice., Methods: Thirty-six patients who attended our clinic, were diagnosed with chronic hepatitis C (CHC), undergoing hemodialysis, and fulfilled the criteria of age >18 years, genotype 1 infection, with a detectable HCV RNA level were considered for the study. Patients with GT1a infection received OBV/PTV/r plus DSV plus RBV for 12 weeks; GT1b infected patients received this regimen without RBV for 12 weeks., Results: The study was conducted on 33 patients. The mean age was 52.30 ±13.77 years, and 70 % of them were male. By the fourth week of treatment, HCV RNA levels decreased below 15 IU/ml in all patients. Sustained virologic response (SVR) 12 rate was 100%. Nine patients had side effects during treatment. Of the patients with side effects, 89.9% were in group 1a and 11.1% in group 1b., Conclusion: In this study, treatment with OBV/PTV/r and DSV with or without RBV resulted in high rates of sustained virologic response in HCV GT1-infected patients with end-stage renal disease (ESRD). SVR was achieved in all patients with few side effects.

Aim: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain., Material and Methods: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded., Results: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin., Conclusions: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV., Competing Interests: José Manuel Sousa has received fees as speaker from AbbVie, MSD and Gilead. Mercedes Vergara has received fees as an advisory board member from Gilead and has given lectures for AbbVie, Intercept, MSD, Janssen-Cilag and Gilead. Federico Pulido has received fees as speaker and advisor from AbbVie, Gilead, Janssen and MSD. Gloria Sánchez-Antolín has acted as speaker for AbbVie, MSD, Gilead Science, Novartis and Astellas. Diego Rincón has given lectures for AbbVie and MSD. Javier Salmerón has received speaker fees and grant funding from AbbVie; he declares no further conflict of interest. Luisa García-Buey has received speaker fees and travel grants from Abbvie, MSD and Gilead. José A. Carrión has received speaker fees from Abbvie, Gilead and MSD and has received fees as Advisor for AbbVie. Manuel Hernández-Guerra has been a consultant to Gilead Sciences, Intercept Pharmaceuticals, Abbvie and Bayer; he has received grant funding from Gilead Sciences and Abbvie. Nuria Espinosa has participated in Clinical Trials managed by Gilead and ViiV Healthcare; she has received advisory board, conference and course fees as well as expenses for attending congresses from Janssen-Cilag, Gilead Sciences, ViiV Healthcare, MSD and Abbvie. Rosa Mª Morillas has acted as a speaker for Gilead, Merck, AbbVie and Intercept, and has participated in advisory boards for AbbVie, Gilead and Intercept. Raul J. Andrade: Advisor/Speaker Bureau: Abbvie, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen; Research Grants: Willmar Schwabe GmbH & Co, Gedeon Richter/Preglem S.A. Manuel Delgado has received scientific advisor fees from Abbie, Gilead, MSD. José M Moreno-Planas has received speaker fees from AbbVie, MSD, Gilead and Bayer. Fernando Menéndez has received fees as advisor from Bayer. Luis Morano has acted as speaker, advisor and/or investigator for Abbvie, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen, Boehringer Ingelheim, Novartis, and Roche Farma. Manuel Rodríguez consults for and is on the speaker’s bureau for Gilead and AbbVie. Sara Lorente has received lecture fees from Abbvie, Gilead Sciences and MSD. Miguel Ángel Von-Wichmann has received fees as speaker and advisor from Abbvie, BMS, Gilead, Janssen, MSD and VIIV. Amanda Manzanares is employee of AbbVie and may hold stock or options. Lander Hijona, Fernando Carnicer, Beatriz Mateos-Muñoz, Antoni Jou, Benjamín Polo-Lorduy, Ángel Rubín, Ana Escarda, Patricia Aguilar, Teresa Aldámiz-Echevarría, Sonia Chimeno-Hernández, Adolfo Gallego, Marta Magaz, Ángel Estébanez, Mikel Rico, Blanca Sampedro, Sonia Izquierdo, José Manuel Zozaya, Senador Morán-Sánchez, Ignacio Martín-Granizo, Marcial Delgado declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Direct-acting antiviral agents (DAAs) have revolutionized treatment of chronic hepatitis C in patients with normal glomerular filtration rate (GFR). However, patients with impaired kidney function have been excluded from several clinical trials. We, therefore, investigated the use, effectiveness, and tolerability of DAAs in patients with GFR less than 30 ml/min in the real-world setting., Patients and Methods: An analysis was done within the German Hepatitis C-Registry on 5733 patients including 46 individuals with a baseline GFR less than 30 ml/min treated with sofosbuvir-based (61%) or paritaprevir/ritonavir-based (39%) regimens., Results: Sustained virological response 12 rates did not differ significantly between patients with baseline GFR less than 30 versus more than 30 ml/min (91 vs. 96%). Nine individuals with a baseline GFR more than 30 ml/min presented with a GFR less than 30 ml/min at the end of treatment. GFR improvement from less than 30 ml/min to more than 30 ml/min was observed in 9/46 cases. Adverse events did not differ in patients with GFR less than 30 versus more than 30 ml/min. However, serious adverse events were significantly more frequent in individuals with GFR less than 30 ml/min and associated with ribavirin., Conclusion: Different DAA therapies can be safely used with high sustained virological response rates in patients with GFR less than 30 ml/min. Ribavirin has to be avoided because of poor tolerability.

Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new direct-acting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir± Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/ Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or non-response (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver- Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/ or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virological-response.

Background and Aims: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015., Material and Methods: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records., Results: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision., Conclusions: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials., Competing Interests: MCL has served as consultant for AbbVie, MSD, Janssen, BMS and Gilead; MRB has received grant Research from Gilead Science, and speaker fees from AbbVie, Gilead and MSD; MR has received speaker fees from AbbVie; MJDM has served as speaker for AbbVie, Gilead, Janssen, and MSD and as a consultant for MSD; MAS has served as advisor for AbbVie, BMS, Gilead, MSD and Roche; CAN has served as consultant for AbbVie and Bayer, and has received speaker fees from AbbVie and Gilead; SMS has served as speaker for AbbVie and MSD; AC has served as consultant for Janssen, and has received speaker fees from Gilead and Janssen; MD has received grant support and consultancy fees from AbbVie, Bayer, Bristol-Myers Squibb, Gilead and Merck, Sharp & Dhome; FGR has served as speaker for AbbVie, Gilead and BMS; MLM has served as a speaker for AbbVie, BMS, Gilead, Janssen, MSD and ViiV; as a consultant for AbbVie, BMS and Janssen and has received research funding from FIPSE 36465/03, FIPSE 36680/07.-NEAT IG5 (NEAT is a project funded by the European Union under the 6th Framework programme) contract number LSHP-CT-2006–037570; MAC has served as a consultant for Gilead and and ViiV healthcare, and has received speaker fees from Janssens, Gilead, ViiV Healthcare; MMA reports personal fees from ViiV Healthcare, Gilead Sciences, Merck, Janssen, AbbVie and ABBOTT Laboratories, outside the submitted work; AR has received consultancy and speaker fees from AbbVie, Gilead Sciences and Merck Sharp & Dohme; JM has received honoraria, speaker fees, consultant fees or funds for research from AbbVie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Roche and ViiV; GB has served as speaker for Nutricia and Palex Medical, and has participated in mentoring for Nefralia and Vifor Fresenius; EGP has received speaker fees from AbbVie and Gilead; LGB has served as consultant for AbbVie and Intercept and has received speaker fees from Gilead and MSD; AA, RMG, CB, TAE, MLG, BPL, LIC, SB, LB, JGS, MJP, IMG, LM, LIdlS, ML and JEL don’t have a financial interest or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this paper; CdA and AM are paid employees of AbbVie and may hold stock or options. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background & Aims: A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs., Methods: PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment., Results: Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements., Conclusions: In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities., Lay Summary: Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) infection remains unclear. Using a systematic review and meta-analysis approach, we aimed to investigate the effect of DAA therapy on sustained virologic response (SVR) among patients with CHC and either active, inactive or no HCC., Methods: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from 1/1/2013 to 9/24/2018. The pooled SVR rates were computed using DerSimonian-Laird random-effects models., Results: We included 49 studies from 15 countries, comprised of 3,341 patients with HCC and 35,701 without HCC. Overall, the pooled SVR was lower in patients with HCC than in those without HCC (89.6%, 95% CI 86.8-92.1%, I 2  = 79.1% vs. 93.3%, 95% CI 91.9-94.7%, I 2  = 95.0%, p = 0.0012), translating to a 4.8% (95% CI 0.2-7.4%) SVR reduction by meta-regression analysis. The largest SVR reduction (18.8%) occurred in patients with active/residual HCC vs. inactive/ablated HCC (SVR 73.1% vs. 92.6%, p = 0.002). Meanwhile, patients with HCC who received a prior liver transplant had higher SVR rates than those who did not (p <0.001). Regarding specific DAA regimens, patients with HCC treated with ledipasvir/sofosbuvir had lower SVR rates than patients without HCC (92.6%, n = 884 vs. 97.8%, n = 13,141, p = 0.026), but heterogeneity was high (I 2  = 84.7%, p <0.001). The SVR rate was similar in patients with/without HCC who were treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 101) (97.2% vs. 94.8%, p = 0.79), or daclatasvir/asunaprevir (91.7% vs. 89.8%, p = 0.66)., Conclusion: Overall, SVR rates were lower in patients with HCC, especially with active HCC, compared to those without HCC, though heterogeneity was high. Continued efforts are needed to aggressively screen, diagnose, and treat HCC to ensure higher CHC cure rates., Lay Summary: There are now medications (direct-acting antivirals or "DAAs") that can "cure" hepatitis C virus, but patients with hepatitis C and liver cancer may be less likely to achieve cure than those without liver cancer. However, patients with liver cancer are also more likely to have advanced liver disease and risk factors that can decrease cure rates, so better controlled studies are needed to confirm these findings., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance-associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1-4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next-generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs, we observed genome-wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments., (© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Background/aims: The Social Security System of our country reimburses only paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD) regime in treatment-naive patients with hepatitis C regardless of kidney disease. Most of our renal transplant (RT) recipients were treated with PrOD. The aim of the present study was to investigate the efficacy and safety of PrOD in RT patients with hepatitis C virus (HCV) infection in a single center real-life experience., Materials and Methods: RT recipients with a post-transplant follow-up of at least 1 year were included in the study. The patients were treated and monitored according to the guidelines. Blood levels of immunosuppressive patients were closely followed up and adjusted., Results: A total of 21 (12 male and nine female) patients were assessed. The age of the patients was 50.8±8.5 years. Ten patients were infected with G1a, 10 patients with G1b, and one patient with G4 HCV. Two patients had compensated cirrhosis. Eighteen patients were treatment-naive, and three were peginterferon+ribavirin-experienced. Sustained virologic response (SVR12) was achieved in all patients. None of the patients discontinued the treatment. Cyclosporine (Csa) and tacrolimus (Tac) doses were reduced to once a day to once a week to maintain the blood level within normal range. The most common adverse effect was anemia in patients receiving ribavirin. Renal functions did not change during the treatment period., Conclusion: In this real-life experience, all of the 21 PrOD-treated RT recipients reached SVR12. Tac or Csa serum levels were maintained within the normal range with close monitoring. PrOD regime can be successfully and safely used in RT recipients with HCV infection with close follow-up.

Patients infected with hepatitis C virus (HCV) treated with interferon-free direct-acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open-label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low-dose ribavirin for 12 weeks in genotype 1a-infected patients without cirrhosis. The primary efficacy endpoint was sustained virologic response at post-treatment Week 12 (SVR12). The primary safety endpoint was haemoglobin <10 g/dL during treatment and decreased from baseline. Overall, 105 patients enrolled. The SVR12 rate was 89.5% (n/N = 94/105; 95% CI, 83.7-95.4). The study did not achieve noninferiority versus the historic SVR12 rate for OBV/PTV/r + DSV plus weight-based ribavirin. Five patients experienced virologic failure, four discontinued, and two had missing SVR12 data. Excluding nonvirologic failures, the SVR12 rate was 94.9% (n/N = 94/99). One patient met the primary safety endpoint. OBV/PTV/r + DSV plus low-dose ribavirin offers an alternative option for patients in whom full-dose ribavirin may compromise tolerability, although noninferiority to the weight-based ribavirin regimen was not met., (© 2019 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Introduction: Despite high efficacy of current direct-acting antiviral agents (DAAs) in treating chronic hepatitis C virus (HCV) infection, a small portion of patients fail treatment. QUARTZ-I was a phase 2, open-label, multicenter, two-part study that assessed the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) with dasabuvir (DSV) with or without the addition of sofosbuvir (SOF) and/or ribavirin (RBV) in DAA treatment-experienced adults with chronic HCV GT1 infection., Materials and Methods: Genotype 1 HCV-infected patients with or without compensated cirrhosis had prior treatment failure to any DAA (part 1) or ledipasvir/SOF (part 2). Patients received OBV/PTV/r + DSV ± SOF with or without RBV for 12 or 24 weeks. The primary endpoint of this study is the percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12)., Results: In part 1 of the study, 95.5% (21/22) of patients achieved SVR12, and in part 2, the SVR12 rate was 85.7% (6/7). Most adverse events (AEs) were mild and moderate in severity. Two serious AEs occurred and were assessed as not being related to study drug, of which one resulted in study drug discontinuation. Two patients experienced grade 3 elevations of serum alanine aminotransferase, and no other grade ≥3 laboratory abnormalities were observed., Conclusion: The multi-targeted regimen of OBV/PTV/r + DSV ± SOF with or without RBV was effective in the treatment of patients who failed previous DAA regimens including NS3/4A protease and NS5A and NS5B polymerase inhibitors. These results provide a promising outcome for patients that traditionally had limited treatment options., (© 2019 Wiley Periodicals, Inc.)

Introduction: Recent studies have suggested a higher recurrence rate of hepatocellular carcinoma (HCC) in patients with a history of HCC and hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antiviral (DAA) agents., Material and Methods: We conducted a prospective analysis of 24 patients with HCV-associated cirrhosis and treated HCC who received ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin for 12 weeks. Prior therapies for HCC included resection (9/24 patients), radiofrequency ablation (RFA) (7/24) and trans-arterial chemoembolization (TACE) (8/24). All patients were eligible for treatment if they had no HCC recurrence 6 months after their last procedure. A control group was defined. All patients were followed every 6 months, with dynamic computed tomography and/or magnetic resonance imaging., Results: The sustained virological response rate per protocol was 21/24 (87.5%). The study group included 14 (59%) males, median age 64 years (51-77), 50% with associated non-alcoholic steatohepatitis and 24% with Child-Pugh A6 points. HCC recurrence rate/100 patient-years was lower in the DAA-HCC group versus control: 5.5 versus 24.6% patient-years for the resection+RFA group ( p  = 0.044), respectively, and 18.6 versus 72.7% patient-years for TACE group ( p  = 0.002). Survival without recurrence was higher in the resection+RFA group (45 compared to 18 months ( p  < 0.001)) and also in the TACE group (44 compared to 11.5 months ( p  = 0.002))., Conclusions: DAA therapy significantly reduced the recurrence rate of HCC and improved survival without recurrence in patients with treated HCV-associated HCC.

Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC 50 values vary from 0.077 μM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC 50 50-100 μM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment-naïve or -experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post-treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off-label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow-up data at post-treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2-96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b-infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro-esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post-baseline Grade 3-4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real-world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real-world setting., (© 2019 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin shows favorable results in hepatitis C virus genotype 1 (HCV-1) patients in terms of safety and efficacy, but real-world data remain limited for those with advanced hepatic fibrosis (fibrosis 3, F3) or compensated cirrhosis (F4). A total of 941 patients treated in four hospitals (the Keelung, the Linkuo, the Chiayi and the Kaohsiung Chang Gung Memorial Hospital) through a nationwide government-funded program in Taiwan were enrolled. Patients with HCV and advanced hepatic fibrosis or compensated cirrhosis received 12 weeks of PrOD in HCV-1b and 12 or 24 weeks of PrOD plus ribavirin therapy in HCV-1a without or with cirrhosis. Advanced hepatic fibrosis or compensated cirrhosis was confirmed by either ultrasonography, fibrosis index based on 4 factors (FIB-4) test, or transient elastography/acoustic radiation force impulse (ARFI). The safety and efficacy (sustained virologic response 12 weeks off therapy, SVR 12 ) were evaluated. An SVR 12 was achieved in 887 of 898 (98.8%) patients based on the per-protocol analysis (subjects receiving ≥1 dose of any study medication and HCV RNA data available at post-treatment week 12). Child-Pugh A6 (odds ratio: 0.168; 95% confidence interval (CI): 0.043-0.659, p = 0.011) was the only significant factor of poor SVR 12 . Fifty-four (5.7%) patients were withdrawn early from the treatment because of hepatic decompensation (n = 18, 1.9%) and other adverse reactions. Multivariate analyses identified old age (odds ratio: 1.062; 95% CI: 1.008-1.119, p = 0.024) and Child-Pugh A6 (odds ratio: 4.957; 95% CI: 1.691-14.528, p = 0.004) were significantly associated with hepatic decompensation. In conclusion, this large real-world cohort proved PrOD with or without ribavirin to be highly effective in chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis. However, Child-Pugh A6 should be an exclusion criterion for first-line treatment in these patients.

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.

Background and Aim: Transient elastography and fibrosis-4 index (FIB-4) have been proposed to access hepatic fibrosis and steatosis for patients with chronic liver disease. This study was to determine the changes of liver stiffness (LS), controlled attenuation parameter (CAP) value and FIB-4 and their associated factors for chronic hepatitis C (CHC) patients who underwent direct-acting antivirals (DAAs)., Patients and Methods: Consecutive patients with CHC in advanced fibrosis or compensated cirrhosis undergoing paritaprevir/ritonavir/ombitasvir plus dasabuvir therapy and with LS and CAP before and 12 weeks after treatment were enrolled. The demographics, clinical characteristics and treatment outcomes were reviewed. The changes of LS, FIB-4, CAP and their associated factors were analyzed., Results: A total of 213 patients (mean age: 63.7 years) with complete recommended treatment were enrolled. All patients achieved sustained virological response at 12 weeks (SVR12) of follow-up. The mean values of LS, CAP and FIB-4 index before treatment were 18.5kPa, 283dB/m and 5.05 respectively. While there was no significant change in CAP, LS and FIB-4 decreased significantly at the time of SVR12 (p<0.001). Compared with follow-up period, LS and FIB-4 decreased rapidly during DDAs. Multivariate analysis showed that higher baseline LS and FIB-4 were associated with greater reductions at the time of SVR12., Conclusion: For CHC patients in advanced fibrosis or compensated cirrhosis, DAAs improved LS and FIB-4 index at SVR12. Higher baseline LS and FIB-4 contributed to greater reductions. However, there was no significant change in CAP value., Competing Interests: The authors have declared that no competing interests exist.

Background/aims: As the most common liver disease in hemodialysis patients, chronic hepatitis C (CHC) can cause cirrhosis and hepatocellular carcinoma, even increase in renal-related mortality. In Turkey, the frequency of anti-hepatitis C virus (HCV) antibodies in hemodialysis patients ranged from 31.4% to 51%. Until recently, the mainstay of the CHC treatment for these patients was pegylated interferon with potential toxicities and low sustained virological response. The 3D regimen, a combination of four drugs (ombitasvir, paritaprevir, dasabuvir, and ritonavir), has recently been used for patients with chronic kidney disease infected with genotype 1a and 1b HCV. The aim of the present study was to present results of 3D treatment for patients with hemodialysis-dependent chronic renal failure (CRF) who were chronically infected with HCV., Materials and Methods: Overall, 25 patients with hemodialysis-dependent CRF who were infected with genotype 1a/1b HCV have been treated using the 3D regimen in our gastroenterology clinic between July 2016 and October 2017. Three patients were administered additional ribavirin 200 mg/day. Serum HCV RNAs, blood chemistry, blood count, and side effects were recorded at 0, 4, and 12 weeks., Results: All 25 patients completed and well tolerated their planned treatment. At the end of 4 weeks, the viral response (defined as HCV RNA clearance) rate was 92%. At the end of 12 weeks of treatment and 3 months after treatment, viral response rates were both 100%., Conclusion: We observed that the treatment with 3D regimen in hemodialysis patients infected with genotype 1 hepatitis C is highly effective and well tolerated.

Introduction: Both hepatitis C virus infection (HCV) and chronic kidney disease (CKD) have been comorbid illnesses with increasing morbidity and mortality. The present study was conducted to present real-life experiences about treatment of HCV and CKD with a fixed-dose combination of paritaprevir 150 mg/day, ritonavir 100 mg/day as a booster, ombitasvir 25 mg/day, and dasabuvir 250 mg twice/day, the PROD regimen., Patients and Methods: This was a multicenter, retrospective cohort study. Seventy-five patients with both HCV and CKD were treated with a PROD-based regimen with or without ribavirin. Fifty-three of 75 patients were on maintenance hemodialysis program. Seven patients had compensated liver cirrhosis. The patients with genotype 1a or compensated liver cirrhosis were treated with the PROD regimen and ribavirin in a dose of 200 mg every other day for 12 weeks. The patients with genotype 1b were treated with PROD for 12 weeks. The patients with genotype 4 were treated with a combination of paritaprevir, ritonavir, ombitasvir, and ribavirin 200 mg every other day., Results: All patients except one were HCV-RNA negative (98.6%) at the end of treatment. One patient had decompensated after the fourth day of therapy. She stopped the treatment, and she was exitus after 2 months. Two patients died of reasons not related to the drugs 2 months after negativity of HCV-RNA. Sustained viral rate 12 weeks after treatment was found in 96% of the patients., Conclusion: The PROD regimen was very effective and safe for treatment in patients with HCV and CKD who were in stages 4 and 5.

Introduction: In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes., Patients and Methods: This is a prospective, interventional, single-center study at Hospital Clínic de Barcelona. All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period (2014-2017) were analyzed (n=20). Data on virologic response, adverse events, and biochemical and hematological parameters during and after DAA therapy were analyzed., Results: All patients achieved sustained virologic response (SVR) and only 40% of patients presented with mild AEs. None of the patients presented with HCV reinfection after a 1-year follow-up period, and thus HCV was eliminated from our HD unit. SVR was associated with a significant increase in hemoglobin and hematocrit, and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose., Conclusion: HCV infection can be safely eliminated from HD units with the use of DAAs, preventing new infections in patients and healthcare staff. In the short term, the achievement of SVR is associated with an improvement in the control of anemia., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

The role of the endogenous interferon (IFN) system has been well characterized during IFN-based therapy for chronic hepatitis C virus (HCV) infection; less is known for direct-acting antivirals (DAAs). In this phase 3b open-label study, we assessed changes in IFN-stimulated genes (ISGs) in non-cirrhotic treatment-naïve or pegIFN/RBV-experienced HCV-GT1a-infected patients receiving paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin (PrOD + R) for 12 weeks. ISG expression was quantified from peripheral blood mononuclear cells at baseline, treatment weeks (TW)2, TW4, TW8, end of treatment (EOT) and at post-treatment week 12. Paired sera were used to assess IFN-α/IFN-related chemokines/cytokines. Twenty-five patients were enrolled. Overall sustained virologic response (SVR)12 was 92% (no virologic failure [VF]) and 100% for those completing the study protocol. Two patients were excluded from the ISG analysis due to lack of post-treatment samples. The majority of ISGs were downregulated at TW2-TW4 (nadir TW4); however, a relative increase was observed at TW8-EOT, although levels were lower than baseline. This downregulation was accompanied by increases in IFN-α/IFN-related chemokines, a finding not observed with T H 1/2-related cytokines. Following SVR, ISG expression returned to TW2 levels. In conclusion, PrOD + R for 12 weeks was well-tolerated with no VF. Our data demonstrate dynamic alterations in innate immune profiles during highly potent IFN-free DAA therapy. The downregulation of ISG post-therapy suggests reversal of the "exhausted" ISG phenotype following SVR, and the rise in ISGs and IFN-α/IFN-responsive chemokines late during therapy suggests resetting of IFN responsiveness that may be relevant in determining duration of or immunological sequelae from DAA therapy, including HBV reactivation., (© 2018 John Wiley & Sons Ltd.)

The aim of this study was to investigate the efficacy and safety of the ombitasvir/ paritaprevir/ ritonavir and dasabuvir in patients with HCV, genotype-1b, in real clinical practice in Ukraine. The study included a total of 50 HCV infection genotype 1b patients receiving ombitasvir/ paritaprevir/ ritonavir and dasabuvir for 12 weeks. The patients were evaluated in respect of demographic, clinical and virological data, sustained virologic response (SVR) and adverse events. The mean age of patients was 52 years (40-60), 42% men, 20% treatment experienced, 42% with compensated cirrhosis. The SVR12 rate of all HCV genotype 1b patients was 96% (95%CI:86,3-99,5%). The most common adverse events were fatigue in 14 (28%) patients, diarrhea in 10 (20%) and headache in 12 (24%). In our study, the real world clinical practice data shows that ombitasvir/ paritaprevir/ ritonavir and dasabuvir for 12 weeks in HCV genotype 1b patients was well tolerated and resulted in 96% SVR12 regardless of previous treatment status and liver fibrosis stage.