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Li Y, Liu W, Li Y, Peng T, Wang J, Zou T. Preparation and antitumor of hyaluronic acid-human serum albumin-indocyanine green-paclitaxel nanoparticles. Int J Biol Macromol 2025; 318:145131. [PMID: 40513730 DOI: 10.1016/j.ijbiomac.2025.145131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 05/29/2025] [Accepted: 06/08/2025] [Indexed: 06/16/2025]
Abstract
Human serum albumin (HSA)-indocyanine green (ICG)-paclitaxel (PTX) nanoparticles have been prepared for tumor photothermal-photodynamic-chemotherapy, which was inevitably internalized by normal cells. Here, hyaluronic acid (HA)-HSA-ICG-PTX nanoparticles were designed for active targeting mediated tumor multimodal therapy. HA as a ligand imparted the characteristics of the nanoparticles to specifically target the CD44 receptors overexpressed tumor cells, while enhancing the stability of the nanoparticles. HSA-ICG-PTX@HA nanoparticles were selectively internalized by CD44 overexpressed cervical and breast cancer (Hela and MCF-7) cells, rather than normal (293) cells lacking the receptor. Moreover, compared with HSA-ICG-PTX nanoparticles, HSA-ICG-PTX@HA nanoparticles exhibited improved tumor cell uptake and cytotoxicity, as well as enhanced photothermal effects and tumor suppressor effects. Therefore, tumor-targeting, human serum protein-based nanoparticles entirely consisting of FDA-approved compounds were demonstrated for fluorescent-photoacoustic-photothermal imaging mediated multimodal tumor therapy.
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Affiliation(s)
- You Li
- State Key Laboratory of Refractories and Metallurgy, Key Laboratory of Coal Conversion & New Carbon Materials of Hubei Province, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China
| | - Wei Liu
- School of Medicine, Jianghan University, Wuhan 430056, PR China
| | - Ying Li
- State Key Laboratory of Refractories and Metallurgy, Key Laboratory of Coal Conversion & New Carbon Materials of Hubei Province, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China
| | - Tao Peng
- GEM (Wuhan) Urban Mining Industrial Group Co., Ltd., Wuhan 430415, PR China
| | - Jing Wang
- Laboratory for Genetic Engineering of Antibodies and Functional Proteins, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
| | - Tao Zou
- State Key Laboratory of Refractories and Metallurgy, Key Laboratory of Coal Conversion & New Carbon Materials of Hubei Province, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.
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2
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Makovich Z, Radosavljevic I, Chapyala S, Handley G, Pena L, Mok S, Friedman M. Rationale for Hepatitis C Virus Treatment During Hematopoietic Stem Cell Transplant in the Era of Novel Direct-Acting Antivirals. Dig Dis Sci 2024; 69:3488-3500. [PMID: 38990268 DOI: 10.1007/s10620-024-08541-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/20/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND AND AIMS Untreated hepatitis C (HCV) infection in patients undergoing hematopoietic stem cell transplantation (HSCT) can lead to worse outcomes. Traditionally, HSCT patients infected with HCV would wait until after immune reconstitution to receive HCV therapy, as the oncologic urgency of transplant would not allow time for a full preceding treatment course of HCV therapy. However, in the era of newer direct-acting antivirals (DAAs), we propose that concomitant treatment of HCV while undergoing HSCT is safe and feasible, while keeping in mind potential drug-drug interactions. METHODS A literature review was performed to summarize the available data on the impact of HCV on patients undergoing HSCT. Drug-drug interactions for DAA's and pertinent HSCT drugs were evaluated using Lexicomp online® and http://hep-druginteractions.org . RESULTS During HSCT, HCV appears to be a conditional risk factor for sinusoidal obstruction syndrome and a potential risk factor for graft versus host disease, both of which are associated with increased mortality. HCV reactivation and exacerbation may impact the use of chemotherapeutics, but available studies haven't shown impact specifically on HSCT. Limited case reports exist but demonstrate safe and effective use DAAs during HSCT. These, along with a drug-drug interaction review demonstrate agents such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are promising DAAs for use in HSCT. CONCLUSION HCV infection may worsen outcomes for patients undergoing HSCT. Concomitant treatment of HCV during HSCT using newer DAAs appears feasible and may improve patient morbidity and mortality, however large-scale studies are needed to further support this practice.
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Affiliation(s)
- Zachary Makovich
- University of South Florida Morsani College of Medicine, 560 Channelside Dr, Tampa, FL, 33602, USA.
| | - Ivana Radosavljevic
- University of South Florida Morsani College of Medicine, 560 Channelside Dr, Tampa, FL, 33602, USA
| | - Shreya Chapyala
- University of South Florida Morsani College of Medicine, 560 Channelside Dr, Tampa, FL, 33602, USA
| | - Guy Handley
- H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Luis Pena
- H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Shaffer Mok
- H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Mark Friedman
- H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
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Panjasawatwong N, Avihingsanon A, Menétrey C, Ribeiro I, Salvadori N, Swanson A, Gillon JY, Tan SS, Thanprasertsuk S, Thongsawat S, Cressey TR, the STORM-C-1 study team. Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment. Antimicrob Agents Chemother 2024; 68:e0000824. [PMID: 38767383 PMCID: PMC11232402 DOI: 10.1128/aac.00008-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/23/2024] [Indexed: 05/22/2024] Open
Abstract
Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.
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Affiliation(s)
- Navarat Panjasawatwong
- Department of Pharmaceutical Care, Faculty of Pharmacy, Payap University, Chiang Mai, Thailand
| | - Anchalee Avihingsanon
- The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Center, Bangkok, Thailand
| | | | - Isabela Ribeiro
- Drugs for Neglected Diseases Initiative, Geneva, Switzerland
| | - Nicolas Salvadori
- AMS-PHPT Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | | | | | - Soek-Siam Tan
- Department of Hepatology, Selayang Hospital, Selayang, Malaysia
| | | | | | - Tim R. Cressey
- AMS-PHPT Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - the STORM-C-1 study team
- Department of Pharmaceutical Care, Faculty of Pharmacy, Payap University, Chiang Mai, Thailand
- The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Center, Bangkok, Thailand
- Drugs for Neglected Diseases Initiative, Geneva, Switzerland
- AMS-PHPT Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Hepatology, Selayang Hospital, Selayang, Malaysia
- Department of Disease Control, Ministry of Public Health, Bangkok, Thailand
- Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Kumar A, Narang RK, Bhatia R. Recent advancements in NS5B inhibitors (2011-2021): Structural insights, SAR studies and clinical status. J Mol Struct 2023; 1293:136272. [DOI: 10.1016/j.molstruc.2023.136272] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2025]
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Medina C, García AH, Crespo FI, Toro FI, Mayora SJ, De Sanctis JB. A Synopsis of Hepatitis C Virus Treatments and Future Perspectives. Curr Issues Mol Biol 2023; 45:8255-8276. [PMID: 37886964 PMCID: PMC10605161 DOI: 10.3390/cimb45100521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
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Affiliation(s)
- Christian Medina
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Alexis Hipólito García
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Francis Isamarg Crespo
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Félix Isidro Toro
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Soriuska José Mayora
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, 779 00 Olomouc, Czech Republic
- The Czech Advanced Technology and Research Institute (Catrin), Palacky University, 779 00 Olomouc, Czech Republic
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Izhari MA. Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. Diagnostics (Basel) 2023; 13:3102. [PMID: 37835845 PMCID: PMC10572573 DOI: 10.3390/diagnostics13193102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/23/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), n = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n = 9) and genotype 5 (n = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure.
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Affiliation(s)
- Mohammad Asrar Izhari
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha 65522, Saudi Arabia
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Minami T, Sato M, Toyoda H, Yasuda S, Yamada T, Nakatsuka T, Enooku K, Nakagawa H, Fujinaga H, Izumiya M, Tanaka Y, Otsuka M, Ohki T, Arai M, Asaoka Y, Tanaka A, Yasuda K, Miura H, Ogata I, Kamoshida T, Inoue K, Nakagomi R, Akamatsu M, Mitsui H, Fujie H, Ogura K, Uchino K, Yoshida H, Hanajiri K, Wada T, Kurai K, Maekawa H, Kondo Y, Obi S, Teratani T, Masaki N, Nagashima K, Ishikawa T, Kato N, Yotsuyanagi H, Moriya K, Kumada T, Fujishiro M, Koike K, Tateishi R. Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals. J Hepatol 2023; 79:S0168-8278(23)00424-5. [PMID: 37716372 DOI: 10.1016/j.jhep.2023.05.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 04/03/2023] [Accepted: 05/23/2023] [Indexed: 09/17/2023]
Abstract
BACKGROUND AND AIMS Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.
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Affiliation(s)
- Tatsuya Minami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital
| | - Tomoharu Yamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Hidetaka Fujinaga
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Masashi Izumiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Yasuo Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Takamasa Ohki
- Department of Gastroenterology, Mitsui Memorial Hospital
| | - Masahiro Arai
- Department of Gastroenterology, Toshiba General Hospital
| | | | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine
| | | | - Hideaki Miura
- Department of Gastroenterology, Tokyo Yamate Medical Center
| | - Itsuro Ogata
- Department of Gastroenterology, Kawakita General Hospital
| | | | - Kazuaki Inoue
- Department of Gastroenterology, Showa University Fujigaoka Hospital
| | - Ryo Nakagomi
- Department of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teacher
| | | | | | - Hajime Fujie
- Department of Gastroenterology, Tokyo Shinjuku Medical Center
| | - Keiji Ogura
- Department of Gastroenterology, Tokyo Metropolitan Police Hospital
| | - Koji Uchino
- Department of Gastroenterology, Japanese Red Cross Medical Center
| | - Hideo Yoshida
- Department of Gastroenterology, Japanese Red Cross Medical Center
| | | | | | | | - Hisato Maekawa
- Department of Gastroenterology and Hepatology, Tokyo Takanawa Hospital
| | - Yuji Kondo
- Department of Gastroenterology and Hepatology, Kyoundo Hospital
| | - Shuntaro Obi
- Department of Gastroenterology and Hepatology, Kyoundo Hospital
| | - Takuma Teratani
- Department of Hepato-Bililary-Pancreatic Medicine, NTT Medical Center Tokyo
| | - Naohiko Masaki
- Clinical Laboratory Department, Center Hospital of the National Center for Global Health and Medicine
| | - Kayo Nagashima
- Department of Gastroenterology, National Disaster Medical Center
| | | | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Hiroshi Yotsuyanagi
- Division of Infectious Disease and Applied Immunology, The University of Tokyo the Institute of Medical Science Research Hospital
| | - Kyoji Moriya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo.
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Ivashkin VT, Chulanov VP, Mamonova NA, Maevskaya MV, Zharkova MS, Tikhonov IN, Bogomolov PO, Volchkova EV, Dmitriev AS, Znojko OO, Klimova EA, Kozlov KV, Kravchenko IE, Malinnikova EY, Maslennikov RV, Mikhailov MI, Novak KE, Nikitin IG, Syutkin VE, Esaulenko EV, Sheptulin AA, Shirokova EN, Yushchuk ND. Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2023; 33:84-124. [DOI: 10.22416/1382-4376-2023-33-1-84-124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Аim:diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary.Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion.Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation.
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Affiliation(s)
- V. T. Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - V. P. Chulanov
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - N. A. Mamonova
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - M. V. Maevskaya
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. S. Zharkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - I. N. Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - P. O. Bogomolov
- M.F. Vladimirsky Moscow Regional Research Clinical Institute
| | - E. V. Volchkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - A. S. Dmitriev
- Sechenov First Moscow State Medical University (Sechenov University)
| | - O. O. Znojko
- Moscow State University of Medicine and Dentistry
| | | | | | | | - E. Yu. Malinnikova
- Department of Virology, Russian Medical Academy of Continuing Professional Education
| | - R. V. Maslennikov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. I. Mikhailov
- North-Western State Medical University named after I.I. Mechnikov
| | | | | | - V. E. Syutkin
- Sklifosovsky Clinical and Research Institute for Emergency Medicine; Russian State Research Center — Burnazyan Federal Medical Biophysical Center
| | | | - A. A. Sheptulin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - E. N. Shirokova
- Sechenov First Moscow State Medical University (Sechenov University)
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Matoba D, Noda T, Kobayashi S, Sasaki K, Iwagami Y, Yamada D, Tomimaru Y, Takahashi H, Doki Y, Eguchi H. Analysis of Short-Term and Long-Term Outcomes of Living Donor Liver Transplantation for Patients with a High Model for End-Stage Liver Disease Score. Transplant Proc 2023:S0041-1345(23)00149-5. [PMID: 37120341 DOI: 10.1016/j.transproceed.2023.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/13/2023] [Indexed: 05/01/2023]
Abstract
BACKGROUND The Model of End-Stage Liver Disease (MELD) scoring system can predict short-term survival among patients awaiting liver transplantation and is used to allocate organs prioritizing liver transplantation. Patients with high MELD scores have been reported to have worse early graft dysfunction and survival. However, recent studies have shown that patients with high MELD scores had satisfactory graft survival, although they showed more postoperative complications. In this study, we examined the effect of the MELD score on the short-term and long-term prognosis of living donor liver transplantation (LDLT). METHODS This study included 102 patients who underwent LDLT in our institution between 2005 and 2020. The patients were divided into 3 groups according to MELD score (low MELD group: ≤20, moderate MELD group: 21-30, and high MELD group: ≥31). Perioperative factors were compared among the 3 groups, and cumulative overall survival rates were calculated using the Kaplan-Meier method. RESULTS The patients' characteristics were comparable, and the median age was 54 years. Hepatitis C virus cirrhosis was the most common primary disease (n = 40), followed by hepatitis B virus (n = 11). The low MELD group consisted of 68 patients (median score: 16, 10-20); the moderate MELD group, 24 patients (median score: 24, 21-30); and the high MELD group, 10 patients (median score: 35, 31-40). The mean operative time (1241 min versus 1278 min versus 1158 min, P = .19) and mean blood loss (7517 mL vs 11162 mL vs 8808 mL, P = .71) were not significantly different among the 3 groups. The vascular and biliary complication rates were similar. The periods of intensive care unit and hospital stay tended to be longer in the high MELD group, but the difference was insignificant. The 1-year postoperative survival rate (85.3 % vs 87.5 % vs 90.0 %, P = .90) and overall survival rate were also not significantly different among the 3 groups. CONCLUSIONS Our study showed that LDLT patients with high MELD scores do not have a worse prognosis than those with low scores.
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Affiliation(s)
- Daijiro Matoba
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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10
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Brzdęk M, Zarębska-Michaluk D, Invernizzi F, Cilla M, Dobrowolska K, Flisiak R. Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C. World J Gastroenterol 2023; 29:949-966. [PMID: 36844142 PMCID: PMC9950869 DOI: 10.3748/wjg.v29.i6.949] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/10/2023] Open
Abstract
Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce 25-516, Poland
| | | | - Federica Invernizzi
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | - Marta Cilla
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
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11
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Krekulová L, Damajka T, Krumphanslová Z, Řehák V. Pilot Outreach Program in Remedis-The Promising Step toward HCV Elimination among People Who Inject Drugs. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 20:501. [PMID: 36612821 PMCID: PMC9819867 DOI: 10.3390/ijerph20010501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 06/17/2023]
Abstract
The global effort to eliminate HCV infection requires new approaches to accessing and testing the affected population in a setting with as low of a threshold as possible. The focus should be on socially marginalized people who inject drugs (PWIDs) and who are not willing or able to visit standard medical services. With this vision, we established an outreach service-a testing point in an ambulance in the park in front of the Main Railway Station of the capital city of Prague-to provide bloodborne disease testing and treatment. The service was available every week on Wednesday afternoon. Over the initial two years of our experience, 168 unique people were tested. Of them, 82 (49%) were diagnosed with chronic HCV infection and were eligible for treatment with antivirals. Of these, 24 (29%) initiated antiviral treatment over the study period, and 17 (71%) of these individuals achieved a documented sustained virological response. Offering medical services in PWIDs' neighborhoods helps overcome barriers and increase the chances that they will become patients and begin HCV treatment. The described outcomes appear promising for reaching the vision of linkage to the care of such a hard-to-reach population and can serve as a feasible model of care for further expansion.
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Affiliation(s)
- Laura Krekulová
- Remedis, s.r.o., Vladimírova 10, 140 00 Prague 4, Czech Republic
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University in Prague, Kateřinská 32, 128 00 Prague 2, Czech Republic
| | - Tomáš Damajka
- Remedis, s.r.o., Vladimírova 10, 140 00 Prague 4, Czech Republic
| | | | - Vratislav Řehák
- Remedis, s.r.o., Vladimírova 10, 140 00 Prague 4, Czech Republic
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12
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Zarębska-Michaluk D, Brzdęk M, Jaroszewicz J, Tudrujek-Zdunek M, Lorenc B, Klapaczyński J, Mazur W, Kazek A, Sitko M, Berak H, Janocha-Litwin J, Dybowska D, Supronowicz Ł, Krygier R, Citko J, Piekarska A, Flisiak R. Best therapy for the easiest to treat hepatitis C virus genotype 1b-infected patients. World J Gastroenterol 2022; 28:6380-6396. [PMID: 36533109 PMCID: PMC9753050 DOI: 10.3748/wjg.v28.i45.6380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/01/2022] [Accepted: 11/19/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND The revolution in treatment of patients with chronic hepatitis C virus (HCV) infection dates back to the introduction of direct-acting antivirals (DAAs). The increase in efficacy was most pronounced in patients infected with genotype (GT) 1b, as this was the most poorly responsive population to treatment during the interferon era.
AIM To identify the most effective interferon-free therapy for GT1b-infected patients and to determine positive and negative predictors of virological response.
METHODS This real-world retrospective analysis included patients chronically infected with GT1b HCV whose data were obtained from the multicenter observational EpiTer-2 database. Treatment effectiveness was evaluated for each therapeutic regimen as the percentage of sustained virological responses (SVR). Assessment of the safety was based on the evaluation of the course of therapy, the occurrence of adverse events including serious ones, deaths during treatment and in the post 12-wk follow-up period.
RESULTS The studied population consisted of 11385 patients with a mean age of 53 ± 14.8 years and a female predominance (53.4%). The majority of them were treatment-naïve (74.6%) and patients with cirrhosis accounted for 24.3%. Of the DAA regimens used, 76.9% were GT-specific with ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin being the most used option (32.4%). A total of 10903 patients responded to treatment resulting in a 98.1% in the per-protocol analysis after excluding 273 patients without SVR data. The effectiveness of all regimens exceeded 90% and the highest SVR of 98.9% was achieved in patients treated with a combination of glecaprevir/pibrentasvir. Logistic regression analyses showed that the virologic response was independently associated with female sex [odds ratio (OR) = 1.67], absence of decompensated cirrhosis at baseline (OR = 2.42) and higher baseline platelets (OR = 1.004 per 1000/μL increase), while the presence of human immunodeficiency virus (HIV) coinfection significantly decreased the odds of response (OR = 0.39). About 95%-100% of patients completed therapy irrespective of the drug regimen. At least one adverse effect occurred in 10.9%-36.3% and most of them were mild. No treatment related deaths have been reported.
CONCLUSION We documented very high effectiveness and a good safety profile across all DAA regimens. Positive predictors of SVR were female sex, absence of decompensated cirrhosis at baseline and higher platelet count while HIV coinfection reduced the effectiveness.
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Affiliation(s)
| | - Michał Brzdęk
- Department of Infectious Diseases, Jan Kochanowski University, Kielce 25-317, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice 40-055, Poland
| | | | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University Gdańsk, Gdańsk 80-214, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Warszawa 00-241, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Medical University of Silesia, Chorzów 41-500, Poland
| | | | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków 31-088, Poland
| | - Hanna Berak
- Hospital for Infectious Diseases, Hospital for Infectious Diseases, Warszawa 02-091, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Medical University Wrocław, Wrocław 50-367, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz 85-030, Poland
| | - Łukasz Supronowicz
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-089, Poland
| | - Rafał Krygier
- Infectious Diseases and Hepatology Outpatient Clinic, Gemini NZOZ, Żychlin 62-571, Poland
| | - Jolanta Citko
- Medical Practice of Infections, Regional Hospital, Olsztyn 10-561, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University Łódź, Łódź 90-419, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-089, Poland
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13
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Ryu JE, Song MJ, Kim SH, Kwon JH, Yoo SH, Nam SW, Nam HC, Kim HY, Kim CW, Yang H, Bae SH, Song DS, Chang UI, Yang JM, Lee SW, Lee HL, Lee SK, Sung PS, Jang JW, Choi JY, Yoon SK. Safety and effectiveness of direct-acting antivirals in patients with chronic hepatitis C and chronic kidney disease. Korean J Intern Med 2022; 37:958-968. [PMID: 35981893 PMCID: PMC9449192 DOI: 10.3904/kjim.2021.486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/11/2021] [Accepted: 01/17/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND/AIMS To evaluate the effectiveness and safety of direct acting antivirals (DAAs) available in chronic kidney disease (CKD) patients with hepatitis C virus (HCV) infection in Korea. METHODS In a retrospective, multicenter cohort study, 362 patients were enrolled from 2015 to 2019. The effectiveness and safety of DAAs including glecaprevir/pibrentasvir, sofosubvir/ribavirin, ledipasvir/sofosbuvir, and daclatasvir/asunaprevir were analyzed for patients according to CKD stage. We evaluated sustained virologic response at week 12 after treatment (SVR12) as primary endpoint. The effectiveness and safety were also evaluated according to CKD stage. RESULTS Among 362 patients, 307 patients completed DAAs treatment and follow-up period after end of treatment. The subjects comprised 87 patients (62 with CKD stage 3 and 25 with CKD stage (4-5), of whom 22 were undergoing hemodialysis). HCV patients with CKD stage 1 and 2 (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2) showed SVR12 of 97.2% and 95.4% respectively. SVR12 of CKD stage 3 and 4-5 (eGFR < 60 mL/min/1.73 m2) patients was 91.9% and 91.6% respectively. Patients undergoing hemodialysis achieved SVR12 (90.9%). Treatment failure of DAAs in stage 1, 2, 3, and 4-5 was 2.8%, 2.7%, 1.6%, and 4%. DAAs showed good safety profile and did not affect deterioration of renal function. CONCLUSION DAAs shows comparable SVR12 and safety in CKD patients (stage 3, 4, and 5) with HCV compared with patients with stage 1 and 2. The effectiveness and safety of DAAs may be related to the treatment duration. Therefore, it is important to select adequate regimens of DAAs and to increase treatment adherence.
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Affiliation(s)
- Ji Eun Ryu
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok-Hwan Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sun Hong Yoo
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soon Woo Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hee Chul Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hee Yeon Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Wook Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Do Seon Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - U Im Chang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hae Lim Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Pil Soo Sung
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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14
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Kuwano A, Yada M, Nagasawa S, Tanaka K, Morita Y, Masumoto A, Motomura K. Hepatitis C virus eradication ameliorates the prognosis of advanced hepatocellular carcinoma treated with sorafenib. J Viral Hepat 2022; 29:543-550. [PMID: 35499194 DOI: 10.1111/jvh.13681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 03/22/2022] [Indexed: 01/27/2023]
Abstract
The risk of hepatocellular carcinoma (HCC) occurrence following hepatitis C virus (HCV) eradication has been previously reported, but the impact of HCV eradication on advanced HCC patient survival remains unclear. Therefore, the present study aimed to evaluate the effect of HCV eradication on the survival outcome of patients with advanced HCC treated with sorafenib. One hundred and three HCV-related advanced HCC patients who were treated with sorafenib were enrolled in this study. Of these, 43 patients were administered antiviral therapy before sorafenib treatment (HCV eradication group), while 60 patients remained HCV-infected (HCV non-eradication group). We analysed the impact of HCV eradication on survival in advanced HCC treated with sorafenib. Median overall survival (OS) was significantly longer in the HCV eradication group than in the HCV non-eradication group (24.0 months vs. 14.1 months; p = 0.001). Although there was no significant difference in the albumin-bilirubin (ALBI) score at the start of treatment between the HCV eradication group and the non-eradication group (p = 0.065), the ALBI score at 2 months after initiation of sorafenib treatment was significantly decreased in the HCV non-eradication group (p < 0.001), but not in the HCV eradication group (p = 0.121). Multivariate logistic analysis revealed HCV eradication (hazard ratio [HR], 0.5; p = 0.006) and ALBI score at the start of treatment (HR, 2.47; p = 0.002) as factors that may contribute to OS. HCV eradication may serve an important role in the survival outcome of advanced HCC patients treated with sorafenib.
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | | | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | - Yusuke Morita
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | | | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
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15
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Farooq M, Khan AW, Ahmad B, Kim MS, Choi S. Therapeutic Targeting of Innate Immune Receptors Against SARS-CoV-2 Infection. Front Pharmacol 2022; 13:915565. [PMID: 35847031 PMCID: PMC9280161 DOI: 10.3389/fphar.2022.915565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
The innate immune system is the first line of host's defense against invading pathogens. Multiple cellular sensors that detect viral components can induce innate antiviral immune responses. As a result, interferons and pro-inflammatory cytokines are produced which help in the elimination of invading viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to Coronaviridae family, and has a single-stranded, positive-sense RNA genome. It can infect multiple hosts; in humans, it is responsible for the novel coronavirus disease 2019 (COVID-19). Successful, timely, and appropriate detection of SARS-CoV-2 can be very important for the early generation of the immune response. Several drugs that target the innate immune receptors as well as other signaling molecules generated during the innate immune response are currently being investigated in clinical trials. In this review, we summarized the current knowledge of the mechanisms underlying host sensing and innate immune responses against SARS-CoV-2 infection, as well as the role of innate immune receptors in terms of their therapeutic potential against SARS-CoV-2. Moreover, we discussed the drugs undergoing clinical trials and the FDA approved drugs against SARS-CoV-2. This review will help in understanding the interactions between SARS-CoV-2 and innate immune receptors and thus will point towards new dimensions for the development of new therapeutics, which can be beneficial in the current pandemic.
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Affiliation(s)
- Mariya Farooq
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Ajou University, Suwon, South Korea
| | - Abdul Waheed Khan
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Bilal Ahmad
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Ajou University, Suwon, South Korea
| | - Moon Suk Kim
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Ajou University, Suwon, South Korea
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16
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Khan M, Rauf W, Habib FE, Rahman M, Iqbal S, Shehzad A, Iqbal M. Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease. BMC Complement Med Ther 2022; 22:98. [PMID: 35366855 PMCID: PMC8976278 DOI: 10.1186/s12906-022-03578-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 03/25/2022] [Indexed: 11/29/2022] Open
Abstract
Background Hepatitis C virus infection is the main cause of liver ailments across the globe. Several HCV genotypes have been identified in different parts of the world. Effective drugs for combating HCV infections are available but not affordable, particularly to infected individuals from resource-limited countries. Hence, cost-effective drugs need to be developed against important HCV drug targets. As Citrus fruits naturally contain bioactive compounds with antiviral activities, the current study was designed to identify antiviral inhibitors from Citrus fruit extracts against an important drug target, NS3 protease, of HCV genotype 3a which is found predominantly in South Asian countries. Methods The full-length NS3 protease alone and the NS3 protease domain in fusion with the cognate NS4A cofactor were expressed in Escherichia coli, and purified by chromatographic techniques. Using the purified protein as a drug target, Citrus extracts were evaluated in a FRET assay, and active ingredients, identified using ESI–MS/MS, were docked to observe the interaction with active site residues of NS3. The best interacting compound was further confirmed through the FRET assay as the inhibitor of NS3 protease. Results Fusion of the NS3 protease domain to the NS4A cofactor significantly improved the purification yield, and NS3-NS4A was functionally more active than the full-length NS3 alone. The purified protein (NS3-NS4A) was successfully employed in a validated FRET assay to evaluate 14 Citrus fruit extracts, revealing that the mesocarp extract of Citrus paradisi, and whole fruit extracts of C. sinesis, C. aurantinum, and C. reticulata significantly inhibited the protease activity of HCV NS3 protease (IC50 values of 5.79 ± 1.44 µg/mL, 37.19 ± 5.92 µg/mL, 42.62 ± 6.89 µg/mL, and 57.65 ± 3.81 µg/mL, respectively). Subsequent ESI-MSn analysis identified a flavonoid, hesperidin, abundantly present in all the afore-mentioned Citrus extracts. Importantly, docking studies suggested that hesperidin interacts with active site residues, and acts as a potent inhibitor of NS3 protease, exhibiting an IC50 value of 11.34 ± 3.83 µg/mL. Conclusions A FRET assay was developed using NS3-NS4A protease, which was successfully utilized for the evaluation of Citrus fruit extracts. Hesperidin, a compound present in the Citrus extracts, was identified as the main flavonoid, which can serve as a cost-effective potent inhibitor of NS3 protease, and could be developed as a drug for antiviral therapy against HCV genotype 3a. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-022-03578-1.
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Kim IJ, Yoo SH, Kim S, Cho YY, Yoo KY, Kim HJ, Lee HW. Low Incidence of Hepatocellular Carcinoma after Antiviral Therapy in Patients with Chronic Hepatitis C and Hemophilia. J Clin Med 2022; 11:jcm11051451. [PMID: 35268541 PMCID: PMC8911386 DOI: 10.3390/jcm11051451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/05/2022] [Accepted: 03/06/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) rarely develops in patients with chronic hepatitis C (CHC) who achieve sustained virological response (SVR). We assessed the incidence of HCC in CHC patients with hemophilia after treatment with pegylated interferon plus ribavirin (PegIFN/RBV) and direct-acting antivirals (DAAs). Methods: Patients (n = 202) were enrolled between March 2007 and July 2019. A total of 139 patients were treated with PegIFN/RBV (genotype 1, n = 98; genotype 2, n = 41). Sixty-three patients were treated with DAAs (genotype 1, n = 44; genotype 2, n = 19). The cumulative incidence rates of HCC were estimated using the Kaplan−Meier method and compared using the log-rank test. Results: For genotype 1, SVR was achieved in 78.6% (77/98) and 90.9% (40/44) of patients in the PegIFN/RBV and DAAs groups, respectively. For genotype 2, SVR was achieved in 95.1% (39/41) and 94.7% (18/19) of patients in the PegIFN/RBV and DAAs groups, respectively. Six HCC cases were identified. The cumulative incidence of HCC was 4.1% at 14 years in PegIFN/RBV and 1.7% at 5 years in DAAs. The 14-year cumulative incidence of HCC was 1.9% in the SVR group and 21.7% in the no-SVR group in the PegIFN/RBV group (p < 0.001). Conclusions: Treatment with PegIFN/RBV led to stable SVR and a low incidence of HCC. Although the follow-up period was short, DAAs led to more stable SVR than PegIFN/RBV and a low incidence of HCC in CHC patients with hemophilia.
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Affiliation(s)
- In Jung Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
| | - Sung Hwan Yoo
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
| | - Sora Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
| | - Young Youn Cho
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06973, Korea;
| | - Ki Young Yoo
- Department of Pediatrics, Korea Hemophilia Foundation Hospital, Seoul 06641, Korea;
| | - Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06973, Korea;
- Correspondence: (H.J.K.); (H.W.L.); Tel.: +82-2-6299-1417 (H.J.K.); +82-2-2019-3315 (H.W.L.); Fax: +82-2-6299-1137 (H.J.K.); +82-2-3463-3882 (H.W.L.)
| | - Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (I.J.K.); (S.H.Y.); (S.K.)
- Correspondence: (H.J.K.); (H.W.L.); Tel.: +82-2-6299-1417 (H.J.K.); +82-2-2019-3315 (H.W.L.); Fax: +82-2-6299-1137 (H.J.K.); +82-2-3463-3882 (H.W.L.)
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Patil VS, Harish DR, Vetrivel U, Roy S, Deshpande SH, Hegde HV. Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. Molecules 2022; 27:molecules27031076. [PMID: 35164341 PMCID: PMC8839135 DOI: 10.3390/molecules27031076] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/15/2022] [Accepted: 01/22/2022] [Indexed: 01/27/2023] Open
Abstract
Terminalia chebula Retz. forms a key component of traditional folk medicine and is also reported to possess antihepatitis C virus (HCV) and immunomodulatory activities. However, information on the intermolecular interactions of phytochemicals from this plant with HCV and human proteins are yet to be established. Thus, by this current study, we investigated the HCV NS3/4A inhibitory and host immune-modulatory activity of phytocompounds from T. chebula through in silico strategies involving network pharmacology and structural bioinformatics techniques. To start with, the phytochemical dataset of T. chebula was curated from biological databases and the published literature. Further, the target ability of the phytocompounds was predicted using BindingDB for both HCV NS3/4A and other probable host targets involved in the immune system. Further, the identified targets were docked to the phytochemical dataset using AutoDock Vina executed through the POAP pipeline. The resultant docked complexes with significant binding energy were subjected to 50 ns molecular dynamics (MD) simulation in order to infer the stability of complex formation. During network pharmacology analysis, the gene set pathway enrichment of host targets was performed using the STRING and Reactome pathway databases. Further, the biological network among compounds, proteins, and pathways was constructed using Cytoscape 3.6.1. Furthermore, the druglikeness, side effects, and toxicity of the phytocompounds were also predicted using the MolSoft, ADVERpred, and PreADMET methods, respectively. Out of 41 selected compounds, 10 were predicted to target HCV NS3/4A and also to possess druglike and nontoxic properties. Among these 10 molecules, Chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose exhibited potent HCV NS3/4A inhibitory activity, as these scored a lowest binding energy (BE) of −8.6 kcal/mol and −7.7 kcal/mol with 11 and 20 intermolecular interactions with active site residues, respectively. These findings are highly comparable with Asunaprevir (known inhibitor of HCV NS3/4A), which scored a BE of −7.4 kcal/mol with 20 key intermolecular interactions. MD studies also strongly suggest that chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose as promising leads, as these molecules showed stable binding during 50 ns of production run. Further, the gene set enrichment and network analysis of 18 protein targets prioritized 10 compounds and were predicted to potentially modulate the host immune system, hemostasis, cytokine levels, interleukins signaling pathways, and platelet aggregation. On overall analysis, this present study predicts that tannins from T. chebula have a potential HCV NS3/4A inhibitory and host immune-modulatory activity. However, further experimental studies are required to confirm the efficacies.
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Affiliation(s)
- Vishal S. Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
| | - Darasaguppe R. Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Correspondence: (D.R.H.); (S.R.)
| | - Umashankar Vetrivel
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- ICMR-National Institute for Research in Tuberculosis, Chetpet, Chennai 600031, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Correspondence: (D.R.H.); (S.R.)
| | - Sanjay H. Deshpande
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Regional Centre for Biotechnology, NCR-Biotech Science Cluster, Faridabad 121001, India
| | - Harsha V. Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
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Pabjan P, Brzdęk M, Chrapek M, Dziedzic K, Dobrowolska K, Paluch K, Garbat A, Błoniarczyk P, Reczko K, Stępień P, Zarębska-Michaluk D. Are There Still Difficult-to-Treat Patients with Chronic Hepatitis C in the Era of Direct-Acting Antivirals? Viruses 2022; 14:96. [PMID: 35062302 PMCID: PMC8779728 DOI: 10.3390/v14010096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 12/17/2022] Open
Abstract
Difficult-to-treat populations with chronic hepatitis C (CHC), in the era of interferon treatment, included patients with liver cirrhosis, kidney impairment, treatment-experienced individuals, and those coinfected with the human immunodeficiency virus. The current study aimed to determine whether, in the era of direct-acting antivirals (DAA), there are still patients that are difficult-to-treat. The study included all consecutive patients chronically infected with hepatitis C virus (HCV) who started interferon-free therapy between July 2015 and December 2020 in the Department of Infectious Diseases in Kielce. The analyzed real-world population consisted of 963 patients, and most of them were infected with genotype 1 (87.6%) with the predominance of subtype 1b and were treatment-naïve (78.8%). Liver cirrhosis was determined in 207 individuals (21.5%), of whom 82.6% were compensated. The overall sustained virologic response, after exclusion of non-virologic failures, was achieved in 98.4%. The univariable analysis demonstrated the significantly lower response rates in males, patients with liver cirrhosis, decompensation of hepatic function at baseline, documented esophageal varices, concomitant diabetes, body mass index ≥25, and previous ineffective antiviral treatment. Despite an overall very high effectiveness, some unfavorable factors, including male gender, genotype 3 infection, liver cirrhosis, and treatment experience, significantly reduce the chances for a virologic response were identified.
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Affiliation(s)
- Paweł Pabjan
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Magdalena Chrapek
- Faculty of Natural Sciences, Jan Kochanowski University, 25-369 Kielce, Poland;
| | - Kacper Dziedzic
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Krystyna Dobrowolska
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Katarzyna Paluch
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Anna Garbat
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Błoniarczyk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Katarzyna Reczko
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Stępień
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
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Kuwano A, Yada M, Nagasawa S, Tanaka K, Morita Y, Masumoto A, Motomura K. Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment. J Viral Hepat 2022; 29:35-42. [PMID: 34661320 DOI: 10.1111/jvh.13625] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/14/2021] [Accepted: 09/21/2021] [Indexed: 01/15/2023]
Abstract
Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1 year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1 year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5 years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8 ng/ml ≥1 year following treatment with DAAs (HR, 9.7; p < .0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1 year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | | | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Yusuke Morita
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Akihide Masumoto
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
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Villamil FG, Massenzio NE, Baré PC, Cocco PA, Cairo FM, Picchio GR. Twenty-year follow-up of an outbreak of hepatitis C in a small rural town of Argentina: The O'Brien Project. Ann Hepatol 2022; 27 Suppl 1:100577. [PMID: 34740846 DOI: 10.1016/j.aohep.2021.100577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/08/2021] [Accepted: 04/08/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES In 1999, a population-based survey showed a 5.6 % (102/1832) prevalence of HCV infection in O'Brien, a small rural town of Argentina. The aim of this study was to assess the impact of screening, clinical evaluation and antiviral therapy on elimination of HCV after 20 years of follow-up. PATIENTS AND METHODS HCV+ subjects (n=102) underwent clinical, biochemical and histological evaluation to assess the presence and severity of liver disease. Antiviral therapy included pegylated interferon + ribavirin in 2005 and direct antiviral agents from 2017. RESULTS All viremic subjects (n=84) had genotype 1b with 90%-97.5% sequence homology scores, suggesting the existence of a common source of infection (use of unsafe injections administered by the same health professional). Liver biopsy (n=55) showed chronic hepatitis in all patients. The prevalence of cirrhosis was 28% overall (29/102) and 34.5% among viremic patients. Sustained virological response (SVR) was obtained in 20/34 (59%) patients treated with interferon. From 2005 to 2017, when oral antivirals became available 37/50 untreated patients died. Median age of this group in 2005 was 67 years. Six interferon non-responders and five naive subjects received direct antiviral agents and all developed SVR. Only 1/31 patient (3.2%) with SVR died and none developed decompensated cirrhosis or HCC. In 2019, a new population-based study showed that the prevalence of HCV in O'Brien decreased 20-fold, from 5.6% to 0.28% (3/1070). CONCLUSIONS Despite the high mortality rate precluding timely access to direct antiviral agents, the O'Brien Project is a good example of HCV micro-elimination studies.
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Affiliation(s)
- Federico Guillermo Villamil
- Liver Transplantation Unit, British Hospital, Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplantation Unit, Hospital El Cruce, Florencio Varela, Provincia Buenos Aires, Argentina.
| | | | - Patricia Cristina Baré
- Instituto de Investigaciones Hematológicas, Instituto de Medicina Experimental CONICET, Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires, Argentina
| | - Paula Andrea Cocco
- Unidad Sanitaria "Martín Espinel Bavio", O'Brien, Provincia Buenos Aires, Argentina
| | - Fernando Mario Cairo
- Liver Transplantation Unit, British Hospital, Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplantation Unit, Hospital El Cruce, Florencio Varela, Provincia Buenos Aires, Argentina
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Lafferty L, Cochrane A, Sheehan Y, Treloar C, Grebely J, Lloyd AR. "That was quick, simple, and easy": Patient perceptions of acceptability of point-of-care hepatitis C RNA testing at a reception prison. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2021; 99:103456. [PMID: 34560624 DOI: 10.1016/j.drugpo.2021.103456] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Current diagnostic pathways require multiple healthcare provider visits and lead to a drop-off in the hepatitis C virus (HCV) testing and treatment care cascade. In prison settings, frequent transitioning between prisons and the community further reduces uptake of testing and treatment. The PIVOT study evaluated a 'one-stop-shop' intervention integrating point-of-care HCV RNA testing, Fibroscan®-based liver disease assessment, and treatment prescription at a reception prison in Australia. This qualitative sub-study was undertaken to assess patient acceptability of point-of-care HCV RNA testing in the reception prison setting. METHODS Twenty-four men in prison enrolled in the PIVOT study participated in semi-structured interviews; all of whom had undergone point-of-care HCV RNA testing in the PIVOT study. Patients were purposefully selected to ensure comparable representation of people with and without a history of injecting drug use and people with and without prior HCV testing experience (standard venepuncture). Sekhon's Theoretical Framework of Acceptability, consisting of seven components (affective attitude, burden, ethicality, intervention coherence, opportunity cost, perceived effectiveness, and self-efficacy), informed this qualitative analysis. RESULTS Acceptability of fingerstick point-of-care HCV RNA testing was evident across four components: affective attitude, burden, self-efficacy, and perceived effectiveness. Patients described point-of-care testing as "quick and easy" (affective attitude), while swift results were viewed as alleviating anxiety associated with long wait times for standard pathology (burden). Patients averse to venepuncture (e.g., fear of needles or poor vein health) found the fingerstick method accessible, thereby enabling participation in HCV screening (self-efficacy). Participants attributed confidence in test results predominantly due to trust in the healthcare system or trust in the personnel administering the test (perceived effectiveness). CONCLUSION People entering custody perceive fingerstick HCV RNA point-of-care testing to be an acceptable method and preferred this method to standard HCV testing via venepuncture. In light of these findings, prison health authorities should consider the role of opt-out point-of-care HCV RNA testing upon prison entry.
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Affiliation(s)
- Lise Lafferty
- Centre for Social Research in Health, UNSW Sydney, Level 1, Goodsell Building, Sydney, NSW, 2052, Australia; The Kirby Institute, UNSW Sydney, Level 6, Wallace Wurth Building, Sydney, NSW, 2052, Australia.
| | - Amanda Cochrane
- The Kirby Institute, UNSW Sydney, Level 6, Wallace Wurth Building, Sydney, NSW, 2052, Australia; Justice and Forensic Mental Health Network, NSW Health, PO Box 150, Matraville, NSW, 2036, Australia
| | - Yumi Sheehan
- The Kirby Institute, UNSW Sydney, Level 6, Wallace Wurth Building, Sydney, NSW, 2052, Australia
| | - Carla Treloar
- Centre for Social Research in Health, UNSW Sydney, Level 1, Goodsell Building, Sydney, NSW, 2052, Australia
| | - Jason Grebely
- The Kirby Institute, UNSW Sydney, Level 6, Wallace Wurth Building, Sydney, NSW, 2052, Australia
| | - Andrew R Lloyd
- The Kirby Institute, UNSW Sydney, Level 6, Wallace Wurth Building, Sydney, NSW, 2052, Australia
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Aisyah DN, Story A, Kremyda-Vlachou M, Kozlakidis Z, Shalcross L, Hayward A. Assessing hepatitis C virus distribution among vulnerable populations in London using whole genome sequencing: results from the TB-REACH study. Wellcome Open Res 2021. [DOI: 10.12688/wellcomeopenres.16907.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background: Injecting drugs substantially increases the risk of hepatitis C virus (HCV) infection and is common in vulnerable population groups, such as the homeless and prisoners. Capturing accurate data on relative genotype distribution within these groups is essential to inform strategies to reduce HCV transmission. The aim of this study was to utilise a next-generation whole-genome sequencing method recently validated by Public Health England, in order to produce near complete HCV genomes. Methods: In total, 98 HCV positive patients were recruited from homeless hostels and drug treatment services through the National Health Services (NHS) Find and Treat (F&T) Service between May 2011 and June 2013 in London, UK. Samples were sequenced by Next-generation sequencing, with 88 complete HCV genomes constructed by a de novo assembly pipeline. They were analysed phylogenetically for an estimate of their genetic distance. Results: Of the 88 complete HCV genomes, 50/88 (56.8%) were genotype 1; 32/88 (36.4%) genotype 3; 4/88 (4.5%) genotype 2; and 1/88 (1.1%) for genotypes 4 and 6 each. Subtype 1a had the highest number of samples (51.1%), followed by subtype 3a (35.2%), 1b (5.7%), and 2b (3.4%). Samples collected from drug treatment services had the highest number of genotype 1 (69%); genotypes 4 and 6 were only found from samples collected in homeless shelters. Small clusters of highly related genomic sequences were observed both across and within the vulnerable groups sampled. Conclusions: Subsequent phylogenetic analysis provides a first indication that there are related HCV sequences amongst the three vulnerable population groups, reflecting their overlapping social behaviours. This study is the first presentation of whole genome HCV sequences from such vulnerable groups in London and paves the way for similar research in the future.
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Bloom DE, Khoury A, Srinivasan V. Estimating the net value of treating hepatitis C virus using sofosbuvir-velpatasvir in India. PLoS One 2021; 16:e0252764. [PMID: 34292958 PMCID: PMC8297876 DOI: 10.1371/journal.pone.0252764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
Recently developed direct-acting antiviral (DAA) treatments for hepatitis C virus (HCV) have been groundbreaking for their high efficacy across disease genotypes and lack of severe side effects. This study uses a cost-of-illness (COI) approach to estimate the net value conferred by this class of drugs using the cost and efficacy of one of these novel drug combinations, sofosbuvir and velpatasvir (SOF/VEL), recently licensed for generic manufacture in India. This study considers COI of lifetime earnings lost by patients and potential secondarily infected individuals due to disability and premature death from HCV infection. Expected net benefits of treatment are substantial for non-cirrhotic (NC) and compensated cirrhotic (CC) patients (ranging from 5,98,003 INR for NC women to 1,05,25,504 INR for CC men). Increased earnings are not sufficient to fully offset cost of treatment for decompensated cirrhotic individuals but treatment may still be justified on the basis of the intrinsic value of health improvements and other treatment benefits.
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Affiliation(s)
- David E. Bloom
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
- * E-mail:
| | - Alexander Khoury
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
| | - V. Srinivasan
- Stanford Graduate School of Business, Stanford, California, United States of America
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Baghel AS, Aghi A, Kumar A. Ru(II)-Catalyzed Controlled Cross-Dehydrogenative Coupling of Benzamides with Activated Olefins via Weakly Coordinating Primary Amides. J Org Chem 2021; 86:9744-9754. [PMID: 34196566 DOI: 10.1021/acs.joc.1c01090] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Ru(II)-catalyzed regioselective ortho-alkenylation of primary benzamides with activated olefins has been realized over the competitive cyclized products. This reaction overall proceeds via a cross-dehydrogenative coupling (CDC) reaction using a simple and weakly coordinating primary amide group in the presence of an inexpensive Ru(II) salt and allows the controlled introduction of olefin motifs at the ortho-position of benzamides. The key to the success of this strategy depends on fine-tuning the reaction conditions. The developed protocol has demonstrated excellent regio/diastereoselectivity and a good functional group tolerance with wide substrate scope and obviates the requirement of external auxiliaries as well as the costly metal catalyst. Detailed mechanistic studies indicate the involvement of the base-assisted internal electrophilic-type substitution (BIES) step in the reaction mechanism.
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Affiliation(s)
- Akanksha Singh Baghel
- Department of Chemistry, Indian Institute of Technology Patna, Bihta, Bihar 801106, India
| | - Anjali Aghi
- Department of Chemistry, Indian Institute of Technology Patna, Bihta, Bihar 801106, India
| | - Amit Kumar
- Department of Chemistry, Indian Institute of Technology Patna, Bihta, Bihar 801106, India
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Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol 2021; 9:409-418. [PMID: 34221927 PMCID: PMC8237136 DOI: 10.14218/jcth.2020.00095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/21/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell's hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host's innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85-99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.
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Affiliation(s)
- Corey Saraceni
- Correspondence to: Corey Saraceni, University of Connecticut School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-8074, USA. Tel: +1-203-733-7408, Fax: +1-860-679-3159, E-mail:
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Progress in hepatitis C virus management in chronic kidney disease. Curr Opin Nephrol Hypertens 2021; 30:493-500. [PMID: 34054074 DOI: 10.1097/mnh.0000000000000729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The current review highlights advances in the use of direct-acting antiviral (DAA) agents in the treatment of hepatitis C virus (HCV) in chronic kidney disease (CKD) stages G4-5, end-stage renal disease, and kidney transplantation. The use of DAA to facilitate kidney transplantation of HCV negative recipients with kidneys from HCV-infected donors and in the management of HCV-related cryoglobulinemia are also reviewed. RECENT FINDINGS DAA treatment results in rates of viral clearance (sustained virological response or SVR) of 90-100% in all studied CKD populations, comparable to SVR rates in the general population. DAA treatment allows safe and effective transplantation of HCV viremic kidneys into uninfected recipients. SUMMARY The high SVR results achieved with DAA allow successful treatment of previously under-treated CKD populations, and encouraged innovative interventions such as the use of HCV-infected donor kidneys to uninfected kidney transplant recipients.
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Nagaty A, Helmy SH, Abd El-Wahab EW. Sofosbuvir-/Daclatasvir-based therapy for chronic HCV and HCV/hepatitis B virus coinfected patients in Egypt. Trans R Soc Trop Med Hyg 2021; 114:200-212. [PMID: 31722032 DOI: 10.1093/trstmh/trz079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/25/2019] [Accepted: 07/11/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Dramatic advances in hepatitis C virus (HCV) treatment were witnessed with the introduction of direct-acting antivirals (DAAs). Generic DAAs with remarkable efficacy and good safety profiles are currently manufactured by local pharmaceutical companies in Egypt. METHODS In the real-world setting, of a total of 367 patients chronically infected with HCV, 289 (277 treatment-naïve and 12 treatment-experienced) patients were enrolled. Approximately 15% of the patients were coinfected with hepatitis B virus (HBV). Patients were treated with sofosbuvir+daclatasvir with or without ribavirin for 12 or 24 wk as the standard of care. HBV DNA levels were monitored throughout the study. RESULTS A sustained virologic response at 12 wk (SVR12) was achieved in 98.3% of the patients. All non-responders were treatment-naïve and the response rate among treatment-experienced patients was 100.0%. Elevated α-fetoprotein and treatment with sofosbuvir+daclatasvir+ribavirin for 6 mo were predictors of non-response (OR [95% CI] = 1.06 [1.02 to 1.1] and 15.9 [1.8 to 136.2]; p<0.05, respectively). No HBV reactivation was noticed throughout the treatment and follow-up periods in HCV/HBV coinfected patients. CONCLUSION The present real-world findings add to the evidence for the efficacy of generic DAAs for the treatment of patients infected with HCV. HBV reactivation is unlikely to occur in those coinfected with HBV. Although liver cirrhosis affected the outcome, pretreatment liver chemistry did not seem to correlate with the results of treatment.
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Affiliation(s)
- Ahmed Nagaty
- Consultant of Hepatogastroentrology and Infectious Diseases, Ministry of Health and Population, 21568 Alexandria, Egypt
| | - Sherine Ha Helmy
- Medical Consultant, R&D Project Innovations, Pharco Pharamaceutical Corporation, 679 El Horreya Road, 21569 Alexandria, Egypt
| | - Ekram W Abd El-Wahab
- Tropical Health Department, High Institute of Public Health, Alexandria University, 165 El Horreya Road, 21561 Alexandria, Egypt
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Irekeola AA, Malek NA, Wada Y, Mustaffa N, Muhamad NI, Shueb RH. Prevalence of HCV genotypes and subtypes in Southeast Asia: A systematic review and meta-analysis. PLoS One 2021; 16:e0251673. [PMID: 34014997 PMCID: PMC8136688 DOI: 10.1371/journal.pone.0251673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/29/2021] [Indexed: 12/14/2022] Open
Abstract
Known for its high genetic diversity and variation in genotypic presence in different regions of the world, hepatitis C virus (HCV) is estimated to infect about 71 million people globally. Selection of an appropriate therapeutic regimen largely depends on the identification of the genotype responsible for the infection. This systematic review and meta-analysis was conducted to provide a comprehensive view of HCV genotype and subtype distribution in Southeast Asia (SEA). The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). We searched five databases without year and language restrictions. Data from 90 eligible studies involving 15,089 genotypes and 9,646 subtypes representing 10 SEA countries were analyzed. The pooled estimates showed that genotype 1 (46.8%) [95% CI, 43.2–50.4; I2 = 92.77%; p < 0.001] was the most dominant HCV genotype in the region, followed by genotype 3 (23.1%) [95% CI, 19.4–27.2; I2 = 93.03%; p < 0.001], genotype 6 (16.5%) [95% CI, 13.8–19.6], genotype 2 (4.6%) [95% CI, 3.5–5.9], genotype 4 (1.1%) [95% CI, 0.7–1.5] and genotype 5 (0.8%) [95% CI, 0.4–1.3]. Philippines had the highest prevalence of genotypes 1 and 2. Genotype 6 became more prevalent after year 2000. Over 40 different subtypes were identified, with subtypes 1b (26.3%), 1a (21.3%), and 3a (14.3%) being the most prevalent of all the reported subtypes. Although on a global scale, genotype 6 is considered highly prevalent in SEA, evidence from this study reveals that it is the third most prevalent genotype within the region.
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Affiliation(s)
- Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
- Microbiology Unit, Department of Biological Sciences, College of Natural and Applied Sciences, Summit University Offa, Offa Kwara State, Nigeria
| | - Nurul Adila Malek
- Department of Pathology, Hospital Sultanah Nur Zahirah, Kuala Terengganu, Terengganu, Malaysia
| | - Yusuf Wada
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
- Department of Zoology, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Nazri Mustaffa
- Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Nur Izat Muhamad
- Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Rafidah Hanim Shueb
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- * E-mail:
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Tani J, Senoh T, Moriya A, Ogawa C, Deguchi A, Sakamoto T, Takuma K, Nakahara M, Oura K, Tadokoro T, Mimura S, Fujita K, Yoneyama H, Kobara H, Morishita A, Himoto T, Tsutsui A, Nagano T, Takaguchi K, Masaki T. Long-Term Outcomes and Evaluation of Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Eradication by Direct-Acting Antiviral Treatment: All Kagawa Liver Disease Group (AKLDG) Study. Cancers (Basel) 2021; 13:cancers13092257. [PMID: 34066708 PMCID: PMC8125844 DOI: 10.3390/cancers13092257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/09/2022] Open
Abstract
There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924-8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016-1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
- Correspondence: ; Tel.: +81-87-891-2156
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kagawa 769-1695, Japan;
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Kagawa 760-0017, Japan;
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Kagawa 763-8502, Japan;
| | - Teppei Sakamoto
- Department of Internal Medicine, Yashima General Hospital, Kagawa 761-0816, Japan;
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa 761-0123, Japan;
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
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Zarębska-Michaluk D. Genotype 3-hepatitis C virus’ last line of defense. World J Gastroenterol 2021; 27:1006-1021. [PMID: 33776369 PMCID: PMC7985731 DOI: 10.3748/wjg.v27.i11.1006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/24/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is one of the leading causes of liver disease globally, affecting approximately 71 million people. The majority of them are infected with genotype (GT) 1 but infections with GT3 are second in frequency. For many years, GT3 was considered to be less pathogenic compared to other GTs in the HCV family due to its favorable response to interferon (IFN)-based regimen. However, the growing evidence of a higher rate of steatosis, more rapid progression of liver fibrosis, and lower efficacy of antiviral treatment compared to infection with other HCV GTs has changed this conviction. This review presents the specifics of the course of GT3 infection and the development of therapeutic options for GT3-infected patients in the era of direct-acting antivirals (DAA). The way from a standard of care therapy with pegylated IFN-alpha (pegIFNα) and ribavirin (RBV) through a triple combination of pegIFNα + RBV and DAA to the highly potent IFN-free pangenotypic DAA regimens is discussed along with some treatment options which appeared to be dead ends. Although the implementation of highly effective pangenotypic regimens is the most recent stage of revolution in the treatment of GT3 infection, there is still room for improvement, especially in patients with liver cirrhosis and those who fail to respond to DAA therapies, particularly those containing inhibitors of HCV nonstructural protein 5A.
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Affiliation(s)
- Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Jan Kochanowski University, Kielce 25-369, Świętokrzyskie, Poland
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Analysis of Different Types of Interferon-Associated Retinopathy in Patients with Chronic Hepatitis C Virus Infection Treated with Pegylated Interferon Plus Ribavirin. Viruses 2021; 13:v13030475. [PMID: 33799370 PMCID: PMC8000314 DOI: 10.3390/v13030475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/24/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
This retrospective cohort study aims to investigate interferon (IFN)-associated retinopathy incidence in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon (PegIFN) plus ribavirin (RBV). We selected 1688 patients undergoing PegIFN/RBV therapy for HCV (HCV-treated cohort), 3376 patients not receiving HCV treatment (HCV-untreated cohort) and 16,880 controls without HCV (non-HCV cohort) from the Taiwan Longitudinal Health Insurance Database. The patients were frequency-matched by age, sex, and index date at a 1:2:10 ratio, and followed up until the end of 2013. Cox proportional hazard regression models were used to compare the incidences of any retinal vascular events, including subtypes, among the three cohorts. Compared with the non-HCV cohort, the HCV-treated cohort had a significantly increased risk of retinopathy (hazard ratio (HR) = 4.98, 95% confidence interval (CI): 2.02–12.3). The risk was particularly prominent for retinal hemorrhage (HR = 12.7, 95% CI: 3.78–42.9). When the HCV-untreated cohort was used as the reference, the aforementioned HRs increased to 9.02 (95% CI: 3.04–26.8) and 32.3 (95% CI: 3.94–265), respectively. This study suggested that PegIFN/RBV therapy significantly increased the risk of retinal hemorrhage but not retinal vascular occlusions in the HCV-treated cohort.
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Hsu SJ, Yu ML, Su CW, Peng CY, Chien RN, Lin HH, Lo GH, Su WW, Kuo HT, Hsu CW, Yang SS, Yang SS, Tseng KC, Qin A, Huang YW, Chuang WL. Ropeginterferon Alfa-2b administered every two weeks for patients with genotype 2 chronic hepatitis C. J Formos Med Assoc 2021; 120:956-964. [PMID: 33077341 DOI: 10.1016/j.jfma.2020.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 09/14/2020] [Accepted: 09/27/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to the 8 to 14 isomers of other on-market pegylated interferon products, allowing every-two-week injection with high tolerability. It received European Medicines Agency marketing authorization in 2019 and Taiwan Biologics License Applications Approval in 2020 for the treatment of polycythemia vera. This study aimed to evaluate the safety and efficacy of Ropeginterferon alfa-2b plus ribavirin in genotype 2 chronic hepatitis C (CHC) patients. METHODS Eighty-six treatment naive patients with genotype 2 CHC were randomized to weekly peginterferon alfa-2a (Peg-IFN-α2a) at 180 μg (n = 22), or every-two-week Ropeginterferon alfa-2b at 270 μg (n = 23), 360 μg (n = 21), 450 μg (n = 20), plus daily oral ribavirin 1000 mg (≤75 kg) or 1200 mg (>75 kg). Patients with rapid virologic response received 16-week regimen while those without RVR received 24-week regimen. The primary endpoint was sustained virologic response at 24 weeks post-treatment (SVR24). RESULTS SVR24 was achieved by 95.5%, 78.3%, 85.7%, and 60% of subjects in Peg-IFN-α2a 180 μg, Ropeginterferon alfa-2b 270 μg, 360 μg, and 450 μg groups, respectively. The safety profile was similar across 4 groups. The incidence rate of adverse event during the treatment period was 0.407, 0.252, 0.395, and 0.347 per patient-week, respectively. CONCLUSION Ropeginterferon alfa-2b, although at only half the number of injections, is as safe and effective as Peg-IFN-α2a for genotype 2 CHC. A phase 3 study to confirm safety and efficacy of Ropeginterferon alfa-2b in genotype 2 CHC is ongoing.
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Affiliation(s)
- Shih-Jer Hsu
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan; Hepatology Medical Center, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan.
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taiwan.
| | - Hsien-Hong Lin
- Division of Gastroenterology and Hepatology, Taipei Tzu Chi Hospital, Taipei, Taiwan.
| | - Gin-Ho Lo
- Division of Gastroenterology, Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
| | - Wei-Wen Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
| | - Hsing-Tao Kuo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.
| | - Chao-Wei Hsu
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taiwan.
| | - Sien-Sing Yang
- Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan.
| | - Sheng-Shun Yang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
| | | | | | - Yi-Wen Huang
- Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan; PharmaEssentia Corp., Taipei, Taiwan; School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Wan-Long Chuang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Treem WR, Palmer M, Lonjon-Domanec I, Seekins D, Dimick-Santos L, Avigan MI, Marcinak JF, Dash A, Regev A, Maller E, Patwardhan M, Lewis JH, Rockey DC, Di Bisceglie AM, Freston JW, Andrade RJ, Chalasani N. Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis. Drug Saf 2021; 44:133-165. [PMID: 33141341 PMCID: PMC7847464 DOI: 10.1007/s40264-020-01014-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.
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Affiliation(s)
| | - Melissa Palmer
- Takeda, Cambridge, MA, USA
- Liver Consulting LLC, New York, NY, USA
| | | | | | | | - Mark I Avigan
- US Food and Drug Administration, Silver Spring, MD, USA
| | | | - Ajit Dash
- , Genentech, South San Francisco, CA, USA
| | - Arie Regev
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Eric Maller
- Pfizer, Collegeville, PA, USA
- MEMS Biopharma Consulting, LLC, Wynnewood, PA, USA
| | | | | | - Don C Rockey
- Medical University of South Carolina, Charleston, SC, USA
| | | | - James W Freston
- University of Connecticut Health Center, Farmington, CT, USA
| | - Raul J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd, Universidad de Málaga, Málaga, Spain
| | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, IN, USA.
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer-related death worldwide.
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Maheden K, Todd B, Gordon CJ, Tchesnokov EP, Götte M. Inhibition of viral RNA-dependent RNA polymerases with clinically relevant nucleotide analogs. Enzymes 2021; 49:315-354. [PMID: 34696837 PMCID: PMC8517576 DOI: 10.1016/bs.enz.2021.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The treatment of viral infections remains challenging, in particular in the face of emerging pathogens. Broad-spectrum antiviral drugs could potentially be used as a first line of defense. The RNA-dependent RNA polymerase (RdRp) of RNA viruses serves as a logical target for drug discovery and development efforts. Herein we discuss compounds that target RdRp of poliovirus, hepatitis C virus, influenza viruses, respiratory syncytial virus, and the growing data on coronaviruses. We focus on nucleotide analogs and mechanisms of action and resistance.
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Affiliation(s)
- Kieran Maheden
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Brendan Todd
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Calvin J Gordon
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Egor P Tchesnokov
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Matthias Götte
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada; Li Ka Shing Institute of Virology at University of Alberta, Edmonton, AB, Canada.
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Abstract
Parenteral transmission is the major route of hepatitis C virus transmission in adults; however, vertical transmission is most common in children. There are several factors that have been shown to be associated with vertical transmission of hepatitis C virus, including hepatitis C virus RNA, human immunodeficiency virus coinfection, and peripheral blood mononuclear cell infection. As there is no effective vaccine to prevent hepatitis C virus infection, and there are no human data describing the safety of the new direct acting antiviral agents in pregnancy, the only preventive strategy for vertical transmission is to treat the hepatitis C virus infection before becoming pregnant. Direct acting antiviral agents are interferon-free, and many are also ribavirin-free. Based on animal studies, sofosbuvir plus ledipasvir may be the best safety profile during pregnancy for now; however, it is too early to recommend treating hepatitis C virus-infected pregnant women with these direct acting antiviral agents currently.
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Lee WYJ, Jones M, Wing PAC, Rajagopal S, Foster GR. The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation. Cell Mol Gastroenterol Hepatol 2020; 11:1163-1175. [PMID: 33248325 PMCID: PMC7903130 DOI: 10.1016/j.jcmgh.2020.11.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS Despite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino the acid polymorphism, A150V, in the polymerase (NS5B) of G3 HCV reduces response to sofosbuvir. We now demonstrate that this polymorphism alters the response to interferon alpha. METHODS Quantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons. RESULTS We show the presence of the A150V polymorphism markedly reduces the response to IFN alpha (IC50 of S52_WT = 1.162 IU/mL and IC50 of S52_A150V = 14.45 IU/mL, 12.4-fold difference). The induction of IFN-stimulated genes in A150V replicon cells is unaffected, but nuclear localization of active protein kinase R (PKR) is reduced. Blockade of PKR activity reduced the antiviral effect of IFN on wild-type replicons, whereas augmented PKR activation promoted the antiviral effect of IFN on A150V replicons. Furthermore, we show that impaired activation of PKR in A150V replicon cells diminishes cellular apoptosis. CONCLUSIONS These results demonstrate that polymorphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.
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Affiliation(s)
- Wing-Yiu Jason Lee
- Centre of Immunobiology, Blizard Institute, Queen Mary University of London, London
| | - Meleri Jones
- Centre of Immunobiology, Blizard Institute, Queen Mary University of London, London
| | - Peter A C Wing
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Swathi Rajagopal
- Centre of Immunobiology, Blizard Institute, Queen Mary University of London, London
| | - Graham R Foster
- Centre of Immunobiology, Blizard Institute, Queen Mary University of London, London.
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Pawlotsky JM, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H. EASL recommendations on treatment of hepatitis C: Final update of the series ☆. J Hepatol 2020; 73:1170-1218. [PMID: 32956768 DOI: 10.1016/j.jhep.2020.08.018] [Citation(s) in RCA: 758] [Impact Index Per Article: 151.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, as well as developments in diagnostic procedures and improvements in therapy and prevention. These therapies make it possible to eliminate hepatitis C as a major public health threat, as per the World Health Organization target, although the timeline and feasibility vary from region to region. These European Association for the Study of the Liver recommendations on treatment of hepatitis C describe the optimal management of patients with recently acquired and chronic HCV infections in 2020 and onwards.
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Cafiero C, Re A, Micera A, Palmirotta R, Monaco D, Romano F, Fabrizio C, Di Francia R, Cacciamani A, Surico PL, D’Amato G, Pisconti S. Pharmacogenomics and Pharmacogenetics: In Silico Prediction of Drug Effects in Treatments for Novel Coronavirus SARS-CoV2 Disease. Pharmgenomics Pers Med 2020; 13:463-484. [PMID: 33116761 PMCID: PMC7568633 DOI: 10.2147/pgpm.s270069] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
The latest developments in precision medicine allow the modulation of therapeutic approaches in different pathologies on the basis of the specific molecular characterization of the patient. This review of the literature coupled with in silico analysis was to provide a selected screening of interactions between single-nucleotide polymorphisms (SNPs) and drugs (repurposed, investigational, and biological agents) showing efficacy and toxicityin counteracting Covid-19 infection. In silico analysis of genetic variants related to each drug was performed on such databases as PharmGKB, Ensembl Genome Browser, www.drugs.com, and SNPedia, with an extensive literature review of papers (to May 10, 2020) on Covid-19 treatments using Medline, Embase, International Pharmaceutical Abstracts, PharmGKB, and Google Scholar. The clinical relevance of SNPs, known as both drug targets and markers, considering genetic variations with known drug responses, and the therapeutic consequences are discussed. In the context of clinical treatment of Covid-19, including infection prevention, control measures, and supportive care, this review highlights the importance of a personalized approach in the final selection of therapy, which is probably essential in the management of the Covid-19 pandemic.
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Affiliation(s)
| | - Agnese Re
- CNR-IASI, Catholic University of Sacred Heart, Rome, Italy
| | - Alessandra Micera
- Research Laboratories in Ophthalmology, IRCCS — Fondazione Bietti, Rome, Italy
| | - Raffaele Palmirotta
- Department of Biomedical Sciences and Clinical Oncology, Oncogenomic Research Center, Aldo Moro University of Bari, Bari, Italy
| | | | - Francesca Romano
- Department of Precision Medicine, Luigi Vanvitelli University of Campania, Napoli, Italy
| | | | - Raffaele Di Francia
- Italian Association of Pharmacogenomics and Molecular Diagnostics, Ancona, Italy
| | - Andrea Cacciamani
- Research Laboratories in Ophthalmology, IRCCS — Fondazione Bietti, Rome, Italy
| | - Pier Luigi Surico
- Oncology and Hematology Department, F Miulli Hospital, Acquaviva delle Fonti, Italy
| | - Gerardo D’Amato
- Endocrine and Metabolic Surgery, A Gemelli Polyclinic Foundation, Rome, Italy
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41
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Moradi M, Mozafari F, Hosseini S, Rafiee R, Ghasemi F. A concise review on impacts of microRNAs in biology and medicine of hepatitis C virus. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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42
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Aleman S, Söderholm J, Büsch K, Kövamees J, Duberg AS. Frequent loss to follow-up after diagnosis of hepatitis C virus infection: A barrier towards the elimination of hepatitis C virus. Liver Int 2020; 40:1832-1840. [PMID: 32294288 DOI: 10.1111/liv.14469] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 02/07/2020] [Accepted: 04/02/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Previous studies on hepatitis C cascade of care have been mainly focused on diagnosis and treatment rate, while less attention has been given to patients lost to follow-up (LTFU) after diagnosis. Analyses of this latter issue on population level are missing. AIMS In this nationwide study of people with HCV, we aimed to estimate the proportion LTFU after HCV diagnosis, characterize them, and analyze their other healthcare contacts. METHODS Patients diagnosed with chronic HCV in the Swedish National Patient Register during 2001-2011 and still alive December 31, 2013, were included. The number of cured patients without need of follow-up was estimated. Visits to HCV specialist care during 2012-2013 were analysed. For those LTFU, other specialist care contacts were studied. RESULTS In total 29 217 patients were included, with 24 733 with need of HCV care. 61% (n = 15 007) of them were LTFU from HCV care in 2012-2013 and 58% did not attend HCV care during the second year after HCV diagnosis. The departments of surgery/orthopaedic or psychiatry/dependency were the most common other non-primary healthcare contacts. Predictors for LTFU were young age, male sex, low education, presence of psychiatric/dependency diagnosis, unmarried and longer duration since diagnosis of HCV. CONCLUSIONS This study showed that almost two-thirds of patients were LTFU after HCV diagnosis, with frequent occurrence early after diagnosis. Efforts to link patients back to HCV care, in combination with early and easy access to HCV treatment and harm reduction, are necessary to reach the HCV elimination goal.
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Affiliation(s)
- Soo Aleman
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Söderholm
- AbbVie AB, Stockholm, Sweden.,Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Katharina Büsch
- AbbVie AB, Stockholm, Sweden.,Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | | | - Ann-Sofi Duberg
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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Mancuso ME, Linari S, Santagostino E, Bartolozzi D, D'Ambrosio R, Borghi M, Lampertico P, Peyvandi F, Castaman G, Aghemo A. High rate of sustained virological response with direct-acting antivirals in haemophiliacs with HCV infection: A multicenter study. Liver Int 2020; 40:1062-1068. [PMID: 31876354 DOI: 10.1111/liv.14337] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/01/2019] [Accepted: 12/19/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Chronic hepatitis C is the main co-morbidity in adult patients with haemophilia (PwH). It causes progressive liver damage leading to end-stage liver disease and/or hepatocellular carcinoma. Eradication of HCV was possible with interferon (IFN)-based regimens in the past and direct-acting antivirals (DAAs) more recently. PwH have been considered "difficult-to-treat" because of several bad predictors of response. The advent of DAAs has provided high rates of sustained virological response (SVR) despite bad prognostic factors. Here, we present the results of antiviral treatment with DAAs in PwH treated in 2 large Italian Hemophilia Treatment Centers. METHODS PwH and chronic hepatitis C sustained by any HCV genotype were eligible for therapy with DAAs, including those with compensated cirrhosis, HIV infection and/or previous failure to IFN-based antiviral therapy. Patients received DAAs for 8-24 weeks according to existing guidelines. SVR was defined as persistent negative serum HCV-RNA at 12 weeks after treatment completion (SVR12). RESULTS Between January 2015 and November 2018, 200 patients aged 21-84 years (median: 50.5) received DAAs. HCV genotype 1 was the most prevalent (158, 79%). Forty patients (20%) were HIV positive, 56 (28%) had cirrhosis and 91 (46%) previously failed interferon-based treatment. Ribavirin was used in 70 (35%). HCV-RNA was undetectable at week 4 in 124/192 (65%) and SVR12 was achieved in 193/195 (99%). No patient had serious side effects related to DAAs. CONCLUSIONS DAAs were safe and highly effective in PwH irrespective of HIV status, stage of liver disease severity and/or previous failure to IFN-based therapy.
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Affiliation(s)
- Maria Elisa Mancuso
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "Angelo Bianchi Bonomi" Hemophilia and Thrombosis Center, Milan, Italy
| | - Silvia Linari
- Centre for Bleeding Disorders, Department of Oncology, Careggi University Hospital, Florence, Italy
| | - Elena Santagostino
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "Angelo Bianchi Bonomi" Hemophilia and Thrombosis Center, Milan, Italy
| | - Dario Bartolozzi
- Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy
| | - Roberta D'Ambrosio
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "A. M. e A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Marta Borghi
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "A. M. e A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "A. M. e A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Flora Peyvandi
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "Angelo Bianchi Bonomi" Hemophilia and Thrombosis Center, Milan, Italy
| | - Giancarlo Castaman
- Centre for Bleeding Disorders, Department of Oncology, Careggi University Hospital, Florence, Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Humanitas Research Hospital IRCCS, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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Khalili JS, Zhu H, Mak NSA, Yan Y, Zhu Y. Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19. J Med Virol 2020; 92:740-746. [PMID: 32227493 PMCID: PMC7228408 DOI: 10.1002/jmv.25798] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/15/2022]
Abstract
Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct antiviral drugs, such as ribavirin, that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. On the basis of the direct antiviral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of antiviral therapy.
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Affiliation(s)
| | - Hai Zhu
- SystImmune Inc, Redmond, Washington
| | | | | | - Yi Zhu
- SystImmune Inc, Redmond, Washington
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45
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Tan YJN, Yong WP, Kochhar JS, Khanolkar J, Yao X, Sun Y, Ao CK, Soh S. On-demand fully customizable drug tablets via 3D printing technology for personalized medicine. J Control Release 2020; 322:42-52. [PMID: 32145267 DOI: 10.1016/j.jconrel.2020.02.046] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/24/2020] [Accepted: 02/27/2020] [Indexed: 10/24/2022]
Abstract
Personalized medicine should ideally be prescribed to every individual because of the unique characteristics (e.g., biological, physical, and medical) of each individual. It is, however, challenging to provide personalized medicine for the mass population of specific individuals effectively and efficiently. This manuscript describes a method of fabricating fully customizable drug tablets for personalized medicine by the 3D printing technology. This method involves the versatile fabrication of the tablets via the specifically designed 3D printed molds of different shapes and sizes, and an intuitive 1-dimensional release of drug that relates the shape of the drug-containing matrix to the release profile. The customization includes all the aspects of varying dosage, duration, release profiles, and combination of multiple drugs. In particular, it has previously been technically difficult to devise a single platform that fabricates carriers that release drug with any desired type of release profiles. This method of fabricating fully customizable tablets is simple, inexpensive, and efficient. Detailed selection and investigation of the materials ensured that the tablet and the method of fabrication are safe (e.g., biocompatible, FDA-approved ingredients used) and other desirable features (e.g., sustained release and high dosage) are achieved. These desirable characteristics of the method thus allow fully customizable drug tablets to be fabricated efficiently on the spot after the diagnosis of individual patients; at the same time, the method can be made widely accessible to the mass population. Hence, the concept of personalized medicine can truly be realized.
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Affiliation(s)
- Yan Jie Neriah Tan
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Wai Pong Yong
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Jaspreet Singh Kochhar
- Procter & Gamble International Operations SA Singapore Branch, 70 Biopolis Street, Singapore 138547, Singapore
| | - Jayant Khanolkar
- Procter & Gamble International Operations SA Singapore Branch, 70 Biopolis Street, Singapore 138547, Singapore
| | - Xiukai Yao
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Yajuan Sun
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Chi Kit Ao
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Siowling Soh
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.
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Chiu WC, Lu ML, Chang CC. Mental Disorders and Interferon Nontreatment in Hepatitis C Virus Infection-a Population Based Cohort Study. Psychiatry Investig 2020; 17:268-274. [PMID: 32151125 PMCID: PMC7113179 DOI: 10.30773/pi.2019.0254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 01/08/2020] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE This study investigates the association between mental disorders and interferon nontreatment in patients with chronic hepatitis C virus (HCV) infection in a large national sample. METHODS Using the National Health Insurance Research Database of Taiwan, we conducted a nationwide population-based study. Each case was matched to five controls by age, sex, urbanization, and income. Conditional logistic regression was used to assess odds of HCV nontreatment in different mental disorders. RESULTS From 1999 to 2013, we identified 92,970 subjects with HCV infection and 15,495 HCV cases (16.7%) had received IFN therapy. Other than chronic obstructive pulmonary disease, the medical diseases and mental disorders were significantly different between IFN and non-IFN treated HCV patients. After adjusting for medical diseases, depressive disorder and anxiety disorder was positively associated with receiving IFN therapy. Patients with schizophrenia, bipolar disorders and alcohol use disorders were significantly less likely to receive interferon. Antidepressant exposure (cumulative daily exposure or cumulative daily dose) was associated with lower odds of IFN treatment. CONCLUSION Our nationwide cohort study demonstrated that INF nontreatment rate was lower in certain mental disorders. Antidepressant exposure might lower the chance of receiving IFN treatment. Our results may help to identify and to overcome the obstacles for HCV treatment and further apply to DAAs regimen.
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Affiliation(s)
- Wei-Che Chiu
- Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan.,School of Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | - Mong-Liang Lu
- Department of Psychiatry, Wan-Fang Hospital, Taipei, Taiwan.,School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Chen Chang
- Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Center of General Education, Tunghai University, Taichung, Taiwan
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47
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Strotman PK, Schmitt DR, Schiff A, Pinzur M. Ankle fusion in patients with chronic hepatitis C. Foot Ankle Surg 2020; 26:151-155. [PMID: 30712992 DOI: 10.1016/j.fas.2019.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 11/12/2018] [Accepted: 01/02/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND It appears that both the incidence and survival of patients infected with hepatitis C have recently demonstrated a significant increase. The goal of this investigation was to determine the associated perioperative risks associated with ankle arthrodesis in this growing population. METHODS The Healthcare Cost and Utilization Project State Inpatient Databases identified patients with chronic hepatitis C infection who underwent ankle arthrodesis between January 2009 and December 2013. International Classification of Diseases, Ninth Revision, codes were used to define the primary composite outcome of death or postoperative complication. Logistic models with frequency weights were used to compare propensity matched groups. RESULTS 7339 patients met inclusion criteria. Of these, 157 patients had a history of chronic Hepatitis C infection. After performing a propensity score match, the final analytic cohort was 157 in the Hepatitis C group and 386 in the non-Hepatitis C group. There was no statistically significant differences in complications between patients with chronic Hepatitis C undergoing ankle fusion and those without Hepatitis C at any post-operative time point (inpatient, 30 days, or 90 days). DISCUSSION Patients with chronic hepatitis C infection undergoing ankle arthrodesis are not at an elevated risk of inpatient, thirty, and ninety day postoperative complications compared to patients without chronic HCV infections. Patients with chronic hepatitis C did not have an increased risk of surgical site infection or mortality at any time point. LEVEL OF EVIDENCE Prognostic Level III.
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Affiliation(s)
- Patrick K Strotman
- Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153-3328, United States.
| | - Daniel R Schmitt
- Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153-3328, United States.
| | - Adam Schiff
- Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153-3328, United States.
| | - Michael Pinzur
- Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153-3328, United States.
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Tani J, Morishita A, Sakamoto T, Takuma K, Nakahara M, Fujita K, Oura K, Tadokoro T, Mimura S, Nomura T, Yoneyama H, Kobara H, Himoto T, Tsutsui A, Senoh T, Nagano T, Ogawa C, Moriya A, Deguchi A, Takaguchi K, Masaki T. Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study. Oncol Lett 2020; 19:2205-2212. [PMID: 32194718 PMCID: PMC7038998 DOI: 10.3892/ol.2020.11341] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023] Open
Abstract
Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0-2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa 760-0017, Japan
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kanonji, Kagawa 769-1695, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Marugame, Kagawa 763-8502, Japan
| | - Kouichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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Costa VD, Delvaux N, Brandão-Mello CE, Nunes EP, de Sousa PSF, de Souza Rodrigues LLLX, Lampe E, do Amaral Mello FC. Prevalence of baseline NS3 resistance-associated substitutions (RASs) on treatment with protease inhibitors in patients infected with HCV genotype 1. Clin Res Hepatol Gastroenterol 2019; 43:700-706. [PMID: 30880098 DOI: 10.1016/j.clinre.2019.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/01/2019] [Accepted: 02/11/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Treatment for hepatitis C has evolved significantly with the licensing of direct-acting antiviral drugs (DAAs). However, one of the limiting factors of the effectiveness of antiviral therapy with protease inhibitors (PIs) is the emergence of resistance caused by point mutations. The aim of this study was to determine the prevalence of resistance-associated substitutions (RASs) in HCV NS3 gene in patients infected with genotype 1 before therapy with simeprevir. METHODS A total of 73 serum samples from 15 treatment-experienced patients with boceprevir/telaprevir and 58 DAA-naïve patients were collected before therapy with DAAs simeprevir, daclatasvir and/or sofosbuvir. Presence of baseline resistance-associated substitutions (RAS) in the serine protease domain of HCV NS3 was analyzed by nucleotide sequencing followed by amino acid deduction. RESULTS Overall RAS prevalence in this study was 13.7% (10/73). RAS prevalence for HCV subtype 1b was 17.4% (4/23) while for HCV subtype 1a was 12% (6/50). Primary mutations V36M/L and R155K were observed only in HCV subtype 1a, whereas T54S and Q80K were identified only in HCV subtype 1b. RAS V36M, which is related to reduction of susceptibility to second-generation PIs, was the most frequent in the study (6.9%; 5/73). CONCLUSIONS Our results indicated that Brazilian isolates of HCV present a distinct pattern of RAS depending on the infecting viral subtype. In contrast to data from other countries, RAS Q80K prevalence in Brazil is low in HCV subtype 1a. This study improves the knowledge of genetic barrier for resistance to PIs involving RASs in chronically infected patients and its possible impact on an unsuccessful treatment outcome, information that might be crucial to upcoming decisions of incorporation of new DAAs in Brazilian guidelines of antiviral therapy against HCV infection.
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Affiliation(s)
- Vanessa Duarte Costa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil.
| | - Nathália Delvaux
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
| | - Carlos Eduardo Brandão-Mello
- Hospital Universitário Gaffrée & Guinle, UNIRIO, R. Mariz e Barros, 775 - Maracanã, 20270-001, Rio de Janeiro, RJ, Brazil
| | - Estevão Portela Nunes
- Instituto Nacional de Infectologia Evandro Chagas, INI/FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-360, Rio de Janeiro, RJ, Brazil
| | - Paulo Sérgio Fonseca de Sousa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
| | | | - Elisabeth Lampe
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
| | - Francisco Campello do Amaral Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
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Alezzi ZMM, Abd El Rehim AY, Fathallah WF, Alamrani MA, Othman FH. Factors Affecting the Virological Response Among Chronic Hepatitis C Virus Patients in Yemen. J Interferon Cytokine Res 2019; 38:38-44. [PMID: 29328881 DOI: 10.1089/jir.2017.0098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Hepatitis C virus (HCV) infection is increasingly seen as a major public health problem, threat, and concern worldwide. In Yemen about 1.7% of the population is infected with chronic hepatitis C. This study aimed to detect the predictors for response to pegylated interferon and ribavirin (Peg-IFN/RBV) in chronic HCV Yemeni patients. The study was conducted on 100 patients with chronic HCV who received Peg-IFN/RBV in the 48th Military Hospital in Sana'a Yemen, from 2011 to 2013. All patients were subjected to complete history taking, thorough clinical examinations, routine laboratory investigation, and abdominal ultrasonography. The HCV RNA was assessed at week 72 of treatment to detect whether the patient achieved sustained virological response (SVR). The SVR was achieved in 64% of the samples. Age above 40, Khat chewing, and obesity were the sociodemographic factors that predict good response for Peg-IFN/RBV combined therapy. Platelet count, alpha feto-protein (AFP), aspartate transaminase (AST), and alanine transaminase (ALT) levels were the basic laboratory investigations that gave favorable response. Significant predictors of sustained response included: older than 40 years (OR = 0.136, P = 0.042), Khat chewer (OR = 0.016, P = 0.008), body mass index (BMI) (OR = 0.055, P = 0.029) and increase in fasting blood glucose (OR = 0.925, P = 0.004), alkaline phosphatase (OR = 0.969, P = 0.001), total and bilirubin (OR = 0.058, P = 0.017), AST (OR = 1.033, P = 0.002), and albumin (OR = 6.490, P = 0.021). Studying the independent variables of response, we revealed that male gender, BMI, ALT >40, AFP >10, viremia >600, and hemoglobin and thyroid stimulating hormone (TSH) levels are variables associated with failure of end of treatment response (ETR) and SVR.
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Affiliation(s)
| | - Ayman Yosry Abd El Rehim
- 2 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Waleed Fouad Fathallah
- 2 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | | | - Fouad Hezam Othman
- 3 Department of Community Medicine, Faculty of Medicine & Health Sciences, Taiz University , Taiz, Yemen
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