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1
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Yang J, Zhuang X, Li Z, Xiong G, Xu P, Ling Y, Zhang G. CPMKG: a condition-based knowledge graph for precision medicine. Database (Oxford) 2024; 2024:baae102. [PMID: 39331730 PMCID: PMC11429523 DOI: 10.1093/database/baae102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/22/2024] [Accepted: 08/27/2024] [Indexed: 09/29/2024]
Abstract
Personalized medicine tailors treatments and dosages based on a patient's unique characteristics, particularly its genetic profile. Over the decades, stratified research and clinical trials have uncovered crucial drug-related information-such as dosage, effectiveness, and side effects-affecting specific individuals with particular genetic backgrounds. This genetic-specific knowledge, characterized by complex multirelationships and conditions, cannot be adequately represented or stored in conventional knowledge systems. To address these challenges, we developed CPMKG, a condition-based platform that enables comprehensive knowledge representation. Through information extraction and meticulous curation, we compiled 307 614 knowledge entries, encompassing thousands of drugs, diseases, phenotypes (complications/side effects), genes, and genomic variations across four key categories: drug side effects, drug sensitivity, drug mechanisms, and drug indications. CPMKG facilitates drug-centric exploration and enables condition-based multiknowledge inference, accelerating knowledge discovery through three pivotal applications. To enhance user experience, we seamlessly integrated a sophisticated large language model that provides textual interpretations for each subgraph, bridging the gap between structured graphs and language expressions. With its comprehensive knowledge graph and user-centric applications, CPMKG serves as a valuable resource for clinical research, offering drug information tailored to personalized genetic profiles, syndromes, and phenotypes. Database URL: https://www.biosino.org/cpmkg/.
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Affiliation(s)
- Jiaxin Yang
- National Genomics Data Center & Bio-Med Big Data Center, Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xinhao Zhuang
- National Genomics Data Center & Bio-Med Big Data Center, Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhenqi Li
- Shanghai Information Center for Life Sciences, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Gang Xiong
- Shanghai Southgene Technology Co., Ltd., Shanghai 201203, China
| | - Ping Xu
- Shanghai Information Center for Life Sciences, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yunchao Ling
- National Genomics Data Center & Bio-Med Big Data Center, Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Guoqing Zhang
- National Genomics Data Center & Bio-Med Big Data Center, Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Shanghai Sixth People’s Hospital, Shanghai 200233, China
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Alshoaibi IA, Al-Gamli A, Abdullah M, Abdo B, Alzanen KH, Alhakamy M, Al-Namer M, Ahmed F, Tamesh M, Mahdi W, Abdo Z, Mohammed M. Effectiveness of Ledipasvir-Sofosbuvir 12 Weeks After Hepatitis C Virus Genotype 1 Infection and the Factors Associated With Sustained Virologic Response: A Retrospective Study. Cureus 2024; 16:e68249. [PMID: 39350869 PMCID: PMC11439843 DOI: 10.7759/cureus.68249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND The combination of ledipasvir and sofosbuvir (LDV/SOF) has been licensed to treat genotype 1 hepatitis C virus infection (HCV) with a 12-week regimen. However, there is scant data from Yemen regarding this combination regimen. Here, we investigate sustained virologic responses (SVR) 12 weeks after HCV treatment with LDV/SOF regimens and the factors that contribute to SVR failure. MATERIAL AND METHOD A retrospective cross-sectional study was conducted at Althora General Hospital in Ibb, Yemen, from June 1, 2019, to October 31, 2022, on 53 cases with HCV genotype 1 infection who received combined therapy of LDV/SOF and completed treatment for 12 weeks. The clinical characteristics and treatment follow-up were obtained from patient medical records. Factors associated with SVR failure were investigated in univariate analysis with odds ratio (OR) and 95% confidence interval (CI). RESULT The mean age was 50 ± 15.3 years, and most cases were female (n=36, 67.9%). Comorbidities were diabetes, hypertension, and fatty liver, which were represented in 12 (22.6%), nine (17.0%), and eight (15.1%) cases, respectively. A total of 13 (24.5%) patients had compensated liver cirrhosis, while the remaining 40 patients (75.5%) were non-cirrhotic healthy individuals. The baseline viral load (HCV RNA) was more than 800000 IU/mL in 21 patients (39.6%). Early virological response (ERV) was achieved in 51 patients (96.2%). After treatment, 46 of the patients (86.8%) achieved SVR at Week 12, while failure occurred in two patients (3.8%) and relapse occurred in five patients (9.4%). Blood liver enzymes, including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, returned to normal, with statistically significant improvements in non-cirrhotic healthy persons than compensated liver cirrhosis individuals (p= 0.006, 0.006, and 0.010; respectively). Factors associated with SVR failure were older age (OR:1.13; 95% CI: 1.03-1.30, p=0.009), presence of liver cirrhosis (OR: 5.48; 95% CI: 1.04-28.98, p=0.031), having diabetes (OR: 6.33; 95% CI: 1.19-37.93, p= 0.019), baseline higher viral load (OR: 2.27; 95% CI: 0.45-12.73, p<0.001), and not achieving EVR (OR:7.63; 95% CI: 3.77- 17.78, p= 0.009). CONCLUSION In this study, we found that LDV/SOF regimens are effective against HCV genotype one infection, allowing for the expansion of 12-week treatment for suitable patients in clinical settings. Additionally, older age, liver cirrhosis, diabetes, higher pretreatment viral load, and non-completion of EVR were associated with SVR failure. However, due to the small number of HCV genotype 1 infected individuals in this study, more corporate data is required to get a clear conclusion.
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Affiliation(s)
| | | | | | - Basheer Abdo
- Internal Medicine, School of Medicine, Ibb University, Ibb, YEM
| | | | | | - Mamoon Al-Namer
- Internal Medicine, School of Medicine, Ibb University, Ibb, YEM
| | - Faisal Ahmed
- Urology, School of Medicine, Ibb University, Ibb, YEM
| | - Munther Tamesh
- Pharmacy, University of Science and Technology, Ibb, YEM
| | - Wadhah Mahdi
- Pharmacy, University of Science and Technology, Ibb, YEM
| | - Zeyad Abdo
- Pharmacy, University of Science and Technology, Ibb, YEM
| | - Marwa Mohammed
- General Practice, School of Medicine, Ibb University, Ibb, YEM
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Wang X, Jing X, Shi J, Liu Q, Shen S, Cheung PPH, Wu J, Deng F, Gong P. A jingmenvirus RNA-dependent RNA polymerase structurally resembles the flavivirus counterpart but with different features at the initiation phase. Nucleic Acids Res 2024; 52:3278-3290. [PMID: 38296832 PMCID: PMC11014250 DOI: 10.1093/nar/gkae042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/06/2024] [Accepted: 01/11/2024] [Indexed: 02/02/2024] Open
Abstract
Jingmenviruses are a category of emerging segmented viruses that have garnered global attention in recent years, and are close relatives of the flaviviruses in the Flaviviridae family. One of their genome segments encodes NSP1 homologous to flavivirus NS5. NSP1 comprises both the methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRP) modules playing essential roles in viral genome replication and capping. Here we solved a 1.8-Å resolution crystal structure of the NSP1 RdRP module from Jingmen tick virus (JMTV), the type species of jingmenviruses. The structure highly resembles flavivirus NS5 RdRP despite a sequence identity less than 30%. NSP1 RdRP enzymatic properties were dissected in a comparative setting with several representative Flaviviridae RdRPs included. Our data indicate that JMTV NSP1 produces characteristic 3-mer abortive products similar to the hepatitis C virus RdRP, and exhibits the highest preference of terminal initiation and shorter-primer usage. Unlike flavivirus NS5, JMTV RdRP may require the MTase for optimal transition from initiation to elongation, as an MTase-less NSP1 construct produced more 4-5-mer intermediate products than the full-length protein. Taken together, this work consolidates the evolutionary relationship between the jingmenvirus group and the Flaviviridae family, providing a basis to the further understanding of their viral replication/transcription process.
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Affiliation(s)
- Xinyu Wang
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei 430207, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuping Jing
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei 430207, China
| | - Junming Shi
- University of Chinese Academy of Sciences, Beijing 100049, China
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China
| | - Qiaojie Liu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei 430207, China
| | - Shu Shen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China
| | - Peter Pak-Hang Cheung
- Department of Chemical Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China
| | - Jiqin Wu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei 430207, China
| | - Fei Deng
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China
| | - Peng Gong
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei 430207, China
- Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin 300350, China
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d'Arminio Monforte A, Tavelli A, Rossotti R, Gagliardini R, Saracino A, Lo Caputo S, Sala M, Quiros-Roldan E, Mussini C, Girardi E, Cozzi-Lepri A, Antinori A, Puoti M. Is HCV elimination among persons living with HIV feasible? Data from the NoCo study in the setting of the ICONA cohort. Liver Int 2023; 43:2130-2141. [PMID: 37649460 DOI: 10.1111/liv.15700] [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: 04/14/2023] [Revised: 07/21/2023] [Accepted: 08/07/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND AND AIMS Whether the HCV test-and-treat strategy impacted on the rate of new HCV infections among PLWH in Italy is unknown. METHODS Prospective study of PLWH in the ICONA network. At baseline, PLWH were tested for HCV-Ab; HCV-RNA (if HCV-Ab positive) and, if positive, treated with DAA. SVR12 indicated eradication. Seroconversions and re-infections were evaluated yearly in HCV-Ab neg and HCV-RNA neg at first screening. We estimated the following: HCV seroconversions, incidence of HCV reinfections, and access to DAA and SVR12 rates tighter with factors associated with each outcome. Data were analysed by Cox regression, Poisson regression and logistic regression models. RESULTS Sixteen thousand seven hundred and forty-three PLWH were included; 27.3% HCV-Ab positive; of these, 39.3% HCV-RNA positive. HCV seroconversion incidence: .48/100 PYFU (95% CI: .36-.65); re-infections incidence: 1.40/100 PYFU (95% CI: .91-2.04). The risk factor for HCV re-infection was young age: aIRR 1.85, 95% CI: 1.17-2.95) per 10 years younger. 86.4% of HCV viremic in follow-up started DAA. PWID vs. heterosexuals (aHR .75, 95% CI .62-.90), HIV-RNA >50 copies/mL (aHR .70, 95% CI .56-.87), HCV genotype other than G1, G2, G3, G4 or with multiple/missing HCV genotype and post-COVID-19 calendar periods were associated with lower DAA access. 922/965 (95.5%) PLWH achieved SVR12. We estimated 72% reduction of chance to achieve SVR12 in PLWH with a CD4 count <200/mm3 (vs. CD4 ≥200/mm3 aOR .18, 95% CI: .07-.46). 95.5% of DAA-treated individuals eradicated HCV, but they represent only 53.2% of HCV viremic PLWH and 66.4% of those in follow-up. HCV-RNA positivity by year decreased from 41.7% in 2017 to 11.7% in 2022. CONCLUSIONS The screening-and-treat campaign implemented in Italy, even if only partially effective, resulted in a dramatic drop in HCV circulation in our cohort.
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Affiliation(s)
| | | | - Roberto Rossotti
- Infectious Diseases Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Roberta Gagliardini
- Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Annalisa Saracino
- Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari, University Hospital Policlinico, Bari, Italy
| | - Sergio Lo Caputo
- Department of Clinical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Matteo Sala
- Unit of Infectious and Tropical Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Eugenia Quiros-Roldan
- Department of Clinical and Experimental Sciences, Unit of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Cristina Mussini
- AOU of Modena, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy
| | - Enrico Girardi
- Scientific Direction, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Alessandro Cozzi-Lepri
- Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, UCL, London, UK
| | - Andrea Antinori
- Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Massimo Puoti
- Infectious Diseases Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- University of Milano-Bicocca, Milan, Italy
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5
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Conti J, Dryden E, Fincke BG, Dunlap S, McInnes DK. Innovative Approaches to Engaging Homeless and Marginally Housed Patients in Care: a Case Study of Hepatitis C. J Gen Intern Med 2023; 38:156-164. [PMID: 35879538 PMCID: PMC9849487 DOI: 10.1007/s11606-022-07708-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 06/16/2022] [Indexed: 01/22/2023]
Abstract
BACKGROUND Homeless and marginally housed (HAMH) individuals experience significant health disparities compared to housed counterparts, including higher hepatitis C virus (HCV) rates. New direct-acting antiviral (DAA) medications dramatically increased screening and treatment rates for HCV overall, but inequities persist for HAMH populations. OBJECTIVE This study examines the range of policies, practices, adaptations, and innovations implemented by Veteran Affairs Medical Centers (VAMCs) in response to Veterans Health Administration (VHA)'s 2016 HCV funding allocation to expand provision of HCV care. DESIGN Ethnographic site visits to six US VAMCs varying in size, location, and availability of Homeless Patient-Aligned Care Teams. Semi-structured qualitative interviews informed by the HCV care continuum were conducted with providers, staff, and HAMH patients to elicit experiences providing and receiving HCV care. Semi-structured field note templates captured clinical care observations. Interview and observation data were analyzed to identify cross-cutting themes and strategies supporting tailored HCV care for HAMH patients. PARTICIPANTS Fifty-six providers and staff working in HCV and/or homelessness care (e.g., infectious disease providers, primary care providers, social workers). Twenty-five patients with varying homeless experiences, including currently, formerly, or at risk of homelessness (n=20) and stably housed (n=5). KEY RESULTS All sites experienced challenges with continued engagement of HAMH individuals in HCV care, which led to the implementation of targeted care strategies to better meet their needs. Across sites, we identified 35 unique strategies used to find, engage, and retain HAMH individuals in HCV care. CONCLUSIONS Despite highly effective, widely available HCV treatments, HAMH individuals continue to experience challenges accessing HCV care. VHA's 2016 HCV funding allocation resulted in rapid adoption of strategies to engage and retain vulnerable patients in HCV treatment. The strategies identified here can help healthcare institutions tailor and target approaches to provide sustainable, high-quality, equitable care to HAMH individuals living with HCV and other chronic illnesses.
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Affiliation(s)
- Jennifer Conti
- Center for Healthcare Organization and Implementation Research, VA Bedford Healthcare System, Bedford, MA, USA.
| | - Eileen Dryden
- Center for Healthcare Organization and Implementation Research, VA Bedford Healthcare System, Bedford, MA, USA
| | - B Graeme Fincke
- Center for Healthcare Organization and Implementation Research, VA Bedford Healthcare System, Bedford, MA, USA
- Department of Health Law, Policy, and Management, Boston University School of Public Health, Boston, MA, USA
| | - Shawn Dunlap
- Center for Healthcare Organization and Implementation Research, VA Bedford Healthcare System, Bedford, MA, USA
| | - D Keith McInnes
- Center for Healthcare Organization and Implementation Research, VA Bedford Healthcare System, Bedford, MA, USA
- Department of Health Law, Policy, and Management, Boston University School of Public Health, Boston, MA, USA
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Liu Q, Wu J, Gong P. Assessment of nucleotide/nucleoside analog intervention in primer-dependent viral RNA-dependent RNA polymerases. STAR Protoc 2022; 3:101468. [PMID: 35761985 PMCID: PMC9214276 DOI: 10.1016/j.xpro.2022.101468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Nucleotide/nucleoside analogs (NAs) are important compounds used in antiviral drug development. To understand the action mode of NA drugs, we present an enzymology protocol to initially evaluate the intervention mechanism of the NTP forms of NAs on a coronaviral RNA-dependent RNA polymerase (RdRP). We describe the preparation of SARS-CoV-2 RdRP proteins and RNA constructs, followed by a primer-dependent RdRP assay to assess NTP forms of NAs. Two representative NA drugs, sofosbuvir and remdesivir, are used for demonstration of this protocol. For complete details on the use and execution of this protocol, please refer to Wu et al. (2021).
Enzymology protocols for nucleotide analog assessment in primer-dependent viral RdRPs Detailed steps to prepare SARS-CoV-2 RdRP proteins and RNA constructs A primer-dependent RdRP assay to assess NTP forms of nucleotide analogs Assessment of two representative NA drugs, sofosbuvir and remdesivir Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
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Affiliation(s)
- Qiaojie Liu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China
| | - Jiqin Wu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China.
| | - Peng Gong
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China; Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, China.
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Elshafie S, Trivedi‐Kapoor R, Ebell M. Safety and efficacy of sofosbuvir-based medication regimens with and without ribavirin in hepatitis C patients: A systematic review and meta-analysis. J Clin Pharm Ther 2022; 47:1149-1158. [PMID: 35678040 PMCID: PMC9545628 DOI: 10.1111/jcpt.13698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/03/2022] [Accepted: 04/25/2022] [Indexed: 12/09/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Sofosbuvir (SOF) is a new and highly effective medication that dramatically improved hepatitis C virus (HCV) management. However, ribavirin (RBV) is still added to SOF-based medication regimens in several clinical scenarios, despite its well-known toxicities. The aim of our study is to systematically review and analyse the impact of adding RBV to SOF-based medication regimens on clinical outcomes among HCV patients. METHODS Included studies were randomized trials comparing the same SOF-based medication regimens with and without RBV in HCV patients and measuring serious adverse events (SAEs) and/or sustained virologic response at 12 weeks post-treatment (SVR-12). Two investigators independently searched PubMed and Cochrane Library through September 2021. The Cochrane Risk of Bias tool was used to assess trials quality. Clinical outcomes were analysed as risk ratios (RR) using a random effects model using R version 4.1.2. RESULTS AND DISCUSSION Our study included a total of 26 trials with 5058 HCV patients. Quality assessment showed moderate risk of bias for most trials. Upon adding RBV, there was no significant difference in SAEs (RR 1.07, 95% CI: 0.77-1.48, I2 = 10%), nor an impact on SVR-12 (RR 1.00, 95% CI: 0.98-1.01, I2 = 41%). There was no evidence of publication bias for either outcome. Subgroup analysis consistently showed lack of benefit among HCV subgroups. Additionally, NCT01826981 was identified as the main source of heterogeneity in the SVR-12 outcome. WHAT IS NEW AND CONCLUSION Our findings suggest nonsignificant differences in safety and efficacy between SOF-based medication regimens with and without RBV which should be considered in clinical practice.
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Affiliation(s)
- Shaimaa Elshafie
- Department of Clinical and Administrative Pharmacy, College of PharmacyUniversity of GeorgiaGeorgiaUSA
- Central Administration for Drug ControlEgyptian Drug AuthorityCairoEgypt
| | - Rupal Trivedi‐Kapoor
- Department of Clinical and Administrative Pharmacy, College of PharmacyUniversity of GeorgiaGeorgiaUSA
| | - Mark Ebell
- Department of Epidemiology, College of Public HealthUniversity of GeorgiaAthensGeorgiaUSA
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Scott DN, Palmer MA, Tidhar MT, Stoove PM, Sacks-Davis DRS, Doyle AJS, Pedrana DAJ, Thompson PA, Wilson PDP, Hellard PM. Assessment of the cost-effectiveness of Australia's risk-sharing agreement for direct-acting antiviral treatments for hepatitis C: a modelling study. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2022; 18:100316. [PMID: 35024654 PMCID: PMC8669355 DOI: 10.1016/j.lanwpc.2021.100316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/29/2021] [Accepted: 10/11/2021] [Indexed: 12/03/2022]
Abstract
BACKGROUND Hepatitis C elimination may be possible with broad uptake of direct-acting antiviral treatments (DAAs). In 2016 the Australian government committed A$1.2 billion for five years of unlimited DAAs (March 2016 to February 2021) in a risk-sharing agreement with pharmaceutical companies. We assess the impact, cost-effectiveness and net economic benefits likely to be realised from this investment. METHODS Mathematical modelling to project outcomes for 2016-2030 included: (S1) a counter-factual scenario (testing/treatment maintained at pre-2016 levels); (S2) the current status-quo (testing/treatment as actually occurred 2016-2019, with trends maintained to 2030); and (S3) elimination scenario (S2 plus testing/treatment rates increased between 2021-2030 to achieve the WHO elimination targets). FINDINGS S1 resulted in 68,800 new hepatitis C infections and 18,540 hepatitis C-related deaths over 2016-2030. The total health system cost (HCV testing, treatment, disease management) was A$3.01 billion and the cost of lost productivity due to absenteeism, presenteeism and premature deaths was A$26.14 billion. S2 averted 15,700 (23%) new infections and 8,500 (46%) deaths by 2030, with a total health system cost of A$3.48 billion, A$472 million more than S1 (A$1.65 billion more in testing/treatment but A$1.20 billion less in disease costs; A$5,752 per QALY gained from a health systems perspective). Productivity loss over 2016-2030 was A$19.96 billion, A$6.17 less than S1, making S2 cost-saving from a societal perspective by 2022 with a net economic benefit of A$5.70 billion by 2030. S3 averted an additional 10,000 infections and 930 deaths compared with S2 and increased the longer-term economic benefit. INTERPRETATION Five years of unrestricted access to DAAs in Australia has led to significant health benefits and is likely to become cost-saving from a societal perspective by 2022. FUNDING Burnet Institute.
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Affiliation(s)
- Dr Nick Scott
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
| | - Ms Anna Palmer
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
| | - Mr Tom Tidhar
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
| | - Prof Mark Stoove
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
| | - Dr Rachel S. Sacks-Davis
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
| | - A/Prof Joseph S. Doyle
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
- Department of Infectious Diseases, The Alfred and Monash University, Melbourne, VIC 3004, Australia
| | - Dr Alisa J. Pedrana
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
| | - Prof Alexander Thompson
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC 3165, Australia
| | | | - Prof Margaret Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, VIC 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
- Department of Infectious Diseases, The Alfred and Monash University, Melbourne, VIC 3004, Australia
- Peter Doherty Institute for Infection and Immunity, Parkville, Australia
- School of Population and Global Health, University of Melbourne
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9
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Madsen LW, Christensen PB, Fahnøe U, Pedersen MS, Bukh J, Øvrehus A. Inferior cure rate in pilot study of 4-week glecaprevir/pibrentasvir treatment with or without ribavirin of chronic hepatitis C. Liver Int 2021; 41:2601-2610. [PMID: 34154034 DOI: 10.1111/liv.14991] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/28/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Shortening the treatment duration for chronic hepatitis C may increase feasibility and reduce the cost of cure. The aims of this study were to compare 4 weeks of glecaprevir/pibrentasvir (GLE/PIB) treatment with and without ribavirin for patients with chronic hepatitis C and favourable baseline characteristics and to monitor the development of resistance-associated substitutions (RAS) and re-treatment outcomes if treatment failed. METHODS We performed an open-label single-centre randomized controlled trial, in which patients with chronic hepatitis C were randomized 1:1 to GLE/PIB ± ribavirin, stratified by genotype 3. The main inclusion criteria were treatment-naive patients, aged 18-49 with all genotypes accepted, and absence of liver fibrosis, determined by liver stiffness measurement less than 8 kPa. Viral genome sequences were determined by deep sequencing at baseline and at the time of relapse. RESULTS A total of 32 patients started treatment. Sustained virological response at week 12 (SVR12) was 59% (10/17) for GLE/PIB without ribavirin and 73% (11/15) for GLE/PIB with ribavirin. Drug target-specific NS5A RAS were detected at baseline for 45% (5/11) of patients with treatment failure and for 14% (3/21) of patients who achieved SVR12. Ten failure patients were retreated 12 weeks with sofosbuvir-based regimens; all have been cured. CONCLUSIONS In this pilot study of 4-week treatment with GLE/PIB with and without ribavirin, we found that baseline RAS were more frequent in patients with virological failure. Development of RAS did occur after short treatment but did not result in retreatment failure with a different regimen. EudraCT no: 2017-005179-21.
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Affiliation(s)
- Lone W Madsen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.,OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.,Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Peer B Christensen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.,OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.,Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Ulrik Fahnøe
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Martin S Pedersen
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Department of Clinical Microbiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Øvrehus
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.,Clinical Institute, University of Southern Denmark, Odense, Denmark
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10
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Palmer AY, Chan K, Gold J, Layton C, Elsum I, Hellard M, Stoove M, Doyle JS, Pedrana A, Scott N. A modelling analysis of financial incentives for hepatitis C testing and treatment uptake delivered through a community-based testing campaign. J Viral Hepat 2021; 28:1624-1634. [PMID: 34415639 DOI: 10.1111/jvh.13596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/20/2021] [Accepted: 08/11/2021] [Indexed: 01/20/2023]
Abstract
Financial incentives may reduce opportunity costs associated with people who become lost to follow-up in hepatitis C treatment programs. We estimated the impact that different financial incentive amounts would need to have on retention in care to maintain the same unit cost per (1) RNA-positive person completing testing (defined as awareness of RNA status) and (2) RNA diagnosed person initiating treatment. Costing data were obtained from a 2019 community-based testing campaign focused on engaging people who inject drugs. For different financial incentive amounts, we modelled the corresponding improvements in retention in care that would be needed to maintain the same overall (1) unit cost per testing completion and (2) unit cost per treatment initiation. In the testing campaign, the unit cost per RNA-positive person completing testing was A$3215 and the unit cost per RNA diagnosed person initiating treatment was A$1055. Modelling found that an incentive of A$500 per RNA-positive person completing testing would result in more people completing testing for the same unit cost if the percentage of attendees receiving their test results increased from 63% to 74%. An incentive of A$200 per RNA diagnosed person initiating treatment would result in more people initiating treatment for the same unit cost if the percentage initiating treatment increased from 67% to 83%. Monetary incentives for completing testing and initiating treatment may be an effective way to increase retention in care without increasing the overall unit cost of completing testing/initiating treatment.
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Affiliation(s)
- Anna Y Palmer
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia
| | - Kico Chan
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia
| | - Judy Gold
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Chloe Layton
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia
| | - Imogen Elsum
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia
| | - Margaret Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne, Victoria, Australia.,The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.,School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia
| | - Mark Stoove
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Joseph S Doyle
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne, Victoria, Australia
| | - Alisa Pedrana
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Nick Scott
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
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11
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Wu J, Wang H, Liu Q, Li R, Gao Y, Fang X, Zhong Y, Wang M, Wang Q, Rao Z, Gong P. Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex. Cell Rep 2021; 37:109882. [PMID: 34653416 PMCID: PMC8498683 DOI: 10.1016/j.celrep.2021.109882] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 07/05/2021] [Accepted: 10/04/2021] [Indexed: 12/02/2022] Open
Abstract
Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an “i+3” delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1′-cyano at the −4 position is responsible for the “i+3” intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1′-modified nucleotide analogs in anti-RNA virus drug development.
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Affiliation(s)
- Jiqin Wu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China
| | - Haofeng Wang
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Qiaojie Liu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China
| | - Rui Li
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Gao
- Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiang Fang
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yao Zhong
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Meihua Wang
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Quan Wang
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
| | - Zihe Rao
- Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China.
| | - Peng Gong
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin 300350, China.
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12
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Balatow P, Sandlin A, Cory TJ. An evaluation of ledipasvir + sofosbuvir for the treatment of chronic hepatitis C infection. Expert Opin Pharmacother 2021; 22:1839-1846. [PMID: 34157923 PMCID: PMC8478781 DOI: 10.1080/14656566.2021.1943359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/11/2021] [Indexed: 10/21/2022]
Abstract
Introduction: Hepatitis C (HCV) is viral disease with a global impact. Over the last 10 years, the treatment of this disease has evolved. Treatment guidelines have evolved to adopt new medications for HCV. These drugs have shown efficacy over 90% throughout the class as well as a better safety profile than the previous recommended pharmacotherapy. Dual-therapy DAAs emerged with FDA approval of Ledipasvir/Sofosbuvir (LDV/SOF) in 2014.Areas Covered: LDV/SOF is a dual-therapy option for chronic HCV patients (>6 months of infection) in select genotypes. This article reviews the studies relevant to the pharmacokinetic/pharmacodynamic properties of these drugs as well as its trials leading to approval.Expert opinion: LDV/SOF is included in the AASLD/IDSA guidelines for the treatment of HCV genotypes 1a and 1b with or without cirrhosis and genotype 4 without cirrhosis with an evidence and recommendation rating of IA. Genotype 4 with cirrhosis and genotypes 5 and 6 carry a Class IIa level B recommendation. The combination is not FDA approved for genotypes 2 and 3. Single-pill regimens, like LDV/SOF, are important to maintain the quality of life of children and other special populations infected with HCV by shortening treatment regimens, avoiding complex pill regimens, and eliminating injection therapies.
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Affiliation(s)
- Pearson Balatow
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center College of Pharmacy, Memphis, USA
| | - Amber Sandlin
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center College of Pharmacy, Memphis, USA
| | - Theodore James Cory
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center College of Pharmacy, Memphis, USA
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13
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Kwon JA, Dore GJ, Hajarizadeh B, Alavi M, Valerio H, Grebely J, Guy R, Gray RT. Australia could miss the WHO hepatitis C virus elimination targets due to declining treatment uptake and ongoing burden of advanced liver disease complications. PLoS One 2021; 16:e0257369. [PMID: 34529711 PMCID: PMC8445464 DOI: 10.1371/journal.pone.0257369] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 08/28/2021] [Indexed: 11/25/2022] Open
Abstract
Australia was one of the first countries to introduce government-funded unrestricted access to direct-acting antiviral (DAA) therapy, with 88,790 treated since March 2016. However, treatment uptake is declining which could potentially undermine Australia's progress towards the WHO HCV elimination targets. Using mathematical modelling, we updated estimates for those living with chronic HCV in Australia, new cases of decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality among the HCV-cured and viraemic populations from 2015 to 2030. We considered various DAA treatment scenarios incorporating annual treatment numbers to 2020, and subsequent uptake per year of 6,790 (pessimistic), 8,100 (intermediate), and 11,310 (optimistic). We incorporated the effects of excess alcohol consumption and reduction in progression to DC and HCC among cirrhosis-cured versus viraemic individuals. At the end of 2020, we estimated 117,810 Australians were living with chronic HCV. New cases per year of DC, HCC, and liver-related mortality among the HCV viraemic population decreased rapidly from 2015 (almost eliminated by 2030). In contrast, the growing population size of those cured with advanced liver disease meant DC, HCC, and liver-related mortality declined slowly. The estimated reduction in liver-related mortality from 2015 to 2030 in the combined HCV viraemic and cured population is 25% in the intermediate scenario. With declining HCV treatment uptake and ongoing individual-level risk of advanced liver disease complications, including among cirrhosis-cured individuals, Australia is unlikely to achieve all WHO HCV elimination targets by 2030.
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Affiliation(s)
- Jisoo A. Kwon
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Gregory J. Dore
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | | | - Maryam Alavi
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Heather Valerio
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Jason Grebely
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Rebecca Guy
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Richard T. Gray
- Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
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14
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Scott N, Win TM, Tidhar T, Htay H, Draper B, Aung PTZ, Xiao Y, Bowring A, Kuschel C, Shilton S, Kyi KP, Naing W, Aung KS, Hellard M. Hepatitis C elimination in Myanmar: Modelling the impact, cost, cost-effectiveness and economic benefits. LANCET REGIONAL HEALTH-WESTERN PACIFIC 2021; 10:100129. [PMID: 34327345 PMCID: PMC8315611 DOI: 10.1016/j.lanwpc.2021.100129] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/25/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023]
Abstract
Background Myanmar has set national hepatitis C (HCV) targets to achieve 50% of people diagnosed and 50% treated by 2030. The WHO has additional targets of reducing incidence by 80% and mortality by 65% by 2030. We aimed to estimate the impact, cost, cost-effectiveness and net economic benefit of achieving these targets. Methods Mathematical models of HCV transmission, disease progression and the care cascade were calibrated to 15 administrative regions of Myanmar. Cost data were collected from a community testing and treatment program in Yangon. Three scenarios were projected for 2020-2030: (1) baseline (current levels of testing/treatment); and testing/treatment scaled up sufficiently to reach (2) the national strategy targets; and (3) the WHO targets. Findings Without treatment scale-up, 333,000 new HCV infections and 97,000 HCV-related deaths were estimated to occur in Myanmar 2020-2030, with HCV costing a total $100 million in direct costs (testing, treatment, disease management) and $10.4 billion in lost productivity. In the model, treating 55,000 people each year was sufficient to reach the national strategy targets and prevented a cumulative 40,000 new infections (12%) and 25,000 HCV-related deaths (25%) 2020-2030. This was estimated to cost a total $189 million in direct costs ($243 per DALY averted compared to no treatment scale-up), but only $9.8 billion in lost productivity, making it cost-saving from a societal perspective by 2024 with an estimated net economic benefit of $553 million by 2030. Reaching the WHO targets required further treatment scale-up and additional direct costs but resulted in greater longer-term benefits. Interpretation Current levels of HCV testing and treatment in Myanmar are insufficient to reach the national strategy targets. Scaling up HCV testing and treatment in Myanmar to reach the national strategy targets is estimated to generate significant health and economic benefits. Funding Gilead Sciences.
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Affiliation(s)
- Nick Scott
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, 553St Kilda Rd, Melbourne 3004, Victoria, Australia
| | - Thin Mar Win
- Burnet Institute Myanmar, Second floor, 226U Wisara Road, Wizaaya Plaza, Bahan Township, Yangon, Myanmar
| | - Tom Tidhar
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia
| | - Hla Htay
- Burnet Institute Myanmar, Second floor, 226U Wisara Road, Wizaaya Plaza, Bahan Township, Yangon, Myanmar
| | - Bridget Draper
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, 553St Kilda Rd, Melbourne 3004, Victoria, Australia
| | - Phyo Thu Zar Aung
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia
| | - Yinzong Xiao
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia.,University of Melbourne, Parkville 3010, Victoria, Australia
| | - Anna Bowring
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia
| | - Christian Kuschel
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia
| | - Sonjelle Shilton
- Foundation for Innovative New Diagnostics (FIND), Yangon, Myanmar
| | - Khin Pyone Kyi
- Myanmar Liver Foundation, 33-35, First Floor, Pathein Street, KyunTaw (Middle) Ward, Sanchaung Township, Yangon, Myanmar
| | - Win Naing
- Department of Hepatology, 500 bedded Specialty Hospital, University of Medicine, Yangon, Myanmar
| | - Khin Sanda Aung
- National Hepatitis Control Program, Myanmar Ministry of Health, Myanmar
| | - Margaret Hellard
- Burnet Institute Melbourne, 85 Commercial Rd, Melbourne 3004, Victoria, Australia.,School of Public Health and Preventive Medicine, Monash University, 553St Kilda Rd, Melbourne 3004, Victoria, Australia.,University of Melbourne, Parkville 3010, Victoria, Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne 3004, Victoria, Australia.,The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Victoria, Australia
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15
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Kwon JA, Chambers GM, Luciani F, Zhang L, Kinathil S, Kim D, Thein HH, Botha W, Thompson S, Lloyd A, Yap L, Gray RT, Butler T. Hepatitis C treatment strategies in prisons: A cost-effectiveness analysis. PLoS One 2021; 16:e0245896. [PMID: 33571196 PMCID: PMC7877645 DOI: 10.1371/journal.pone.0245896] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
In Australian prisons approximately 20% of inmates are chronically infected with hepatitis C virus (HCV), providing an important population for targeted treatment and prevention. A dynamic mathematical model of HCV transmission was used to assess the impact of increasing direct-acting antiviral (DAA) treatment uptake on HCV incidence and prevalence in the prisons in New South Wales, Australia, and to assess the cost-effectiveness of alternate treatment strategies. We developed four separate models reflecting different average prison lengths of stay (LOS) of 2, 6, 24, and 36 months. Each model considered four DAA treatment coverage scenarios of 10% (status-quo), 25%, 50%, and 90% over 2016–2045. For each model and scenario, we estimated the lifetime burden of disease, costs and changes in quality-adjusted life years (QALYs) in prison and in the community during 2016–2075. Costs and QALYs were discounted 3.5% annually and adjusted to 2015 Australian dollars. Compared to treating 10% of infected prisoners, increasing DAA coverage to 25%, 50%, and 90% reduced HCV incidence in prisons by 9–33% (2-months LOS), 26–65% (6-months LOS), 37–70% (24-months LOS), and 35–65% (36-months LOS). DAA treatment was highly cost-effective among all LOS models at conservative willingness-to-pay thresholds. DAA therapy became increasingly cost-effective with increasing coverage. Compared to 10% treatment coverage, the incremental cost per QALY ranged from $497-$569 (2-months LOS), -$280–$323 (6-months LOS), -$432–$426 (24-months LOS), and -$245–$477 (36-months LOS). Treating more than 25% of HCV-infected prisoners with DAA therapy is highly cost-effective. This study shows that treating HCV-infected prisoners is highly cost-effective and should be a government priority for the global HCV elimination effort.
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Affiliation(s)
- Jisoo A. Kwon
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Georgina M. Chambers
- National Perinatal Epidemiology and Statistics Unit (NPESU), Centre for Big Data Research in Health and School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- * E-mail:
| | - Fabio Luciani
- School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia
| | - Lei Zhang
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
- The Melbourne Sexual Health Centre, Alfred Health, Carlton, Melbourne, VIC, Australia
| | | | - Dennis Kim
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Hla-Hla Thein
- Toronto Health Economics and Technology Assessment Collaborative (THETA), Toronto General Hospital Research Institute, University of Toronto and University Health Network, Toronto, ON, Canada
| | - Willings Botha
- RTI Health Solutions, Research Triangle Park, NC, United States of America
| | - Sandra Thompson
- Combined Universities of Rural Health, Geraldton, WA, Australia
| | - Andrew Lloyd
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Lorraine Yap
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | | | - Tony Butler
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
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16
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Chopra D, Bhandari B. Sofosbuvir: Really Meets the Unmet Needs for Hepatitis C Treatment? Infect Disord Drug Targets 2020; 20:2-15. [PMID: 30113002 DOI: 10.2174/1871526518666180816101124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 07/31/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C remains a major public health concern with a prevalence of more than 1% worldwide. Of late, with the discovery of newer drugs, chronic HCV treatment has touched new dimensions. The treatment has progressed from Interferons to Pegylated interferon (Peg IFN) based therapy, with or without ribavirin to treatment with orally active Direct Acting Antivirals (DAA) with Peg IFN and ribavirin and eventually to various combinations of DAA, without IFN. Introduction of newer DAAs has transfigured the treatment of chronic HCV. Chronic HCV patients with advanced liver disease, psychiatric condition, anemia or autoimmune diseases, not eligible for Peg IFN based therapy have a ray of hope now. Amongst all DAAs, nucleoside inhibitors have been the most promising agent. Thus the present review focuses on Sofosbuvir, one of the most effective nucleoside inhibitors; in terms of potency, resistance profile, activity against all genotypes of HCV and adverse effects. FDA approved Sofobuvir for clinical use in 2013. Chemically, it is 2'-deoxy-2'-α-fluoro-β-Cmethyluridine- 5'-triphosphate; a phosphoramidate prodrug that is activated by enzyme present in human liver. It is a highly potent inhibitor of HCV NS5B polymerase. Efficacy of the Sofosbuvir has been established in various phase 2 and phase 3 clinical trials like PROTON, ELECTRON, FUSION, POSITRON etc. Sofosbuvir has a good safety profile with few mild to moderate adverse effects. Evidence reveals that sofosbuvir has substantial impact on the treatment of HCV.
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Affiliation(s)
- Deepti Chopra
- Department of Pharmacology and Physiology, Government Institute of Medical Sciences, Greater Noida, U.P, India
| | - Bharti Bhandari
- Department of Pharmacology and Physiology, Government Institute of Medical Sciences, Greater Noida, U.P, India
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17
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Deng Y, Campbell F, Han K, Theodore D, Deeg M, Huang M, Hamatake R, Lahiri S, Chen S, Horvath G, Manolakopoulos S, Dalekos GN, Papatheodoridis G, Goulis I, Banyai T, Jilma B, Leivers M. Randomized clinical trials towards a single-visit cure for chronic hepatitis C: Oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants. J Viral Hepat 2020; 27:699-708. [PMID: 32096313 DOI: 10.1111/jvh.13282] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 01/30/2020] [Accepted: 02/10/2020] [Indexed: 12/09/2022]
Abstract
Single-visit cures for chronic hepatitis C are lacking. We conducted two clinical studies towards the goal of developing a regimen for single-visit cure. In a randomized, open-label, Phase 2 study (RG101-04), investigators enrolled 26 adult chronic hepatitis C patients to evaluate safety and efficacy of single subcutaneous injection of RG-101 (4 mg/kg) and daily oral tablets of GSK2878175 (20 mg) for 6, 9 or 12 weeks. In another randomized, double-blind, single dose Phase 1 study (RG101-06), investigators enrolled 18 healthy men to assess safety and PK of GSK2878175 long-acting injectable at 100, 200 or 400 mg. In RG101-04, SVR48 rates were 50%, 56% and 89%, for the 6, 9 and 12 weeks treatment arms, respectively. All AEs were mild or moderate in severity (≤Grade 2). In RG101-06 at 400 mg, the mean duration of GSK2878175 plasma levels above in vitro therapeutic concentrations for GT1b was 41 days. All AEs were Grade 2 or less. In conclusion, single injection of RG-101 combined with 12 weeks of GSK2878175 oral tablets was generally well tolerated and resulted in high SVR rates in chronic hepatitis C patients. Single injections of GSK2878175 long-acting injectable were also well tolerated; however, higher doses would be required if used in combination with RG-101 to achieve the SVR rates observed in the oral combination study to enable a single-visit curative regimen.
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Affiliation(s)
- Yanli Deng
- GlaxoSmithKline, Collegeville, Pennsylvania, USA
| | | | - Kelong Han
- GlaxoSmithKline, Collegeville, Pennsylvania, USA
| | | | - Mark Deeg
- Regulus Therapeutics Inc., San Diego, California, USA
| | - Michael Huang
- Regulus Therapeutics Inc., San Diego, California, USA
| | - Robert Hamatake
- GlaxoSmithKline, Research Triangle Park, North Carolina, USA
| | - Soumi Lahiri
- GlaxoSmithKline, Collegeville, Pennsylvania, USA
| | | | | | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, GI-Liver Unit, Hippocratio General Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Institute of Internal Medicine and Hepatology, University Hospital of Larisa, Larisa, Greece
| | - George Papatheodoridis
- 2nd Department of Internal Medicine, GI-Liver Unit, Hippocratio General Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Goulis
- Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Martin Leivers
- GlaxoSmithKline, Research Triangle Park, North Carolina, USA
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18
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Upscaling prevention, testing and treatment to control hepatitis C as a public health threat in Dar es Salaam, Tanzania: A cost-effectiveness model. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2019; 88:102634. [PMID: 31882272 DOI: 10.1016/j.drugpo.2019.102634] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 10/21/2019] [Accepted: 12/11/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND Hepatitis C (HCV) elimination strategies are required for low and middle-income countries (LMICs), because although treatment access is currently limited, this is unlikely to remain the case forever. We estimate and compare the impact, cost and cost-effectiveness of a variety of prevent, test and treat strategies for HCV in Dar es Salaam, Tanzania. METHODS A mathematical model. RESULTS Without intervention, the HCV epidemic in Dar es Salaam was estimated to result in US$29.1 million in disease costs between 2018 and 2030. Maintaining existing harm reduction coverage (4% needle and syringe program, 42% opioid substitution therapy) over this period was estimated to prevent 22% of injecting drug use-acquired HCV infections compared to a zero coverage scenario. Implementing antibody/RNA, serum-based HCV core antigen (HCVcAg) and dry blood spot (DBS) HCVcAg test/treat programs among PWID increased the total cost by US$0.7 million, US$3.1 million and US$6.5 million respectively by 2030; however this expenditure led to 57%, 61% and 73% reductions in annual incidence among PWID, 25%, 27% and 33% reductions overall annual incidence (PWID+non-PWID), and reduced HCV prevalence among PWID from 27% to 9%, 8% and 5%, respectively. The Ab/RNA, serum-based and DBS HCVcAg test/treat programs cost US$689, US$2857 and US$5400 per disability-adjusted life year averted, respectively, compared to no test/treat program. CONCLUSION Primary prevention among PWID can provide important reductions in HCV transmission in the absence of treatment availability. HCV Ab/RNA or serum-based HCVcAg test/treat programs among PWID are likely to be cost-effective in Dar es Salaam, with serum-based HCVcAg test/treat achieving greater impact due to a simpler diagnostic process and better retention in care. If used for regular testing of PWID, the additional coverage benefits of non-laboratory-based DBS HCVcAg tests in LMICs would outweigh their reduced sensitivity.
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19
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Abstract
Evidence for the existence of another hepatitis-causing pathogen, other than the known hepatitis A and B viruses, emerged in the mid-1970s. A frustrating search of 15 years was ended by the identification of the hepatitis C virus in 1989 using a recombinant DNA immunoscreening method. This discovery quickly led to blood tests that eliminated posttransfusion hepatitis C and could show the partial efficacy of type 1 interferon-based therapies. Subsequent knowledge of the viral replication cycle then led to the development of effective direct-acting antivirals targeting its serine protease, polymerase, and nonstructural protein 5A that resulted in the approval of orally available drug combinations that can cure patients within a few months with few side effects. Meanwhile, vaccine strategies have been shown to be feasible, and they are still required to effectively control this global epidemic.
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Affiliation(s)
- Michael Houghton
- Li Ka Shing Applied Virology Institute, Department of Medical Microbiology & Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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20
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Smolders EJ, Jansen AME, Ter Horst PGJ, Rockstroh J, Back DJ, Burger DM. Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations: A 2019 Update. Clin Pharmacokinet 2019; 58:1237-1263. [PMID: 31114957 PMCID: PMC6768915 DOI: 10.1007/s40262-019-00774-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug-drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.
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Affiliation(s)
- Elise J Smolders
- Department of Pharmacy, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands.
- Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
| | - Anouk M E Jansen
- Department of Pharmacy, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands
| | - Peter G J Ter Horst
- Department of Pharmacy, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands
| | - Jürgen Rockstroh
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - David J Back
- Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK
| | - David M Burger
- Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands
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21
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Scott N, Wilson DP, Thompson AJ, Barnes E, El-Sayed M, Benzaken AS, Drummer HE, Hellard ME. The case for a universal hepatitis C vaccine to achieve hepatitis C elimination. BMC Med 2019; 17:175. [PMID: 31530275 PMCID: PMC6749704 DOI: 10.1186/s12916-019-1411-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/19/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. METHODS The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018-2030. RESULTS The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15-113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6-8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7-10.8) billion cost reduction across 78 countries (47%). CONCLUSIONS These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.
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Affiliation(s)
- Nick Scott
- Disease Elimination Program, Burnet Institute, Melbourne, Australia. .,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Australia.
| | - David P Wilson
- Disease Elimination Program, Burnet Institute, Melbourne, Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Australia
| | - Alexander J Thompson
- Department of Medicine, The University of Melbourne, Parkville, Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Eleanor Barnes
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.,NIHR Oxford Biomedical Research Centre, Oxford University NHS Trust, Oxford, UK
| | - Manal El-Sayed
- Department of Paediatrics, Ain Shams University, Cairo, Egypt
| | | | - Heidi E Drummer
- Disease Elimination Program, Burnet Institute, Melbourne, Australia.,Department of Microbiology, Monash University, Clayton, Australia.,Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Australia
| | - Margaret E Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Australia.,Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Australia.,Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, Australia
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22
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Jones CR, Flower BF, Barber E, Simmons B, Cooke GS. Treatment optimisation for hepatitis C in the era of combination direct-acting antiviral therapy: a systematic review and meta-analysis. Wellcome Open Res 2019; 4:132. [PMID: 31754636 PMCID: PMC6854875 DOI: 10.12688/wellcomeopenres.15411.1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2019] [Indexed: 12/11/2022] Open
Abstract
Background: Prior to direct-acting antiviral (DAA) therapy, personalised medicine played an important role in the treatment of hepatitis C virus (HCV). Whilst simplified treatment strategies are central to treatment scale-up, some patients will benefit from treatment optimisation. This systematic review and meta-analysis explores treatment optimisation strategies in the DAA era. Methods: We systematically searched Medline, Embase, and Web of Science for studies that adopted a stratified or personalised strategy using a licensed combination DAA regimen, alone or with additional agents. We performed a thematic analysis to classify optimisation strategies and a meta-analysis of sustained virologic response rates (SVR), exploring heterogeneity with subgroup analyses and meta-regression. Results: We included 64 studies (9450 participants). Thematic analysis found evidence of three approaches: duration, combination, and/or dose optimisation. We separated strategies into those aiming to maintain SVR in the absence of predictors of failure, and those aiming to improve SVR in the presence of predictors of failure. Shortened duration regimens achieve pooled SVR rates of 94.2% (92.3-95.9%) for 8 weeks, 81.1% (75.1-86.6%) for 6 weeks, and 63.1% (39.9-83.7%) for ≤4 weeks. Personalised strategies (100% vs 87.6%; p<0.001) and therapy shortened according to ≥3 host/viral factors (92.9% vs 81.4% or 87.2% for 1 or 2 host/viral factors, respectively; p=0.008) offer higher SVR rates when shortening therapy. Hard-to-treat HCV genotype 3 patients suffer lower SVR rates despite treatment optimisation (92.6% vs 98.2%; p=0.001). Conclusions: Treatment optimisation for individuals with multiple predictors of treatment failure can offer high SVR rates. More evidence is needed to identify with confidence those individuals in whom SVR can be achieved with shortened duration treatment.
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Affiliation(s)
| | - Barnaby F. Flower
- Department of Infectious Disease, Imperial College London, London, W2 1NY, UK
- Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam
| | - Ella Barber
- Department of Infectious Disease, Imperial College London, London, W2 1NY, UK
| | - Bryony Simmons
- Department of Infectious Disease, Imperial College London, London, W2 1NY, UK
| | - Graham S. Cooke
- Department of Infectious Disease, Imperial College London, London, W2 1NY, UK
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23
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International Liver Transplantation Society Asian Consensus on the Management of Hepatitis C Virus Infection in Resource Limited Setting-From Noncirrhotic to Decompensated Disease and After Liver Transplantation. Transplantation 2019; 103:733-746. [PMID: 30335692 DOI: 10.1097/tp.0000000000002453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The population of Asia exceeds 4.4 billion people. Chronic hepatitis C virus (HCV) infection in Asia is characterized by specific distribution of genotypes, lack of access to specific therapeutic agents, relatively high cost of treatment, and lack of experienced healthcare providers. Clear consensus on the diagnosis, management, and monitoring of HCV infection specific to the Asian region is a major unmet need. The consensus guidelines documents that have been published to date by major medical societies presume access to an array of direct acting antiviral agents and diagnostic tests that are not broadly applicable to resource limited settings, including Asia. METHODS To address the lack of an Asia-specific set of HCV treatment guidelines, we assembled a panel of 15 HCV experts in the field of hepatology from India, Indonesia, Myanmar, Vietnam, Pakistan, Philippines, and Mongolia convened in April 2017 to review the updated literature and provide recommendations on the diagnosis and management of chronic HCV infection that reflects local conditions. RESULTS An evidence-based comprehensive compilation of the literature supported by the graded recommendations from the expert panel for the optimization of the diagnosis, pretreatment, on treatment, and posttreatment assessments, and management of chronic HCV infection has been presented in this article. CONCLUSIONS With the evolving treatment landscape and addition of several new direct-acting antiviral agents and combination regimens into the therapeutic armamentarium, the current article may serve as a guide to the clinicians in optimizing the diagnosis and treatment selection for the management of chronic HCV infection in resource-limited settings.
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24
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Colombo MG, Musabaev EI, Ismailov UY, Zaytsev IA, Nersesov AV, Anastasiy IA, Karpov IA, Golubovska OA, Kaliaskarova KS, AC R, Hadigal S. Consensus on management of hepatitis C virus infection in resource-limited Ukraine and Commonwealth of Independent States regions. World J Gastroenterol 2019; 25:3897-3919. [PMID: 31413526 PMCID: PMC6689802 DOI: 10.3748/wjg.v25.i29.3897] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 06/04/2019] [Accepted: 06/08/2019] [Indexed: 02/06/2023] Open
Abstract
Globally, 69.6 million individuals were infected with hepatitis C virus (HCV) infection in 2016. Of the six major HCV genotypes (GT), the most predominant one is GT1, worldwide. The prevalence of HCV in Central Asia, which includes most of the Commonwealth of Independent States (CIS), has been estimated to be 5.8% of the total global burden. The predominant genotype in the CIS and Ukraine regions has been reported to be GT1, followed by GT3. Inadequate HCV epidemiological data, multiple socio-economic barriers, and the lack of region-specific guidelines have impeded the optimal management of HCV infection in this region. In this regard, a panel of regional experts in the field of hepatology convened to discuss and provide recommendations on the diagnosis, treatment, and pre-, on-, and posttreatment assessment of chronic HCV infection and to ensure the optimal use of cost-effective antiviral regimens in the region. A comprehensive evaluation of the literature along with expert recommendations for the management of GT1-GT6 HCV infection with the antiviral agents available in the region has been provided in this review. This consensus document will help guide clinical decision-making during the management of HCV infection, further optimizing treatment outcomes in these regions.
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Affiliation(s)
- Massimo Giuseppe Colombo
- Research and Clinical Center, Department of Medicine, Humanitas Hospital, Rozzano 20089, MI, Italy
| | - Erkin Isakovich Musabaev
- Research Institute of Virology, Scientific Research Institute of Virology, Tashkent 100194, Uzbekistan
| | - Umed Yusupovich Ismailov
- Hepatoсenter, Research Institute of Virology, Scientific Research Institute of Virology, Tashkent 100194, Uzbekistan
| | - Igor A Zaytsev
- Department of Therapy, Infectious Diseases and Dermatology, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Alexander V Nersesov
- Department of Gastroenterology and Hepatology, National Research Institute of Cardiology and Internal Diseases, Almaty 050000, Kazakhstan
| | | | | | - Olga A Golubovska
- Department Infectious Diseases, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | | | - Ravishankar AC
- Medical Affairs, Mylan Pharmaceuticals Private Limited, Kadubeesanahalli, Bengaluru 560103, India
| | - Sanjay Hadigal
- Medical Affairs, Mylan Pharmaceuticals Private Limited, Kadubeesanahalli, Bengaluru 560103, India
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25
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Han B, Martin R, Xu S, Parvangada A, Svarovskaia ES, Mo H, Dvory-Sobol H. Sofosbuvir susceptibility of genotype 1 to 6 HCV from DAA-naïve subjects. Antiviral Res 2019; 170:104574. [PMID: 31394118 DOI: 10.1016/j.antiviral.2019.104574] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/23/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
High sequence diversity of HCV may lead to variation in susceptibility to antiviral agents amongst different genotypes and subtypes of the virus. We assessed the susceptibility to sofosbuvir of chimeric replicons carrying the full length NS5B coding region from 479 HCV infected, treatment-naïve patients, including 15 subtypes in 6 genotypes. NS5B replicon vectors with subtype 1b, subtype 4a and subtype 6a backbone were modified to support testing of patient samples. We also evaluated sofosbuvir susceptibility in a panel of 331 replicons containing engineered NS5B inhibitor resistance-associated substitutions. The mean 50% effective sofosbuvir concentration (EC50) amongst different genotypes ranged from 32 (subtype 2a) to 130 nM (genotype 4); while some variation in susceptibility amongst patient isolates was observed, the 95th percentile for any genotype did not exceed 189 nM. Levels of resistance to sofosbuvir in replicons containing S282T were between 2.4 and 18 fold-change in EC50; no other single NS5B resistance-associated substitution demonstrated reduced sofosbuvir susceptibility. These data suggest that S282T is the only known substitution that confers detectable resistance to sofosbuvir in vitro. Sofosbuvir displayed potent antiviral activity across a diverse range of NS5B mutants and HCV clinical isolates in multiple subtypes of genotypes 1 to 6.
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Affiliation(s)
- Bin Han
- Gilead Sciences, Foster City, CA, USA
| | | | - Simin Xu
- Gilead Sciences, Foster City, CA, USA
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26
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Leahy J, Thom H, Jansen JP, Gray E, O'Leary A, White A, Walsh C. Incorporating single-arm evidence into a network meta-analysis using aggregate level matching: Assessing the impact. Stat Med 2019; 38:2505-2523. [PMID: 30895655 DOI: 10.1002/sim.8139] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 11/27/2018] [Accepted: 02/14/2019] [Indexed: 01/21/2023]
Abstract
Increasingly, single-armed evidence is included in health technology assessment submissions when companies are seeking reimbursement for new drugs. While it is recognized that randomized controlled trials provide a higher standard of evidence, these are not available for many new agents that have been granted licenses in recent years. Therefore, it is important to examine whether alternative strategies for assessing this evidence may be used. In this work, we examine approaches to incorporating single-armed evidence formally in the evaluation process. We consider matching aggregate level covariates to comparator arms or trials and including this evidence in a network meta-analysis. We consider two methods of matching: (i) we include the chosen matched arm in the data set itself as a comparator for the single-arm trial; (ii) we use the baseline odds of an event in a chosen matched trial to use as a plug-in estimator for the single-arm trial. We illustrate that the synthesis of evidence resulting from such a setup is sensitive to the between-study variability, formulation of the prior for the between-design effect, weight given to the single-arm evidence, and extent of the bias in single-armed evidence. We provide a flowchart for the process involved in such a synthesis and highlight additional sensitivity analyses that should be carried out. This work was motivated by a hepatitis C data set, where many agents have only been examined in single-arm studies. We present the results of our methods applied to this data set.
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Affiliation(s)
- Joy Leahy
- School of Computer Science and Statistics, Trinity College Dublin, The University of Dublin, Dublin, Ireland
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Howard Thom
- Bristol Medical School: Population Health Sciences, University of Bristol, Bristol, UK
| | - Jeroen P Jansen
- Department of Health Research and Policy Epidemiology, Stanford University School of Medicine, Stanford, California
| | - Emma Gray
- School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Arthur White
- School of Computer Science and Statistics, Trinity College Dublin, The University of Dublin, Dublin, Ireland
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Cathal Walsh
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
- Department of Mathematics and Statistics, Health Research Institute and MACSI, University of Limerick, Limerick, Ireland
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27
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Raja R, Baral S, Dixit NM. Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era. Immunol Rev 2019; 285:55-71. [PMID: 30129199 DOI: 10.1111/imr.12689] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.
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Affiliation(s)
- Rubesh Raja
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Subhasish Baral
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Narendra M Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India
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28
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A proof-of-concept study in HCV-infected Huh7.5 cells for shortening the duration of DAA-based triple treatment regimens. Biomed Pharmacother 2019; 116:108976. [PMID: 31103827 DOI: 10.1016/j.biopha.2019.108976] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/04/2019] [Accepted: 05/08/2019] [Indexed: 12/23/2022] Open
Abstract
With the development of more effective direct-acting antivirals (DAAs), dual- or triple-therapy regimens represent the major strategy used to cure chronic hepatitis C virus (HCV) infection. Thus, shorter treatment duration regimens with low burden, few adverse effects and good patient adherence are urgently needed. This study theoretically demonstrates a proof-of-concept approach for shortening therapy duration by examining HCV-infected Huh7.5 cells after treatment with a high or low fixed dose of three DAAs (simeprevir + daclatasvir + sofosbuvir) for 6-15 days. The results demonstrated that HCV-infected Huh7.5 cells achieved an ultrarapid virologic response with undetectable HCV RNA and protein and were cured after treatment with the triple-therapy regimen for 15 days. When the treatment duration was shortened, virologic relapse might occur after treatment with a low fixed dose of the three DAAs for 9 days and did occur after treatment with a low fixed dose for 6 days, although HCV was below detectable levels at the end of treatment. However, virologic relapse could be avoided with treatment of a high fixed dose of the three DAAs for 9 or 6 days. Although a virologic breakthrough occurred after an intermittent treatment regimen at the low fixed dose, the high fixed dose cured HCV-positive Huh7.5 cells with intermittent treatment. In conclusion, HCV is persistently present below detectable levels in HCV-infected Huh7.5 cells for a long time after treatment, and a shortened therapy duration is associated with an increased risk of virologic relapse, but virologic relapse or breakthrough might be avoided by treatment with a combination of more highly effective DAAs.
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29
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Scott N, Stoové M, Wilson DP, Keiser O, El-Hayek C, Doyle J, Hellard M. Eliminating hepatitis C virus as a public health threat among HIV-positive men who have sex with men: a multi-modelling approach to understand differences in sexual risk behaviour. J Int AIDS Soc 2019; 21. [PMID: 29314670 PMCID: PMC5810343 DOI: 10.1002/jia2.25059] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 12/18/2017] [Indexed: 12/12/2022] Open
Abstract
Introduction Outbreaks of hepatitis C virus (HCV) infections among HIV‐positive men who have sex with men (MSM) have been observed globally. Using a multi‐modelling approach we estimate the time and number of direct‐acting antiviral treatment courses required to achieve an 80% reduction in HCV prevalence among HIV‐positive MSM in the state of Victoria, Australia. Methods Three models of HCV transmission, testing and treatment among MSM were compared: a dynamic compartmental model; an agent‐based model (ABM) parametrized to local surveillance and behavioural data (“ABM1”); and an ABM with a more heterogeneous population (“ABM2”) to determine the influence of extreme variations in sexual risk behaviour. Results Among approximately 5000 diagnosed HIV‐positive MSM in Victoria, 10% are co‐infected with HCV. ABM1 estimated that an 80% reduction in HCV prevalence could be achieved in 122 (inter‐quartile range (IQR) 112 to 133) weeks with 523 (IQR 479 to 553) treatments if the average time from HCV diagnosis to treatment was six months. This was reduced to 77 (IQR 69 to 81) weeks if the average time between HCV diagnosis and treatment commencement was decreased to 16 weeks. Estimates were consistent across modelling approaches; however ABM2 produced fewer incident HCV cases, suggesting that treatment‐as‐prevention may be more effective in behaviourally heterogeneous populations. Conclusions Major reductions in HCV prevalence can be achieved among HIV‐positive MSM within two years through routine HCV monitoring and prompt treatment as a part of HIV care. Compartmental models constructed with limited behavioural data are likely to produce conservative estimates compared to models of the same setting with more complex parametrizations.
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Affiliation(s)
- Nick Scott
- Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Vic., Australia
| | - Mark Stoové
- Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Vic., Australia
| | - David P Wilson
- Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia
| | - Olivia Keiser
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Carol El-Hayek
- Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia
| | - Joseph Doyle
- Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne, Vic., Australia
| | - Margaret Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Vic., Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne, Vic., Australia
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30
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Edmunds BL, Miller ER, Tsourtos G. The distribution and socioeconomic burden of Hepatitis C virus in South Australia: a cross-sectional study 2010-2016. BMC Public Health 2019; 19:527. [PMID: 31068170 PMCID: PMC6505114 DOI: 10.1186/s12889-019-6847-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 04/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus infection (HCV) is a communicable disease of increasing global importance with 1.75 million new infections and 400,000 related deaths annually. Until recently, treatment options have had low uptake and most infected people remain untreated. New Direct Acting Antiviral medications can clear the virus in around 95% of cases, with few side-effects. These medications are restricted in most countries but freely accessible in Australia, yet most people still remain untreated. This study applies a cross-sectional research design to investigate the socio-spatial distribution of HCV in South Australia, to identify vulnerable populations, and examine epidemiological factors to potentially inform future targeted strategies for improved treatment uptake. METHOD HCV surveillance data were sourced from South Australia's Communicable Diseases Control Branch and socio-economic population data from the Australian Bureau of Statistics from January 2010 to December 2016 inclusive. HCV cases were spatially mapped at postcode level. Multivariate logistic regression identified independent predictors of demographic risks for HCV notification and notification source. RESULTS HCV notifications (n = 3356) were seven times more likely to be from people residing in the poorest areas with high rates of non-employment (75%; n = 1876) and injecting drug use (74%; n = 1862) reported. Notifications among Aboriginal and Torres Strait Islander people were around six times that of non-Indigenous people. HCV notifications negatively correlated (Spearman's rho - 0.426; p < 0.001) with socio-economic status (residential postcode socio-economic resources Index). History of imprisonment independently predicted HCV diagnoses in lesser economically-resourced areas (RR1.5; p < 0.001). Independent predictors of diagnosis elsewhere than in general practices were non-employment (RR 4.6; p = 0.028), being male (RR 2.5; p < 0.001), and younger than mean age at diagnosis (RR 2.1; p = 0.006). CONCLUSIONS Most people diagnosed with HCV were from marginalised sub-populations. Given general practitioners are pivotal to providing effective HCV treatment for many people in Australia a most concerning finding was that non-employed people were statistically less likely to be diagnosed by general practitioners. These findings highlight a need for further action aimed at improving healthcare access and treatment uptake to help reduce the burden of HCV for marginalised people, and progress the vision of eliminating HCV as a major public health threat.
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Affiliation(s)
| | - Emma Ruth Miller
- Flinders University, GPO Box 2100, Adelaide, 5001 South Australia
| | - George Tsourtos
- Flinders University, GPO Box 2100, Adelaide, 5001 South Australia
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31
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Habib S, Azam M, Siddiqui AH, Rajdev K, Chalhoub M. Hepatocellular Carcinoma After Successful Treatment of Hepatitis C Virus with Ledipasvir/Sofosbuvir Presenting as Acute Pulmonary Tumor Embolism. Cureus 2019; 11:e4336. [PMID: 31187001 PMCID: PMC6541161 DOI: 10.7759/cureus.4336] [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] [Indexed: 11/09/2022] Open
Abstract
Hepatitis C virus (HCV)-induced cirrhosis is a major cause of hepatocellular carcinoma (HCC) worldwide. HCC is an aggressive malignancy in which tumor thrombus can invade portal vein, hepatic veins and inferior vena cava (IVC) in the later stages. Our case brings to attention, HCV patient population who might need long-term follow-up to ensure HCV clearance. Physicians should ensure appropriate follow-up after treatment of HCV and should emphasize on the ongoing screening for HCC in patients with cirrhosis or advanced fibrosis, regardless of antiviral treatment outcome.
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Affiliation(s)
- Saad Habib
- Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, USA
| | - Mohammed Azam
- Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, USA
| | - Abdul Hasan Siddiqui
- Pulmonary and Critical Care Medicine, Staten Island University Hospital, Northwell Health, Staten Island, USA
| | - Kartikeya Rajdev
- Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, USA
| | - Michel Chalhoub
- Pulmonary and Critical Care Medicine, Staten Island University Hospital, Northwell Health, Staten Island, USA
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32
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Yeh TK, Kang IJ, Hsu TA, Lee YC, Lee CC, Hsu SJ, Tian YW, Yang HY, Chen CT, Chao YS, Yueh A, Chern JH. A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus. Eur J Med Chem 2019; 167:245-268. [PMID: 30772607 DOI: 10.1016/j.ejmech.2019.02.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 02/02/2019] [Accepted: 02/04/2019] [Indexed: 12/24/2022]
Abstract
A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC50 = 0.003 nM) than daclatasvir (GT1b EC50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC50 > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
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Affiliation(s)
- Teng-Kuang Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Iou-Jiun Kang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Tsu-An Hsu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Yen-Chun Lee
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Chung-Chi Lee
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Sheng-Ju Hsu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Ya-Wen Tian
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Hui-Yun Yang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Chiung-Tong Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Yu-Sheng Chao
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Andrew Yueh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Jyh-Haur Chern
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC.
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33
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Yates MK, Seley-Radtke KL. The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Res 2019; 162:5-21. [PMID: 30529089 PMCID: PMC6349489 DOI: 10.1016/j.antiviral.2018.11.016] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/24/2018] [Accepted: 11/30/2018] [Indexed: 12/13/2022]
Abstract
This is the second of two invited articles reviewing the development of nucleoside analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. As with the first paper, rather than providing a chronological account, we have chosen to examine particular examples of structural modifications made to nucleoside analogues that have proven fruitful as various antiviral, anticancer, and other therapeutics. The first review covered the more common, and in most cases, single modifications to the sugar and base moieties of the nucleoside scaffold. This paper focuses on more recent developments, especially nucleoside analogues that contain more than one modification to the nucleoside scaffold. We hope that these two articles will provide an informative historical perspective of some of the successfully designed analogues, as well as many candidate compounds that encountered obstacles.
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Affiliation(s)
- Mary K Yates
- Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA
| | - Katherine L Seley-Radtke
- Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA.
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34
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Kwon JA, Dore GJ, Grebely J, Hajarizadeh B, Guy R, Cunningham EB, Power C, Estes C, Razavi H, Gray RT. Australia on track to achieve WHO HCV elimination targets following rapid initial DAA treatment uptake: A modelling study. J Viral Hepat 2019; 26:83-92. [PMID: 30267593 DOI: 10.1111/jvh.13013] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 09/13/2018] [Indexed: 12/22/2022]
Abstract
Subsidized direct-acting antiviral (DAA) treatment recently became available to all adults living with chronic hepatitis C virus (HCV) in Australia. Based on rapid uptake (32 600 people initiated DAA in 2016), we estimated the impact on HCV epidemiology and mortality in Australia and determined if Australia can meet the WHO HCV elimination targets by 2030. Using a mathematical model, we simulated pessimistic, intermediate and optimistic DAA treatment scenarios in Australia over 2016-2030. We assumed treatment and testing rates were initially higher for advanced fibrosis and the same across HCV transmission risk level sub-populations. We also assumed constant testing rates after 2016. We compared the results to the 2015 level and a counterfactual (IFN-based) scenario. During 2016-2030, we estimated an intermediate DAA treatment scenario (2016, 32 600 treated; 2017, 21 370 treated; 2018 17 100 treated; 2019 and beyond, 13 680 treated each year) would avert 40 420 new HCV infections, 13 260 liver-related deaths (15 320 in viraemic; -2060 in cured) and 10 730 HCC cases, equating to a 53%, 63% and 75% reduction, respectively, compared to the IFN-based scenario. The model also estimated that Australia will meet the WHO targets of incidence and treatment by 2028. Time to a 65% reduction in liver-related mortality varied considerably between HCV viraemic only cases (2026) and all cases (2047). Based on a feasible DAA treatment scenario incorporating declining uptake, Australia should meet key WHO HCV elimination targets in 10 to15 years. The pre-DAA escalation in those with advanced liver disease makes the achievement of the liver-related mortality target difficult.
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Affiliation(s)
- Jisoo A Kwon
- Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | | | - Jason Grebely
- Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | | | - Rebecca Guy
- Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | | | | | - Chris Estes
- Center for Disease Analysis (CDA), Lafayette, Colorado
| | - Homie Razavi
- Center for Disease Analysis (CDA), Lafayette, Colorado
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35
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Scott N, Sacks-Davis R, Pedrana A, Doyle J, Thompson A, Hellard M. Eliminating hepatitis C: The importance of frequent testing of people who inject drugs in high-prevalence settings. J Viral Hepat 2018; 25:1472-1480. [PMID: 30047625 DOI: 10.1111/jvh.12975] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 06/27/2018] [Accepted: 06/30/2018] [Indexed: 12/11/2022]
Abstract
Modelling suggests that more frequent screening of people who inject drugs (PWID) and an improved care cascade are required to achieve the WHO hepatitis C virus (HCV) elimination target of an 80% reduction in incidence by 2030. We determined the testing frequencies (2-yearly, annually, 6-monthly and 3-monthly) and retention in care required among PWID to achieve the HCV incidence reduction target through treatment as prevention in low (25%), medium (50%) and high (75%) chronic HCV prevalence settings. Mathematical modelling of HCV transmission among PWID, capturing testing, treatment and other features of the care cascade were employed. In low-prevalence settings, 2-yearly antibody testing of PWID was estimated to reach the elimination target by 2027-2030 depending on retention in care, with annual testing reducing the time by up to 3 years. In medium-prevalence settings, if close to 90% testing coverage were achieved, then annual antibody testing of PWID would be sufficient. If testing coverage were lower (80%), 6-monthly antibody testing with at least 70% retention in care or annual HCV RNA/cAg testing would be required. In high-prevalence settings, even 3-monthly HCV RNA/cAg testing of PWID was unable to achieve the incidence reduction target. Thus, for geographical areas or subpopulations with high prevalence, WHO incidence targets are unlikely to be met without 3-monthly RNA/cAg testing accompanied by other prevention measures. Novel testing strategies, such as rapid point-of-care antibody testing or replacing antibody testing with RNA/cAg tests as a screening tool, can provide additional population-level impacts to compensate for imperfect follow-up or testing coverage.
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Affiliation(s)
- Nick Scott
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia
| | - Rachel Sacks-Davis
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia
| | - Alisa Pedrana
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia
| | - Joseph Doyle
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne, Victoria, Australia
| | - Alexander Thompson
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.,Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
| | - Margaret Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia.,Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia.,Department of Infectious Diseases, The Alfred and Monash University, Melbourne, Victoria, Australia
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36
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Wagner R, Randolph JT, Patel SV, Nelson L, Matulenko MA, Keddy R, Pratt JK, Liu D, Krueger AC, Donner PL, Hutchinson DK, Flentge C, Betebenner D, Rockway T, Maring CJ, Ng TI, Krishnan P, Pilot-Matias T, Collins C, Panchal N, Reisch T, Dekhtyar T, Mondal R, Stolarik DF, Gao Y, Gao W, Beno DA, Kati WM. Highlights of the Structure-Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530). J Med Chem 2018; 61:4052-4066. [PMID: 29653491 DOI: 10.1021/acs.jmedchem.8b00082] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.
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Affiliation(s)
- Rolf Wagner
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - John T Randolph
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Sachin V Patel
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Lissa Nelson
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Mark A Matulenko
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Ryan Keddy
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - John K Pratt
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Dachun Liu
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - A Chris Krueger
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Pamela L Donner
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Douglas K Hutchinson
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Charles Flentge
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - David Betebenner
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Todd Rockway
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Clarence J Maring
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Teresa I Ng
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Preethi Krishnan
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Tami Pilot-Matias
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Christine Collins
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Neeta Panchal
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Thomas Reisch
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Tatyana Dekhtyar
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Rubina Mondal
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - DeAnne F Stolarik
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Yi Gao
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Wenqing Gao
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - David A Beno
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
| | - Warren M Kati
- Global Pharmaceutical Research and Development , AbbVie , 1 North Waukegan Road , North Chicago , Illinois 60064 , United States
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37
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Shafran SD, Shaw D, Charafeddine M, Agarwal K, Foster GR, Abunimeh M, Pilot-Matias T, Pothacamury RK, Fu B, Cohen E, Cohen DE, Gane E. Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III). J Viral Hepat 2018; 25:118-125. [PMID: 28833938 DOI: 10.1111/jvh.12782] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 07/19/2017] [Indexed: 12/15/2022]
Abstract
The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.
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Affiliation(s)
- S D Shafran
- Division of Infectious Diseases, Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada
| | - D Shaw
- Royal Adelaide Hospital, Adelaide, SA, Australia
| | | | - K Agarwal
- Institute of Liver Studies, Kings College Hospital, London, UK
| | - G R Foster
- Queen Mary University of London, Barts Health, London, UK
| | | | | | | | - B Fu
- AbbVie Inc., North Chicago, IL, USA
| | - E Cohen
- AbbVie Inc., North Chicago, IL, USA
| | | | - E Gane
- Liver Unit, Auckland City Hospital, Auckland, New Zealand
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38
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Ferreira VL, Tonin FS, Assis Jarek NA, Ramires Y, Pontarolo R. Efficacy of Interferon-Free Therapies for Chronic Hepatitis C: A Systematic Review of All Randomized Clinical Trials. Clin Drug Investig 2018; 37:635-646. [PMID: 28409482 DOI: 10.1007/s40261-017-0521-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND OBJECTIVES Second-generation direct-acting antivirals (DAAs) have recently arisen as more effective and safer treatments for chronic hepatitis C. These drugs can be combined into treatments without interferon (IFN), and are therefore called IFN-free therapies. OBJECTIVE The objective of this study systematic review was to evaluate the efficacy of IFN-free therapies for the treatment of chronic hepatitis C, and thus increase the clinical evidence for these therapies. METHODS A systematic review was conducted in accordance with Cochrane Collaboration recommendations. A search was performed in six different electronic databases using 'clinical trials', 'hepatitis C' and 'interferon-free' as the main descriptors, and studies that conformed to the inclusion criteria had their data extracted, including study information, baseline characteristics, and efficacy outcomes (sustained virologic response, rapid virologic response, and virologic failure). RESULTS Sixty-four randomized clinical trials including 15 different therapies were included in a total of 15,731 patients infected with the hepatitis C virus, mostly with genotype 1, and mainly treated for 12 or 24 weeks. The sustained virologic response rate after 12 weeks of treatment was approximately 89%, while the virologic failure rate was below 5%. CONCLUSIONS Second-generation DAAs presented several advantages: virologic response values higher than the average achieved by previous IFN-based therapies, reduced treatment duration, and the possibility of different combinations of therapies to meet patient needs. Thus, IFN-free therapies appear to be valuable alternatives for the treatment of chronic hepatitis C.
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Affiliation(s)
- Vinicius L Ferreira
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil.
| | - Fernanda S Tonin
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
| | - Nayara A Assis Jarek
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
| | - Yohanna Ramires
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
| | - Roberto Pontarolo
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
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39
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Barone M, Iannone A, Shahini E, Ippolito AM, Brancaccio G, Morisco F, Milella M, Messina V, Smedile A, Conti F, Gatti P, Santantonio T, Tundo P, Lauletta G, Napoli N, Masetti C, Termite AP, Francavilla R, Di Leo A, Pesce F, Andriulli A. A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: The ital-c network study. J Viral Hepat 2018; 25:56-62. [PMID: 28787102 DOI: 10.1111/jvh.12765] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/11/2017] [Indexed: 02/07/2023]
Abstract
The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir-ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24 weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (P = .002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (P = .002), prevalence of Child-Pugh class A (P = .002), lower MELD scores (P = .001) and smaller number of nonresponders (P = .04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P = .007 and P = .008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir-ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.
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Affiliation(s)
- M Barone
- Department of Emergency and Organ Transplantation, Section of Gastroenterology, AOU Policlinico, University of Bari, Bari, Italy
| | - A Iannone
- Department of Emergency and Organ Transplantation, Section of Gastroenterology, AOU Policlinico, University of Bari, Bari, Italy
| | - E Shahini
- Department of Emergency and Organ Transplantation, Section of Gastroenterology, AOU Policlinico, University of Bari, Bari, Italy
| | - A M Ippolito
- Division of Gastroenterology, "Casa Sollievo Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, Italy
| | - G Brancaccio
- Clinics of Infectious Diseases, "Federico II" University of Naples, Naples, Italy
| | - F Morisco
- Division of Gastroenterology, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - M Milella
- Clinics of Infectious Diseases, University of Bari, Bari, Italy
| | - V Messina
- Infectious and Tropical Diseases Unit, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | - A Smedile
- Department of Medical Sciences, University of Turin, Turin, Italy
- Department of Gastroenterology and Hepatology, Azienda Ospedaliera Cittàdella Salute e della Scienza, Turin, Italy
| | - F Conti
- Department of Medical and Surgical Sciences (DIMEC), Centre for the Study of Hepatitis, University of Bologna, Bologna, Italy
| | - P Gatti
- Internal Medicine, Hospital of Ostuni, Ostuni, Italy
| | - T Santantonio
- Clinics of Infectious Diseases, University of Foggia, Foggia, Italy
| | - P Tundo
- Division of Infectious Diseases, Hospital of Galatina, Galatina, Italy
| | - G Lauletta
- Clinics of Internal Medicine "G. Baccelli", University of Bari, Bari, Italy
| | - N Napoli
- Clinics of Internal Medicine "C. Frugoni", University of Bari, Bari, Italy
| | - C Masetti
- Hepatology and Liver Transplantation Unit, University of Tor Vergata, Rome, Italy
| | - A P Termite
- Liver Unit, Hospital of Castellaneta, Castellaneta, Italy
| | - R Francavilla
- Unit of Infectious Diseases, Hospital of Bisceglie, Bisceglie, Italy
| | - A Di Leo
- Department of Emergency and Organ Transplantation, Section of Gastroenterology, AOU Policlinico, University of Bari, Bari, Italy
| | - F Pesce
- Department of Emergency and Organ Transplantation, Section of Nephrology, AOU Policlinico, University of Bari, Bari, Italy
| | - A Andriulli
- Division of Gastroenterology, "Casa Sollievo Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, Italy
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Borgia G, Maraolo AE, Nappa S, Gentile I, Buonomo AR. NS5B polymerase inhibitors in phase II clinical trials for HCV infection. Expert Opin Investig Drugs 2017; 27:243-250. [PMID: 29271672 DOI: 10.1080/13543784.2018.1420780] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection might be the first chronic viral disease to be eradicated without the introduction of a prophylactic vaccine. This is essentially due to therapeutic revolution encapsulated by the advent of direct-acting antivirals (DAA) agents, whose efficacy, safety and tolerability (all oral regimens) have made the previous standard of care (interferon plus ribavirin) a vestige of the past. The new regimens achieve very high response rates and have an excellent tolerability profile. Notwithstanding, the first wave of DAAs has brought over problems regarding costs and failures which warrant research and development of further antiviral molecules. AREAS COVERED This review outlines the main clinical data concerning novel NS5B polymerase inhibitors currently in pipeline, focusing on the ones that have completed a phase 2 trial. EXPERT OPINION NS5B is one the main viral target for anti-HCV therapy. The large majority of the approved regimens so far include a NS5B inhibitor. Although not frequently, failure related to mutations can occur. The potential place in therapy in the mid-term of new NS5B inhibitors may be, in the first instance, the role of backbone in salvage combinations with DAAs of other classes.
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Affiliation(s)
- Guglielmo Borgia
- a Department of Clinical Medicine and Surgery , University of Naples "Federico II" , Naples , Italy
| | - Alberto Enrico Maraolo
- a Department of Clinical Medicine and Surgery , University of Naples "Federico II" , Naples , Italy
| | - Salvatore Nappa
- a Department of Clinical Medicine and Surgery , University of Naples "Federico II" , Naples , Italy
| | - Ivan Gentile
- a Department of Clinical Medicine and Surgery , University of Naples "Federico II" , Naples , Italy
| | - Antonio Riccardo Buonomo
- a Department of Clinical Medicine and Surgery , University of Naples "Federico II" , Naples , Italy
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Emmanuel B, Wilson EM, O'Brien TR, Kottilil S, Lau G. Shortening the duration of therapy for chronic hepatitis C infection. Lancet Gastroenterol Hepatol 2017; 2:832-836. [PMID: 28802815 PMCID: PMC5737004 DOI: 10.1016/s2468-1253(17)30053-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 01/31/2017] [Accepted: 02/01/2017] [Indexed: 12/11/2022]
Abstract
Combination direct-acting antiviral therapy of 8-24 weeks is highly effective for the treatment of chronic hepatitis C infection. However, shortening the treatment duration to less than 8 weeks could potentially reduce overall treatment costs and improve adherence. Here we explore the arguments for and against the development of short-duration regimens and existing data on treatment for 6 weeks or less among patients with chronic hepatitis C virus genotype 1 infection. Additionally, we identify potential predictors of response to short-course combination therapies with direct-acting antiviral drugs that might be explored in future clinical trials.
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Affiliation(s)
- Benjamin Emmanuel
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eleanor M Wilson
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - George Lau
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, China
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Li Z, Chen ZW, Li H, Ren H, Hu P. Prevalence of hepatitis C virus-resistant association substitutions to direct-acting antiviral agents in treatment-naïve hepatitis C genotype 1b-infected patients in western China. Infect Drug Resist 2017; 10:377-392. [PMID: 29184422 PMCID: PMC5673042 DOI: 10.2147/idr.s146595] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) are potent and highly efficacious. However, resistance-associated substitutions (RASs) relevant to DAAs can impair treatment effectiveness even at baseline. Moreover, the prevalence of baseline RASs in HCV genotype 1b-infected patients in western China is still unclear. Materials and methods Direct sequencing of the HCV NS3, NS5A, and NS5B regions was performed in baseline serum samples of 70 DAAs treatment-naïve HCV 1b-infected patients in western China. The sequences were analyzed with MEGA version 5.05 software. Evolutionary patterns of RASs and amino-acid covariance patterns in the NS3, NS5A, and NS5B genes were analyzed by MEGA and Cytoscape (version 3.2.1), respectively. Results The presence of at least one RAS in the NS3 region (C16S, T54S, Q80R/L, A87T, R117H, S122G, V132I, V170I) was observed in 85.48% (53 of 62) of patients, RASs in the NS5A region (L28M, R30Q, Q54H, P58S/T, Q62H/R, Y93H) were observed in 42.42% (28 of 66) of patients, and RASs in the NS5B region (N142S, A300T, C316N, A338V, S365A, L392I, M414L, I424V, A442T, V499A, S556G) were observed in 100% (44 of 44) of patients. Evolutionary patterns of RASs and amino-acid covariance patterns for the NS3, NS5A, and NS5B genes are reported. Conclusion The prevalence of RASs relevant to DAAs detected in the NS3, NS5A, and NS5B regions of HCV 1b from DAA treatment-naïve patients is high. Therefore, more attention should be paid to RASs associated with DAAs in the upcoming DAA-treatment era in China.
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Affiliation(s)
- Zhao Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Wei Chen
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hu Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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German P, Mathias A, Brainard DM, Song Q, Ling J, Kearney BP. A Thorough QT Study to Evaluate the Effects of Supratherapeutic Doses of Ledipasvir on the QTc Interval in Healthy Subjects. Clin Pharmacol Drug Dev 2017; 7:641-651. [DOI: 10.1002/cpdd.390] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 07/27/2017] [Indexed: 11/07/2022]
Affiliation(s)
| | | | | | | | - John Ling
- Gilead Sciences, Inc.; Foster City CA USA
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Weng Q, Li X, Ren H, Xie J, Pan X, Xu J, Chen N. Membranous nephropathy associated with hepatitis C virus infection treated with corticosteroids and Ledipasvir-Sofosbuvir: a case report and review of literature. Oncotarget 2017; 8:22299-22303. [PMID: 28223549 PMCID: PMC5400664 DOI: 10.18632/oncotarget.15397] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 01/25/2017] [Indexed: 01/26/2023] Open
Abstract
Background Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. As many clinical cases have reported, it may be associated with hepatitis C virus (HCV) infection. Antiviral therapy can be various. Case summary We report a case of patient with chronic HCV infection and MN, who presented with was proteinuria. He was treated with ledipasvir and sofosbuvir (Harvoni; Gilead Sciences, Foster City, CA) and was found to be virus-free. Conclusion We have reported this case to provide insight into whether Ledipasvir-Sofosbuvir should be administered for HCV-related glomerulonephritis.
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Affiliation(s)
- Qinjie Weng
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiao Li
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hong Ren
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jingyuan Xie
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaoxia Pan
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jing Xu
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Nan Chen
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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El Sherif O, Afhdal N, Curry M. No one size fits all-Shortening duration of therapy with direct-acting antivirals for hepatitis C genotype 1 infection. J Viral Hepat 2017; 24:808-813. [PMID: 28581634 DOI: 10.1111/jvh.12734] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 04/10/2017] [Indexed: 12/24/2022]
Abstract
The advent of shorter duration, highly effective and well-tolerated interferon-free therapy now provides an opportunity for virtually all HCV-infected individuals to be cured. However, there continues to be a need to simplify and shorten treatment duration. Shortening therapy to 8 weeks with sofosbuvir and ledipasvir can be considered in treatment patients with HCV genotype 1 infection and low baseline viral load. A number of other 8-week dual and triple therapy direct-acting antiviral (DAA) regimens are in advanced clinical development. Several small studies have further demonstrated the feasibility of 6 weeks of sofosbuvir therapy in combination with an NS5A inhibitor and a protease inhibitor for HCV genotype 1. Four weeks of therapy with various combinations of the currently available DAAs appears to be suboptimal with poor response rates observed in phase 2 trials. Response-guided therapy is another promising tool that may allow for shorter therapy but require further research. Shortening therapy and retreating relapsers may be a viable cost-saving measure, but requires further cost-benefit analysis and more data on the impact of resistance on retreatment options.
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Affiliation(s)
- O El Sherif
- Hepatology Centre, St. James's Hospital, Dublin 8, Ireland.,Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - N Afhdal
- Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - M Curry
- Beth Israel Deaconess Medical Centre, Boston, MA, USA
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Nguyen THT, Guedj J, Uprichard SL, Kohli A, Kottilil S, Perelson AS. The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics? Sci Rep 2017; 7:10233. [PMID: 28860456 PMCID: PMC5579268 DOI: 10.1038/s41598-017-09776-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023] Open
Abstract
High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.
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Affiliation(s)
- Thi Huyen Tram Nguyen
- IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France
| | - Jérémie Guedj
- IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France. .,Hopital Henri Mondor, Université Paris-Est, Creteil, France.
| | - Susan L Uprichard
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois, USA
| | - Anita Kohli
- Dignity Health, St. Joseph's Hospital, Phoenix, Arizona, USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA
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Scott N, Doyle JS, Wilson DP, Wade A, Howell J, Pedrana A, Thompson A, Hellard ME. Reaching hepatitis C virus elimination targets requires health system interventions to enhance the care cascade. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2017; 47:107-116. [PMID: 28797497 DOI: 10.1016/j.drugpo.2017.07.006] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 05/28/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Modelling suggests that achieving the World Health Organization's elimination targets for hepatitis C virus (HCV) is possible by scaling up use of direct-acting antiviral (DAA) therapy. However, poor linkage to health services and retention in care presents a major barrier, in particular among people who inject drugs (PWID). We identify and assess the cost-effectiveness of additional health system interventions required to achieve HCV elimination targets in Australia, a setting where all people living with HCV have access to DAA therapy. METHODS We used a dynamic HCV transmission and liver-disease progression mathematical model among current and former PWID, capturing testing, treatment and other features of the care cascade. Interventions tested were: availability of point-of-care RNA testing; increased testing of PWID; using biomarkers in place of liver stiffness measurement; and scaling up primary care treatment delivery. RESULTS The projected treatment uptake in Australia reduced the number of people living with HCV from approximately 230,000 in 2015 to approximately 24,000 by 2030 and reduced incidence by 45%. However, the majority (74%) of remaining infections were undiagnosed and among PWID. Scaling up primary care treatment delivery and using biomarkers in place of liver stiffness measurement only reduced incidence by a further 1% but saved AU$32 million by 2030, with no change to health outcomes. Additionally replacing HCV antibody testing with point-of-care RNA testing increased healthcare cost savings to AU$62 million, increased incidence reduction to 64% and gained 11,000 quality-adjusted life years, but critically, additional screening of PWID was required to achieve HCV elimination targets. CONCLUSION Even with unlimited and unrestricted access to HCV DAA treatment, interventions to improve the HCV cascade of care and target PWID will be required to achieve elimination targets.
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Affiliation(s)
- Nick Scott
- Burnet Institute, Melbourne, VIC 3004, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC 3008, Australia.
| | - Joseph S Doyle
- Burnet Institute, Melbourne, VIC 3004, Australia; Department of Infectious Diseases, The Alfred and Monash University, Melbourne, VIC 3004, Australia
| | | | - Amanda Wade
- Burnet Institute, Melbourne, VIC 3004, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC 3008, Australia
| | - Jess Howell
- Burnet Institute, Melbourne, VIC 3004, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC 3008, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia; Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC 3165, Australia
| | | | - Alexander Thompson
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia; Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC 3165, Australia
| | - Margaret E Hellard
- Burnet Institute, Melbourne, VIC 3004, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC 3008, Australia; Department of Infectious Diseases, The Alfred and Monash University, Melbourne, VIC 3004, Australia
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Abstract
BACKGROUND There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN). PATIENTS AND METHODS Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups. RESULTS No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups. CONCLUSION DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.
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A fixed-dose combination of ledipasvir and sofosbuvir ± ribavirin for treatment of hepatitis C infection: a systematic review and meta-analysis. DRUGS & THERAPY PERSPECTIVES 2017. [DOI: 10.1007/s40267-017-0401-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Biomy R, Abdelshafy M, Abdelmonem A, Abu-Elenin H, Ghaly G. Effect of Chronic Hepatitis C Virus Treatment by Combination Therapy on Cardiovascular System. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2017; 11:1179546817713204. [PMID: 28804248 PMCID: PMC5484549 DOI: 10.1177/1179546817713204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 04/16/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND The prevalence of hepatitis C virus (HCV) in Egypt is quite high, and the combined oral direct-acting antiviral agents (DAAs) may have impressive results. OBJECTIVE To assess the cardiovascular effects of DAAs in patients with HCV. METHODS A total of 170 patients with HCV were divided into 2 groups: first group (100 patients) received triple combination therapy (pegylated interferon alfa, sofosbuvir, and ribavirin, whereas the second group (70 patients) received dual combination therapy (sofosbuvir and simeprevir). Group 1 patients were followed up for 1 year more than 3 visits, whereas group 2 patients were followed up for 6 months more than 2 visits; and the end point of the study was the development of a major cardiovascular event (eg, congestive heart failure, echocardiographic evidence of left ventricular dysfunction, occurrence of significant arrhythmias, or acute coronary syndrome). The following parameters were accomplished: medical history and clinical examination, electrocardiogram, echo-Doppler study, and laboratory investigations. RESULTS No significant differences were found between the 2 study groups regarding demographic criteria. None of the both group patients had developed any major cardiac event. No significant changes were observed regarding ST-T wave abnormalities, arrhythmias, or QT interval. None of the both group patients developed echocardiographic regional wall motion abnormalities at baseline or at study end. Systolic function parameters showed minute nonsignificant changes over study visits. Diastolic function parameters showed nonsignificant changes between baseline and 6-month and 12-month visits. CONCLUSIONS The DAAs used in combination regimen with interferon or used orally in combination do not significantly affect the cardio-vascular system.
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Affiliation(s)
- Reda Biomy
- Faculty of Medicine, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | | | | | | | - George Ghaly
- Al-Sahel Teaching Hospital, Cardiology Department Cairo, Egypt
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