|
1
|
El-Yazbi AF, Elashkar NE, Ahmed HM, Talaat W, Abdel-Hay KM. Cost-effective green chromatographic method for the simultaneous determination of four commonly used direct-acting antiviral drugs in plasma and various pharmaceutical formulations. Microchem J 2021. [DOI: 10.1016/j.microc.2021.106512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
2
|
Xiao L, Wu X, Zhang F, Wang J, Xu X, Li L. Changes of inflammatory cytokines/chemokines during ravidasvir plus ritonavir-boosted danoprevir and ribavirin therapy for patients with genotype 1b hepatitis C infection. J Med Virol 2020; 92:3516-3524. [PMID: 32525562 DOI: 10.1002/jmv.26161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/05/2020] [Accepted: 06/07/2020] [Indexed: 01/02/2023]
Abstract
This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment-naïve non-cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV-host interactions during anti-HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12-weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12-weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy-five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment-related serious AEs or AEs leading to discontinuation were reported. The serum HCV-RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon-inducible protein-10 (IP-10) decreased after anti-HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP-10 has the potential to be an indicator of innate immune viral recognition.
Collapse
Affiliation(s)
- Lanlan Xiao
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxin Wu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Wang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaowei Xu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
3
|
Liu XH, Zhang X, Lu ZH, Zhu YS, Wang T. Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection. Biomed Pharmacother 2020; 133:111035. [PMID: 33254013 PMCID: PMC7671653 DOI: 10.1016/j.biopha.2020.111035] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/10/2020] [Accepted: 11/15/2020] [Indexed: 02/08/2023] Open
Abstract
The pandemic of SARS-CoV-2 has posed significant threats to public health worldwide. Target-based drug development is a promising approach against SARS-CoV-2 infection. Nonstructural proteins may play critical roles from drug design perspectives. Insights into NSPs of different viruses could streamline novel drug development. Outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 have produced high pathogenicity and mortality rates in human populations. However, to meet the increasing demand for treatment of these pathogenic coronaviruses, accelerating novel antiviral drug development as much as possible has become a public concern. Target-based drug development may be a promising approach to achieve this goal. In this review, the relevant features of potential molecular targets in human coronaviruses (HCoVs) are highlighted, including the viral protease, RNA-dependent RNA polymerase, and methyltransferases. Additionally, recent advances in the development of antivirals based on these targets are summarized. This review is expected to provide new insights and potential strategies for the development of novel antiviral drugs to treat SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Xiao-Huan Liu
- School of Biological Science, Jining Medical University, Jining, China
| | - Xiao Zhang
- School of Biological Science, Jining Medical University, Jining, China
| | - Zhen-Hua Lu
- College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
| | - You-Shuang Zhu
- School of Biological Science, Jining Medical University, Jining, China
| | - Tao Wang
- School of Biological Science, Jining Medical University, Jining, China.
| |
Collapse
|
|
4
|
Mostafa AM, Saafan HA, Al-Tawashi AS, Kasem MH, Alaa AM, Eltobgy MM, Moubarak AS, Gharib MM, Awwad MA, Omar HM, El-Derany MO. Interleukin-17 haplotyping predicts hepatocellular carcinoma in sofosbuvir, pegylated interferon-alpha-2a & ribavirin treated chronic hepatitis C patients. Virus Res 2020; 292:198226. [PMID: 33171166 DOI: 10.1016/j.virusres.2020.198226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 09/22/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023]
Abstract
Suspect has been directed towards some direct acting antivirals (DAAs) due to their reported association with hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients. The mechanisms behind HCC development, following CHC treatment, were not well understood and may be linked to genetic variabilities in different patients which affect several cytokine productions involved in angiogenesis and inflammation. Of these variabilities, is the genetic polymorphisms in the interleukin-17 (IL-17) A receptor gene. Being an important pleiotropic cytokine, this study aimed to investigate the association between haplotypes in IL-17A receptor rs2275913 and rs3819024 and development of HCC in CHC patients treated with either triple therapy (sofosbuvir (SOF), pegylated interferon-alpha-2a (Peg-IFNα-2a) & ribavirin(RBV)) or with dual therapy (Peg-IFNα-2a&RBV). A cohort of 100 CHC patients was recruited in this study. Samples were tested for single nucleotide polymorphism (SNPs) in IL-17A receptor (rs2275913 and rs3819024) using TaqMan Genotyping assay. Our results showed that the presence of G-G haplotype in IL-17A (rs2275913& rs3819024) is inversely associated with HCC development in patients receiving triple therapy. While, high serum AFP levels are directly associated with HCC development in patients receiving triple therapy. However, in patients receiving dual therapy, HCC development was only associated with high serum alpha fetoprotein (AFP) levels and was not correlated to any specific allele in our studied SNPs. Such results highlight the importance of IL17A receptor gene haplotyping in the prediction of HCC development in patients receiving triple therapy. These results will aid in performing tailored, personalized strategy for CHC treatment.
Collapse
Affiliation(s)
- Ahmed M Mostafa
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Hesham A Saafan
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University, Cairo, Egypt
| | - Ahmed S Al-Tawashi
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Muhannad H Kasem
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ahmed M Alaa
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mahmoud M Eltobgy
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ahmed S Moubarak
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Manar M Gharib
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mohamed A Awwad
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Hazem M Omar
- Radiology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Marwa O El-Derany
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| |
Collapse
|
|
5
|
Said A, Weiss M, Varhelyi A, Farago R, Ballweg C, Rice J, Agarwal P, Fernandez L, Foley D. Utilization of hepatitis C viremic donors for liver transplant recipients without hepatitis C. A veterans transplant center report. Transpl Infect Dis 2020; 23:e13466. [PMID: 32931616 DOI: 10.1111/tid.13466] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/24/2020] [Accepted: 09/06/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND We report our experience utilizing liver donors with HCV Viremia (RNA+) for HCV-negative recipients (HCV D+R-) at a Veterans Affairs (VA) transplant center. METHODS In 2018, we introduced an informed consent process for HCV D+R- liver transplants. RESULTS Eight HCV D+R- liver transplants (LT) were performed. Median time from listing to LT was 189 days (range 41-511). Median MELD at LT was 23.5 (median MELD at LT of 31 for center). All recipients developed HCV viremia after transplant. Median time to DAA initiation was 10 days after viremia (range 3-25). After transplant, the DAAs used were Mavyret in five recipients and Epclusa in three, all for 12 weeks. All eight patients completed DAA therapy and achieved negative HCV RNA by end of therapy (ETR) and seven reached sustained virologic response (SVR) by 12 weeks after end of therapy. One patient died from chronic ischemic encephalopathy after ETR, before SVR. CONCLUSIONS HCV D+R- is a practical strategy to expand the pool of donor organs. It shortened waiting time, allowing patients to receive transplants at lower MELD scores. VA liver transplant programs have provided universal and timely access to post-transplant HCV DAA therapy after donor-derived infection.
Collapse
Affiliation(s)
- Adnan Said
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - Matthew Weiss
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - Anna Varhelyi
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - Rebecca Farago
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - Cristy Ballweg
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - John Rice
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - Parul Agarwal
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - Luis Fernandez
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| | - David Foley
- University of Wisconsin School of Medicine and Public Health and William S Middleton, VA Medical Center, Madison, WI, USA
| |
Collapse
|
|
6
|
Analysis of drug-resistance-associated mutations and genetic barriers in hepatitis C virus NS5B sequences in China. Arch Virol 2020; 165:2013-2020. [PMID: 32601956 DOI: 10.1007/s00705-020-04713-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/22/2020] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) NS5B protein is an RNA-dependent RNA polymerase that is required for viral genome replication and constitutes the most important target region for drugs being developed as direct-acting antivirals (DAAs) against HCV genotype 1. However, the extreme genetic variability leading to drug resistance mutations and genetic barriers has dramatically compromised the effectiveness of DAA therapy. The purpose of this study was to analyze the genetic variability of NS5B polymerase in HCV patients from different provinces of China to identify the impact of these resistance sites on genetic barriers. We analyzed 3489 NS5B sequences of HCV strains circulating in different regions of China, obtained from the GenBank database, 153 of which were from three cities in Sichuan Province (Yibin, Zigong and Zhangzhou). Sequence alignment was conducted using MEGA 6.0, the genetic information was translated into amino acids, and the percentage of polymorphic amino acid sites was calculated. The Vijver method was used to evaluate the occurrence of genetic barriers in HCV NS5B sequences. Blood samples were collected from 153 HCV patients from Sichuan for NS5B sequence analysis using real-time PCR and the Sanger method. Of the 17 antiviral drug resistance sites summarized from the published literature, nine were found in Chinese NS5B sequences, and C316Y was identified as the dominant mutation. Analysis of genetic barriers revealed that the probability of mutation to a drug-resistance-associated amino acid, in response to selective pressure from antiviral drugs was 100% at site 96 and 99.7% at site 282. Our study is the first to analyze the drug resistance sites and to evaluate genetic barriers in NS5B sequences that could affect the responsiveness of Chinese HCV patients to DAA therapy. The results provide a valuable basis for drug development and introduction of foreign-origin antiviral drugs in China that targeting the HCV NS5B region.
Collapse
|
|
7
|
Tsertsvadze T, Gamkrelidze A, Nasrullah M, Sharvadze L, Morgan J, Shadaker S, Gvinjilia L, Butsashvili M, Metreveli D, Kerashvili V, Ezugbaia M, Chkhartishvili N, Abutidze A, Kvaratskhelia V, Averhoff F. Treatment outcomes of patients with chronic hepatitis C receiving sofosbuvir-based combination therapy within national hepatitis C elimination program in the country of Georgia. BMC Infect Dis 2020; 20:30. [PMID: 31924172 PMCID: PMC6954615 DOI: 10.1186/s12879-019-4741-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 12/27/2019] [Indexed: 12/25/2022] Open
Abstract
Background Georgia has one of the highest HCV prevalence in the world and launched the world’s first national HCV elimination programs in 2015. Georgia set the ambitious target of diagnosing 90% of people living with HCV, treating 95% of those diagnosed and curing 95% of treated patients by 2020. We report outcomes of Sofosbuvir (SOF) based treatment regimens in patients with chronic HCV infection in Georgia. Methods Patients with cirrhosis, advanced liver fibrosis and severe extrahepatic manifestations were enrolled in the treatment program. Initial treatment consisted of SOF plus ribavirin (RBV) with or without pegylated interferon (INF). Sustained virologic response (SVR) was defined as undetectable HCV RNA at least 12 weeks after the end of treatment. SVR were calculated using both per-protocol and modified intent-to-treat (mITT) analysis. Results for patients who completed treatment through 31 October 2018 were analyzed. Results Of the 7342 patients who initiated treatment with SOF-based regimens, 5079 patients were tested for SVR. Total SVR rate was 82.1% in per-protocol analysis and 74.5% in mITT analysis. The lowest response rate was observed among genotype 1 patients (69.5%), intermediate response rate was achieved in genotype 2 patients (81.4%), while the highest response rate was among genotype 3 patients (91.8%). Overall, SOF/RBV regimens achieved lower response rates than IFN/SOF/RBV regimen (72.1% vs 91.3%, P < 0.0001). In multivariate analysis being infected with HCV genotype 2 (RR =1.10, CI [1.05–1.15]) and genotype 3 (RR = 1.14, CI [1.11–1.18]) were associated with higher SVR. Patients with cirrhosis (RR = 0.95, CI [0.93–0.98]), receiving treatment regimens of SOF/RBV 12 weeks, SOF/RBV 20 weeks, SOF/RBV 24 weeks and SOF/RBV 48 weeks (RR = 0.85, CI [0.81–0.91]; RR = 0.86, CI [0.82–0.92]; RR = 0.88, CI [0.85–0.91] and RR = 0.92, CI [0.87–0.98], respectively) were less likely to achieve SVR. Conclusions Georgia’s real world experience resulted in high overall response rates given that most patients had severe liver damage. Our results provide clear evidence that SOF plus IFN and RBV for 12 weeks can be considered a treatment option for eligible patients with all three HCV genotypes. With introduction of next generation DAAs, significantly improved response rates are expected, paving the way for Georgia to achieve HCV elimination goals.
Collapse
Affiliation(s)
- Tengiz Tsertsvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia. .,Ivane Javakhishvili Tbilisi State University, Faculty of Medicine, Tbilisi, Georgia.
| | - Amiran Gamkrelidze
- National Center for Disease control and public health, 99, Kakheti highway, 0198, Tbilisi, Georgia
| | - Muazzam Nasrullah
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Lali Sharvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Faculty of Medicine, Tbilisi, Georgia.,Hepatology Clinic HEPA, Tbilisi, Georgia
| | - Juliette Morgan
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Shaun Shadaker
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Lia Gvinjilia
- CDC Foundation, Georgia Hepatitis C Elimination Program, Tbilisi, Georgia
| | | | | | - Vakhtang Kerashvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | - Marina Ezugbaia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Akaki Abutidze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Francisco Averhoff
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| |
Collapse
|
|
8
|
Federico A, Caprio GG, Dalise AM, Barbieri M, Dallio M, Loguercio C, Paolisso G, Rizzo MR. Cirrhosis and frailty assessment in elderly patients: A paradoxical result. Medicine (Baltimore) 2020; 99:e18501. [PMID: 31914020 PMCID: PMC6959886 DOI: 10.1097/md.0000000000018501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/15/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022] Open
Abstract
The frailty represents a key determinant of elderly clinical assessment, especially because it allows the identification of risk factors potentially modifiable by clinical and therapeutic interventions. The frailty assessment in elderly patients usually is made by using of Fried criteria. However, to assess the frailty in cirrhotic patients, multiple but different tools are used by researchers. Thus, we aimed to compare frailty prevalence in elderly patients with well-compensated liver cirrhosis and without cirrhosis, according to Fried criteria.Among 205 elderly patients screened, a total of 148 patients were enrolled. The patients were divided into 2 groups according to the presence/absence of well-compensated liver cirrhosis.After clinical examination with conventional scores of cirrhosis, all patients underwent anthropometric measurements, nutritional, biochemical, comorbidity, and cognitive performances. Frailty assessment was evaluated according to Fried frailty criteria.Unexpectedly, according to the Fried criteria, non-cirrhotic patients were frailer (14.2%) than well-compensated liver cirrhotic patients (7.5%). The most represented Fried criterion was the unintentional weight loss in non-cirrhotic patients (10.1%) compared to well-compensated liver cirrhotic patients (1.4%). Moreover, cumulative illness rating scale -G severity score was significantly and positively associated with frailty status (r = 0.234, P < .004). In a multivariate linear regression model, only female gender, body mass index and mini nutritional assessment resulted associated with frailty status, independently of other confounding variables.Despite the fact that elderly cirrhotic patients are considered to be frailer than the non-cirrhotic elderly patient, relying solely on "mere visual appearance," our data show that paradoxically non-cirrhotic elderly patients are frailer than elderly well-compensated liver cirrhotic patients. Thus, clinical implication of this finding is that frailty assessment performed in the well-compensated liver cirrhotic patient can identify those cirrhotic patients who may benefit from tailored interventions similarly to non-cirrhotic elderly patients.
Collapse
Affiliation(s)
| | | | - Anna Maria Dalise
- Department of Advanced Medical and Surgical Sciences - University of Campania Luigi Vanvitelli Naples, Italy
| | - Michelangela Barbieri
- Department of Advanced Medical and Surgical Sciences - University of Campania Luigi Vanvitelli Naples, Italy
| | | | | | - Giuseppe Paolisso
- Department of Advanced Medical and Surgical Sciences - University of Campania Luigi Vanvitelli Naples, Italy
| | - Maria Rosaria Rizzo
- Department of Advanced Medical and Surgical Sciences - University of Campania Luigi Vanvitelli Naples, Italy
| |
Collapse
|
|
9
|
MacBrayne CE, Marks KM, Fierer DS, Naggie S, Chung RT, Hughes MD, Kim AY, Peters MG, Brainard DM, Seifert SM, Castillo-Mancilla JR, Bushman LR, Anderson PL, Kiser JJ. Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate. J Antimicrob Chemother 2019; 73:2112-2119. [PMID: 29746648 DOI: 10.1093/jac/dky146] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/21/2018] [Indexed: 12/12/2022] Open
Abstract
Background The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions. Objectives To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate. Methods HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS. Results Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment. Conclusions These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.
Collapse
Affiliation(s)
- Christine E MacBrayne
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | | | | | | | | | | | | | | | | | - Sharon M Seifert
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | | | - Lane R Bushman
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Peter L Anderson
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Jennifer J Kiser
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| |
Collapse
|
|
10
|
Cusato J, De Nicolò A, Boglione L, Favata F, Ariaudo A, Mornese Pinna S, Carcieri C, Guido F, Avataneo V, Cariti G, Di Perri G, D'Avolio A. Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study. J Antimicrob Chemother 2019; 73:1659-1664. [PMID: 29509884 DOI: 10.1093/jac/dky053] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/25/2018] [Indexed: 12/12/2022] Open
Abstract
Background Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes. Objectives In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport. Patients and methods Allelic discrimination was performed through real-time PCR, whereas plasma concentrations were evaluated through liquid chromatography. One hundred and thirteen patients were enrolled. Results Sofosbuvir concentrations were below the limit of quantification since the drug was converted into its GS-331007 metabolite. ABCB1 2677 G>T (P = 0.044) and HNF4α 975 C>G (P = 0.049) SNPs were associated with GS-331007 metabolite plasma concentrations. In linear multivariate analysis, liver stiffness, insulin resistance, baseline haemoglobin and haematocrit and SNPs in the ABCB1 gene (3435 CT/TT and 1236 TT genotypes) were significant predictors of GS-331007 concentrations. Furthermore, we performed sub-analyses considering the anti-HCV concomitant drug and HCV genotype, identifying specific polymorphisms associated with GS-331007 plasma concentrations: ABCB1 3435 C>T and HNF4α975 C>G in patients treated with daclatasvir, ABCB1 2677 G>T with ledipasvir and ABCB1 3435 C>T, ABCB1 2677 G>T, ABCG2 421 C>A and ABCG2 1194 + 928 C>A with ribavirin. Conclusions In this study we suggested sofosbuvir GS-331007 metabolite plasma levels were affected by variants in the ABCB1 and HNFα genes.
Collapse
Affiliation(s)
- Jessica Cusato
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Amedeo De Nicolò
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Lucio Boglione
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Fabio Favata
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Alessandra Ariaudo
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Simone Mornese Pinna
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Chiara Carcieri
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Federica Guido
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Valeria Avataneo
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Giuseppe Cariti
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| |
Collapse
|
|
11
|
Nguyen E, Trinh S, Trinh H, Nguyen H, Nguyen K, Do A, Levitt B, Do S, Nguyen M, Purohit T, Shieh E, Nguyen MH. Sustained virologic response rates in patients with chronic hepatitis C genotype 6 treated with ledipasvir+sofosbuvir or sofosbuvir+velpatasvir. Aliment Pharmacol Ther 2019; 49:99-106. [PMID: 30467877 DOI: 10.1111/apt.15043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 09/19/2018] [Accepted: 10/10/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotype 6 (GT 6) is the predominant genotype among certain Asian populations. The availability of newer DAA options is limited in many parts of Asia. AIM To compare sustained virologic response (SVR-12) rates between ledipasvir and sofosbuvir (LDV+SOF) and velpatasvir+SOF (SOF+VEL) for patients with HCVGT6 infection. METHOD Retrospective study of consecutive adult HCVGT6 patients identified via ICD 9 code: 070.5 from United States treatment centers. Treatment was LDV+SOF or SOF+VEL for 8-24 weeks. A 1:1 propensity score matching (PSM) on HCV RNA, cirrhosis, alanine aminotransferase, aspartate aminotransferase, platelets, and fibrosis score was conducted among the treatment-naïve HCVGT6 patients to balance groups and isolate treatment effects. RESULTS After exclusion criteria, 149 patients remained (n = 135 treatment-naïve; n = 14 treatment-experienced). The mean age was 63.8 ± 10.2 years, 66.9% male, and 93.9% Vietnamese. In treatment-naïve arm, 52.2% LDV+SOF cohort were cirrhotic compared to 11.6% SOF+VEL cohort (P < 0.0001). SVR-12 for LDV+SOF was 96.4% and 100% for the SOF+VEL cohort (P = 0.22). SVR-12 for cirrhotic patients was 95.4% (n = 41/43) for LDV+SOF and 100.0% (n = 5/5) for SOF+VEL (P = 0.62). After PSM (n = 33 per group), LDV+SOF SVR-12 rate was 97.0% compared to SOF+VEL SVR-12 of 100% (P = 0.31). The treatment-experienced group (n = 14), were all treated with LDV+SOF with an SVR-12 of 92.3%. CONCLUSION Whether treatment-naïve, treatment-experienced, or cirrhotic patients with HCV GT 6 residing in the US had excellent outcomes when treated with SOF+VEL or LDV+SOF. Since LDV+SOF is more readily available globally, our results may provide clinicians with a treatment option when cost and availability limit the treatment choice.
Collapse
Affiliation(s)
| | - Sam Trinh
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, California
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, California
| | - Huy Nguyen
- San Jose Gastroenterology, San Jose, California
| | | | - Aivien Do
- Digestive Health Associates of Texas, P.A., Richardson, Texas
| | | | - Son Do
- Digestive Health Associates of Texas, P.A., Richardson, Texas
| | - My Nguyen
- San Jose Gastroenterology, San Jose, California
| | | | | | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, California
| |
Collapse
|
|
12
|
Perales C. Quasispecies dynamics and clinical significance of hepatitis C virus (HCV) antiviral resistance. Int J Antimicrob Agents 2018; 56:105562. [PMID: 30315919 DOI: 10.1016/j.ijantimicag.2018.10.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/01/2018] [Accepted: 10/06/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) follows quasispecies dynamics in infected hosts and this influences its biology, how the virus diversifies into several genotypes and many subtypes, and how viral populations respond to antiviral therapies. Despite current antiviral combinations being able to cure a great percentage of HCV-infected patients, the presence of resistance-associated substitutions (RASs) diminishes the success of antiviral therapies, which is a main concern in the re-treatment of patients treated with direct-acting antiviral agents. Current methodologies such as ultra deep sequencing are ideal tools to obtain a detailed representation of the mutant spectrum composition circulating in infected patients. Such knowledge should allow optimisation of rescue treatments. A new mechanism of antiviral resistance not based on the selection of RASs but on high viral fitness is discussed.
Collapse
Affiliation(s)
- Celia Perales
- Liver Unit, Internal Medicine Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
| |
Collapse
|
|
13
|
Yeon JE. Does the old-fashioned sofosbuvir plus ribavirin treatment in genotype 2 chronic hepatitis C patients still works for Koreans? Clin Mol Hepatol 2018; 24:294-296. [PMID: 30200750 PMCID: PMC6166101 DOI: 10.3350/cmh.2018.1009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023] Open
Affiliation(s)
- Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
Collapse
|
|
14
|
Ford MM, Jordan AE, Johnson N, Rude E, Laraque F, Varma JK, Hagan H. Check Hep C: A Community-Based Approach to Hepatitis C Diagnosis and Linkage to Care in High-Risk Populations. JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE 2018; 24:41-48. [PMID: 28141668 DOI: 10.1097/phh.0000000000000519] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT In New York City (NYC), an estimated 146 500 people, or 2.4% of the adult population, have chronic hepatitis C virus (HCV) infection and half may be unaware of their infection. Despite a 2014 state law requiring health care providers to screen for HCV infection in primary care settings, many high-risk HCV-positive persons are not, and a large proportion of those screened do not receive RNA testing to confirm infection, or antiviral therapies. OBJECTIVE The NYC Department of Health's Check Hep C program was designed to increase hepatitis C diagnosis and improve linkage to care at community-based organizations. DESIGN Coordinated, evidence-based practices were implemented at 12 sites, including HCV antibody testing, immediate blood draw for RNA testing, and patient navigation to clinical services. RESULTS From May 2012 through April 2013, a total of 4751 individuals were tested for HCV infection and 880 (19%) were antibody-positive. Of antibody-positive participants, 678 (77%) had an RNA test, and of those, 512 (76%) had current infection. Of all participants, 1901 were born between 1945 and 1965, and of those, 201 (11%) were RNA-positive. Ever having injected drugs was the strongest risk factor for HCV infection (40% vs 3%; adjusted odds ratio [AOR] = 19.1), followed by a history of incarceration (18% vs 4%; AOR = 2.2). Of the participants with current infection, 85% attended at least 1 follow-up hepatitis C medical appointment. Fourteen patients initiated hepatitis C treatment at a Check Hep C site and 6 initiators achieved cure. CONCLUSION The community-based model successfully identified persons with HCV infection and linked a large proportion to care. The small number of patients initiating hepatitis C treatment in the program identified the need for patient navigation in high-risk populations. Results can be used to inform screening and linkage-to-care strategies and to support the execution of hepatitis C screening recommendations.
Collapse
Affiliation(s)
- Mary M Ford
- Bureau of Communicable Disease (Mss Ford and Johnson, Mr Rude, Dr Laraque) and Division of Disease Control (Mr Varma), New York City Department of Health and Mental Hygiene, Long Island City, New York; and Center for Drug Use and HIV Research, New York University College of Nursing, New York, New York (Dr Hagan and Ms Jordan)
| | | | | | | | | | | | | |
Collapse
|
|
15
|
The Mexican consensus on the treatment of hepatitis C. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2018. [DOI: 10.1016/j.rgmxen.2017.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
|
|
16
|
Aiza-Haddad I, Ballesteros-Amozurrutia A, Borjas-Almaguer OD, Castillo-Barradas M, Castro-Narro G, Chávez-Tapia N, Chirino-Sprung RA, Cisneros-Garza L, Dehesa-Violante M, Flores-Calderón J, Flores-Gaxiola A, García-Juárez I, González-Huezo MS, González-Moreno EI, Higuera-de la Tijera F, Kershenobich-Stalnikowitz D, López-Méndez E, Malé-Velázquez R, Marín-López E, Mata-Marín JA, Méndez-Sánchez N, Monreal-Robles R, Moreno-Alcántar R, Muñoz-Espinosa L, Navarro-Alvarez S, Pavia-Ruz N, Pérez-Ríos AM, Poo-Ramírez JL, Rizo-Robles MT, Sánchez-Ávila JF, Sandoval-Salas R, Torre A, Torres-Ibarra R, Trejo-Estrada R, Velarde-Ruiz Velasco JA, Wolpert-Barraza E, Bosques-Padilla F. The Mexican consensus on the treatment of hepatitis C. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2018; 83:275-324. [PMID: 29803325 DOI: 10.1016/j.rgmx.2017.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/17/2017] [Accepted: 11/02/2017] [Indexed: 12/12/2022]
Abstract
The aim of the Mexican Consensus on the Treatment of HepatitisC was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitisC treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary.
Collapse
Affiliation(s)
| | | | - O D Borjas-Almaguer
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | - G Castro-Narro
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | | | - L Cisneros-Garza
- Centro de Enfermedades Hepáticas del Hospital San José, Monterrey, Nuevo León, México
| | | | - J Flores-Calderón
- Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Ciudad de México, México
| | | | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | - E I González-Moreno
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | | | - E López-Méndez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática, Guadalajara, Jalisco, México
| | | | - J A Mata-Marín
- Hospital de Infectología del Centro Médico Nacional «La Raza», Ciudad de México, México
| | | | - R Monreal-Robles
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | - L Muñoz-Espinosa
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | - N Pavia-Ruz
- Hospital Infantil de México «Federico Gómez», Ciudad de México, México
| | - A M Pérez-Ríos
- Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - J L Poo-Ramírez
- Clínica San Jerónimo de Salud Hepática y Digestiva, Ciudad de México, México
| | | | - J F Sánchez-Ávila
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | - A Torre
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | | | | | | | | |
Collapse
|
|
17
|
Cusato J, De Nicolò A, Boglione L, Favata F, Ariaudo A, Mornese Pinna S, Carcieri C, Guido F, Avataneo V, Cariti G, Di Perri G, D'Avolio A. Vitamin D pathway genetic variants are able to influence sofosbuvir and its main metabolite pharmacokinetics in HCV mono-infected patients. INFECTION GENETICS AND EVOLUTION 2018; 60:42-47. [PMID: 29452294 DOI: 10.1016/j.meegid.2018.02.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/24/2018] [Accepted: 02/12/2018] [Indexed: 02/07/2023]
Abstract
Vitamin D levels and genetic variants were associated with drug outcome/toxicity and concentrations. The plasma exposure of GS-331007, the main sofosbuvir metabolite, has been related to SVR. We evaluated the impact of polymorphisms in genes (CYP27B1, CYP24A1, VDBP and VDR) related to vitamin D pathway on sofosbuvir and GS-331007 plasma levels in HCV mono-infected patients at one month of treatment. Polymorphisms were investigated through real-time PCR; drug plasma quantification was performed through a UHPLC-MS/MS method. GS-331007 levels were associated with CYP24A1rs2248359 and VDRCdx2 variants in all the analyzed patients and linear regression analysis showed that sex, body mass index, HCV genotype, baseline estimated glomerular filtration rate, VDRCdx2AG/GG and CYP27B1-1260TT genotypes significantly predict concentrations. We performed sub-analyses considering the HCV genotype and the concomitant drug, identifying polymorphisms associated with GS-331007 concentrations. This is the first study focusing on vitamin D pathway gene variants and DAAs concentrations, but further studies are required.
Collapse
Affiliation(s)
- Jessica Cusato
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy.
| | - Amedeo De Nicolò
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Lucio Boglione
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Fabio Favata
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Alessandra Ariaudo
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Simone Mornese Pinna
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Chiara Carcieri
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Federica Guido
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Valeria Avataneo
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Giuseppe Cariti
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| |
Collapse
|
|
18
|
Zia A, Ali M, Aziz H, Zia M, Shinwari ZK, Raza A. A case of a patient infected with a hepatitis C virus genotype 3a multidrug resistant variant in Pakistan. Infect Dis Poverty 2018; 7:11. [PMID: 29429413 PMCID: PMC6389057 DOI: 10.1186/s40249-018-0386-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 01/10/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Approximately 10 million people in Pakistan are infected with the hepatitis C virus (HCV). Most patients develop chronic hepatitis, with rare cases of spontaneous clearance. However, little is known about multidrug resistant viral variants in Pakistan. FINDINGS This case study describes a 47-year-old male diagnosed with chronic HCV genotype 3a infection in 2003. After an initial diagnosis of viral infection, the patient remained treatment naïve for 5 years. He received two therapy cycles of interferon (IFN) plus ribavirin (RBV) in 2007 and 2010, however, he was non-responsive to the therapy. The patient then received an additional two treatment cycles of pegylated IFN α-2b plus RBV (in 2011 and 2013); he was still non-responsive. In 2016, the patient underwent sofosbuvir plus RBV combination therapy, however, the sustained virological response was still not achieved. The host genetic factor was found to be heterozygous guanine and thymine (GT) and cytosine and thymine (CT) genotypes of rs8099917 and rs12979860 polymorphism of IL28B, respectively. Phylogenetic analysis suggests that the resistant variant belong to an out-group and may require triple therapy. CONCLUSIONS This is the first case that reports on a HCV-infected individual who was a non-responder to multiple IFN therapies in Pakistan. Further studies are needed to understand multidrug-resistant HCV variants in the Pakistani population.
Collapse
Affiliation(s)
- Asad Zia
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Muhammad Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Hafsa Aziz
- Nuclear Oncology and Radiotherapy Institute (NORI), Islamabad, Pakistan
| | - Muhammad Zia
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Zabta Khan Shinwari
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Abida Raza
- National Institute of Lasers and Optronics (NILOP), Nanomedicine Research Labs, Islamabad, Pakistan
| |
Collapse
|
|
19
|
Karchava M, Chkhartishvili N, Sharvadze L, Abutidze A, Dvali N, Gatserelia L, Dzigua L, Bolokadze N, Dolmazashvili E, Kotorashvili A, Imnadze P, Gamkrelidze A, Tsertsvadze T. Impact of hepatitis C virus recombinant form RF1_2k/1b on treatment outcomes within the Georgian national hepatitis C elimination program. Hepatol Res 2018; 48:36-44. [PMID: 28258606 DOI: 10.1111/hepr.12890] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 03/02/2017] [Accepted: 03/02/2017] [Indexed: 02/08/2023]
Abstract
AIM Hepatitis C virus (HCV) recombinant form RF1_2k/1b is common in ethnic Georgians. This chimera virus contains genomic fragments of genotype 2 and genotype 1 and is misclassified as genotype 2 by standard genotyping. We aimed to identify RF1_2k/1b strains among genotype 2 patients and assess its impact on treatment outcomes. METHODS The study included 148 patients with HCV genotype 2 as determined by 5-untranslated region/core genotyping assay. RF1_2k/1b was identified by sequencing the non-structural protein 5B region. Patients were treated within the national hepatitis C elimination program with sofosbuvir/ribavirin (SOF/RBV), interferon (IFN)/SOF/RBV, or ledipasvir (LDV)/SOF/RBV. RESULTS Of 148 patients, 103 (69.5%) had RF1_ 2k/1b. Sustained virologic response (SVR) data was available for 136 patients (RF1_ 2k/1b, n = 103; genotype 2, n = 33). Sustained virologic response was achieved in more genotype 2 patient than in RF1_2k/1b patients (97.0% vs. 76.7%, P = 0.009). Twelve weeks of LDV/SOF/RBV treatment was highly effective (100% SVR) in both genotypes. Among RF1_2k/1b patients, LDV/SOF/RBV for 12 weeks was superior (100% SVR) to SOF/RBV for 12 weeks (56.4%, P < 0.0001) or 20 weeks (79.2%, P = 0.05). Twelve weeks of IFN/SOF/RBV also showed better response than SOF/RBV for 12 weeks (88.9% vs. 56.4%, P = 0.02) in these patients. CONCLUSIONS High prevalence of the RF1_2k/1b strain can significantly affect treatment outcomes. Treatment with IFN/SOF/RBV and especially LDV/SOF/RBV ensured significantly higher SVR in patients infected with RF1_2k/1b strain compared to standard HCV genotype 2 treatment with SOF/RBV. There is a need to reassess existing methods for the management of HCV genotype 2 infections, especially in areas with high prevalence of the RF1_2k/1b strain.
Collapse
Affiliation(s)
- Marine Karchava
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Hepatology Clinic- Hepa, Tbilisi, Georgia
| | | | - Lali Sharvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Hepatology Clinic- Hepa, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Akaki Abutidze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Hepatology Clinic- Hepa, Tbilisi, Georgia
| | - Natia Dvali
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | - Lana Gatserelia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Hepatology Clinic- Hepa, Tbilisi, Georgia
| | - Lela Dzigua
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | - Natalia Bolokadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Ekaterine Dolmazashvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Hepatology Clinic- Hepa, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Adam Kotorashvili
- National Center for Diseases Control and Public Health, Tbilisi, Georgia
| | - Paata Imnadze
- National Center for Diseases Control and Public Health, Tbilisi, Georgia
| | - Amiran Gamkrelidze
- National Center for Diseases Control and Public Health, Tbilisi, Georgia
| | - Tengiz Tsertsvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Hepatology Clinic- Hepa, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| |
Collapse
|
|
20
|
Iqbal S, Yousuf MH, Yousaf MI. Dramatic response of hepatitis C patients chronically infected with hepatitis C virus genotype 3 to sofosbuvir-based therapies in Punjab, Pakistan: A prospective study. World J Gastroenterol 2017; 23:7899-7905. [PMID: 29209131 PMCID: PMC5703919 DOI: 10.3748/wjg.v23.i44.7899] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/06/2017] [Accepted: 09/13/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To prospectively evaluate the efficacy of sofobuvir (SOF) in hepatitis C patients infected with hepatitis C virus (HCV) genotype 3 in Pakistan.
METHODS The present study was performed with the coordination of gastroenterology and pathology departments of Shalamar Hospital Lahore from August 2014 to May 2016. The total number of patients included in this study was 1375 and all of them were infected with HCV genotype 3. On the basis of drug combinations, all the patients were separated into two groups. The first group of patients was treated for 24 wk with SOF (Sovaldi® by Gilead Sciences) plus ribavirin (RBV) [Ribazol® by Getz Pharma Pakistan (PVT) Ltd], while the patients of the second group were treated with SOF + RBV + pegylated-interferon (pegIFN) alfa-2a (Ropegra by Roach) for 12 wk. HCV genotyping and viral load measurement were performed on fully automated Abbott Real-Time PCR system (Abbott m24sp automated nucleic acid extraction system and Abbott m2000rt amplification system; abbott Molecular, Des Plaines, IL, United States). For the assessment of sustained virological response (SVR), all HCV RNA negative patients were followed for 12 weeks after the treatment completion. Any patient with less than 12 IU/mL viral load after 12 wk of treatment completion was considered as a sustained virological responder (SVR-12).
RESULTS A total of 1375 patients chronically infected with HCV genotype 3 were treated with two drug combinations SOF + RBV and SOF + RBV + pegIFN alfa-2a. On the basis of these drug combinations, patients were divided into two groups (first and second). Overall SVR-12 was excellent in both groups (99.17% and 97.91%). Older patients (> 40 years) of second group showed lower SVR-12 (93.46%) compared to first group older patients (98.79%), while in the younger patients of both groups, the SVR-12 rate was almost the same (99.54% in first group and 99.05% in second group). No such difference regarding SVR-12 rate was seen in males and females of first group patients (99.68% and 98.88%, respectively), while in second group the males were found to be better responders compared to females (98.96% and 95%). The SVR-12 rate in previously treated patients of first group was better (99.34%) than second group (93.70%), while naïve patients of second group were marginally better responders (99.25%) than first group (97.80%). Rapid viral response at week-4 was found to be a very effective predictor for assessing the SVR rate at this stage of therapy in both groups. Headache, anemia and fatigue were common side effects in both groups either treated with SOF + RBV or SOF + RBV + pegIFN alfa-2a, while the overall percentage of the side effects was higher in second group.
CONCLUSION The remarkable SVR response rate of HCV genotype 3 infected patients to SOF provided a new way to look forward to eliminate hepatitis C from our region.
Collapse
Affiliation(s)
- Sajjad Iqbal
- Department of Pathology, Shalamar Hospital, Lahore 54840, Pakistan
| | - Muhammad Haroon Yousuf
- Department of Gastroenterology and Hepatology, Shalamar Hospital, Lahore 54840, Pakistan
| | | |
Collapse
|
|
21
|
Chen Y, Yu C, Yin X, Guo X, Wu S, Hou J. Hepatitis C virus genotypes and subtypes circulating in Mainland China. Emerg Microbes Infect 2017; 6:e95. [PMID: 29089588 PMCID: PMC5717081 DOI: 10.1038/emi.2017.77] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 06/19/2017] [Accepted: 07/18/2017] [Indexed: 02/07/2023]
Abstract
The hepatitis C virus (HCV) exhibits global genotypic diversity. HCV genotyping plays an important role in epidemiological studies and clinical management. Herein, we report the results of HCV genotype and subtype detection in a large number of clinical samples, as performed by an independent laboratory in China. In total, four HCV genotypes and 18 subtypes were identified among 32 030 patients from 29 provinces and municipalities in China. Five dominant subtypes were detected from 98.84% of the samples: 1b (n=16 713, 52.18%), 2a (n=9188, 28.69%), 3b (n=2261, 7.06%), 6a (n=2052, 6.41%) and 3a (n=1479, 4.62%). Twelve rare subtypes were detected, of which four (that is, 6b, 6j, 6q and 6r) are reported for the first time in the Chinese population. Genotypes 4, 5 and 7 were not detected. Mixed infections of the dominant subtypes were found in a small portion of samples (n=65, 0.203%), in the following combinations: 1b–2a, 1b–3b, 1b–6a, 3a–3b, 1b–3a and 2a–6a. No mixed infections with rare subtypes were found. Males, compared with females, showed higher HCV subtype diversity, a lower percentage of HCV1b and 2a and a higher percentage of rare subtypes and mixed infections. Our analyses revealed the comprehensive distribution patterns of HCV genotypes in the general population of mainland China. HCV genotypic patterns were differentially distributed on the basis of geography, sex and age.
Collapse
Affiliation(s)
- Ying Chen
- Guangzhou Kingmed Center for Clinical Laboratory, Guangzhou, China.,College of Laboratory Medicine, Tianjin Medical University, Tianjin, China
| | - Changshun Yu
- Guangzhou Kingmed Center for Clinical Laboratory, Guangzhou, China.,College of Laboratory Medicine, Tianjin Medical University, Tianjin, China
| | - Xueru Yin
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaolei Guo
- Guangzhou Kingmed Center for Clinical Laboratory, Guangzhou, China
| | - Shangwei Wu
- Guangzhou Kingmed Center for Clinical Laboratory, Guangzhou, China.,College of Laboratory Medicine, Tianjin Medical University, Tianjin, China
| | - Jinlin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
22
|
Ali M, Khan T, Fatima K, Ali QUA, Ovais M, Khalil AT, Ullah I, Raza A, Shinwari ZK, Idrees M. Selected hepatoprotective herbal medicines: Evidence from ethnomedicinal applications, animal models, and possible mechanism of actions. Phytother Res 2017; 32:199-215. [PMID: 29047177 PMCID: PMC7167792 DOI: 10.1002/ptr.5957] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 08/30/2017] [Accepted: 09/26/2017] [Indexed: 02/06/2023]
Abstract
Insight into the hepatoprotective effects of medicinally important plants is important, both for physicians and researchers. Main reasons for the use of herbal medicine include their lesser cost compared with conventional drugs, lesser undesirable drug reactions and thus high safety, and reduced side effects. The present review focuses on the composition, pharmacology, and results of experimental trials of selected medicinal plants: Silybum marianum (L.) Gaertn., Glycyrrhiza glabra, Phyllanthus amarus Schumach. & Thonn., Salvia miltiorrhiza Bunge., Astragalus membranaceus (Fisch.) Bunge, Capparis spinosa (L.), Cichorium intybus (L.), Solanum nigrum (L.), Sapindus mukorossi Gaertn., Ginkgo biloba (L.), Woodfordia fruticosa (L.) Kurz, Vitex trifolia (L.), Schisandra chinensis (Turcz.) Baill., Cuscuta chinensis (Lam.), Lycium barbarum, Angelica sinensis (Oliv.) Diels, and Litsea coreana (H. Lev.). The probable modes of action of these plants include immunomodulation, stimulation of hepatic DNA synthesis, simulation of superoxide dismutase and glutathione reductase to inhibit oxidation in hepatocytes, reduction of intracellular reactive oxygen species by enhancing levels of antioxidants, suppression of ethanol-induced lipid accumulation, inhibition of nucleic acid polymerases to downregulate viral mRNA transcription and translation, free radical scavenging and reduction of hepatic fibrosis by decreasing the levels of transforming growth factor beta-1, and collagen synthesis in hepatic cells. However, further research is needed to identify, characterize, and standardize the active ingredients, useful compounds, and their preparations for the treatment of liver diseases.
Collapse
Affiliation(s)
- Muhammad Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Tariq Khan
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan.,Department of Biotechnology, University of Malakand Chakdara Dir (L)-18000, Khyber Pakhtunkhwa, Pakistan
| | - Kaneez Fatima
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Qurat Ul Ain Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Muhammad Ovais
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Ali Talha Khalil
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Ikram Ullah
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Abida Raza
- National Institute of Laser and Optronics, Nilore, 45650, Pakistan
| | - Zabta Khan Shinwari
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, 45320, Pakistan
| | - Muhammad Idrees
- Hazara University Mansehra, Khyber Pakhtunkhwa, 21120, Pakistan.,Center for Applied Molecular Biology (CAMB), University of the Punjab, Lahore, 53700, Pakistan
| |
Collapse
|
|
23
|
Nagaty A, Abd El-Wahab EW. Real-life results of sofosbuvir based therapy in chronic hepatitis C -naïve and -experienced patients in Egypt. PLoS One 2017; 12:e0184654. [PMID: 28981513 PMCID: PMC5628811 DOI: 10.1371/journal.pone.0184654] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/28/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND More than ten million Egyptians are infected with HCV. Every one of them is going to infect about three to four persons every year. Treating those patients is a matter of national security. A dramatic improvement in hepatitis C virus (HCV) infection treatment was achieved in the last five years. A new era of direct-acting antivirals is now dawning in Egypt. OBJECTIVE(S) We share in this report our clinical experience in treating chronic HCV Egyptian patients with Sofosbuvir based regimens to evaluate its safety and efficacy on real life practical ground. METHODS A total of 205 chronic HCV patients (195 naive and 15 experienced) were enrolled in the study. Patient were treated with Sofosbuvir+Ribavirin 24 weeks as standard of care. Two interferon eligible patients were treated with PEG-INF+ Sofosbuvir+Ribavirin for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response at 24 weeks after cessation of therapy. RESULTS The overall response rate was 97.1%. Sustained virological response rate did not differ among treatment-naive patients and patients with previous history of IFN-based therapy. Portal hypertension, prediabetes, and lack of early virologic response were predictors of non response. No clinically significant treatment-emergent adverse effects were noted. No treatment discontinuation was encountered. CONCLUSION In the real-life setting, Sofosbuvir based regimens for 24 weeks has established an efficacious and well tolerated treatment in naïve and experienced patients with chronic HCV genotype 4 infection; although shorter treatment durations may be possible. However, patient follow up should extent to at least 6 months post-treatment and verifying viral load on yearly basis is warranted to track any late relapse.
Collapse
Affiliation(s)
- Ahmed Nagaty
- Consultant of Hepatology and Infectious Diseases, Ministry of Health, Alexandria, Egypt
| | - Ekram W. Abd El-Wahab
- Tropical Health Department, High Institute of Public Health, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
24
|
Elbaz T, Elserafy M, Elakel W, Mohey MA, Abdo M, Hassany M, Mehrez M, Abouelkhair M, Yosry A, Omar A, Waked I, Elsayed MH, Mahran Z, Elshazly Y, Elgarem N, Gaballa A, Doss W, Esmat G. Serious Adverse Events with Sofosbuvir Combined with Interferon and Ribavirin: Real-Life Egyptian Experience. J Interferon Cytokine Res 2017; 37:348-353. [PMID: 28777714 DOI: 10.1089/jir.2016.0131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is a serious problem worldwide that was under-recognized till recently. The prevalence of chronic hepatitis C virus (HCV) is estimated to be 180 million people worldwide. Treatment of chronic HCV using combined pegylated interferon and ribavirin (PEG/RIBA) has long been the standard of care with modest response. In our study, we will report the real-life experience of serious adverse events (SAEs) that were reported by the National Committee for Control of Viral Hepatitis (NCCVH, Cairo, Egypt) program while treating chronic HCV using the triple therapy, sofosbuvir combined with pegylated interferon and ribavirin (PEG/RIBA/SOF), which led to premature discontinuation of treatment. This retrospective analysis included a total of 6,989 chronic HCV patients who were treated by the NCCVH. They received the triple antiviral therapy in 26 treatment centers in Egypt using PEG/RIBA/SOF for 12 weeks. Among 6,989 patients who were treated in 26 treatment centers related to NCCVH, 406 cases (5.9%) reported SAEs and prematurely stopped their treatment. Triple therapy PEG/RIBA/SOF was an important intermediate milestone between interferon-based therapy and the interferon-free all-oral direct acting antiviral agents (DAAs). Results of this study were the leading cause of discontinuation of interferon-based therapy and introduction of interferon-free all-oral treatment protocols, incorporating DAAs from different classes as soon as they gain approval.
Collapse
Affiliation(s)
- Tamer Elbaz
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Magdy Elserafy
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Wafaa Elakel
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Mohammad A Mohey
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Mahmoud Abdo
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Mohamed Hassany
- 2 Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute , Cairo, Egypt
| | - Mai Mehrez
- 2 Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute , Cairo, Egypt
| | - Mahmoud Abouelkhair
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Ayman Yosry
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Ashraf Omar
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| | - Imam Waked
- 3 National Liver Institute, Menoufiya University , Shebeen EL Kom, Egypt
| | - Manal Hamdy Elsayed
- 4 Faculty of Medicine, Pediatric Department, Ain Shams University , Cairo, Egypt
| | - Zakaria Mahran
- 5 Faculty of Medicine, Tropical Medicine Department, Ain Shams University , Cairo, Egypt
| | - Yahia Elshazly
- 6 Faculty of Medicine, Internal Medicine Department, Ain Shams University , Cairo, Egypt
| | - Noman Elgarem
- 7 Internal Medicine Department, Cairo University , Cairo, Egypt
| | - Aly Gaballa
- 7 Internal Medicine Department, Cairo University , Cairo, Egypt
| | - Wahid Doss
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
- 2 Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute , Cairo, Egypt
| | - Gamal Esmat
- 1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt
| |
Collapse
|
|
25
|
Abstract
Metabolic disorders are common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic and clinical data indicate an overprevalence of lipids abnormalite, steatosis, insuline resistance (IR) and diabetes mellitus in HCV patients, suggesting that HCV itself may interact with glucido-lipidic metabolism. HCV interacts with the host lipid metabolism by several mechanisms leading to hepatic steatosis and hypolipidemia which are reversible after viral eradication. Liver and peripheral IR are HCV genotype/viral load dependent and improved after viral eradication. This article examines examine the relationship between HCV, lipid abnormalities, steatosis, IR, and diabetes and the pathogenic mechanisms accounting for these events in HCV-infected patients.
Collapse
Affiliation(s)
- Lawrence Serfaty
- Hepatology Department, INSERM UMR_S 938, APHP, Saint-Antoine Hospital, UPMC Univ Paris 06, Paris, France.
| |
Collapse
|
|
26
|
Tsai PC, Liu TW, Tsai YS, Ko YM, Chen KY, Lin CC, Huang CI, Liang PC, Lin YH, Hsieh MY, Hou NJ, Huang CF, Yeh ML, Lin ZY, Chen SC, Dai CY, Chuang WL, Huang JF, Yu ML. Identification of groups with poor cost-effectiveness of peginterferon plus ribavirin for naïve hepatitis C patients with a real-world cohort and database. Medicine (Baltimore) 2017; 96:e6984. [PMID: 28562549 PMCID: PMC5459714 DOI: 10.1097/md.0000000000006984] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 04/05/2017] [Accepted: 04/19/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naïve CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. METHODS A total of 1809 treatment-naïve chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. RESULTS The average medical-care cost was USD $4823 (±$2984) per treatment and $6105 (±$3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P < .001). Treatment-naïve G1 patients of old ages, those with advanced fibrosis, high viral loads, or interleukin-28B unfavorable genotypes, or those without a rapid virological response (RVR: undetectable HCV RNA at week 4), or those with complete early virological response (cEVR: undetectable HCV RNA at week 12). Treatment-naïve G2 patients with high viral loads or without RVR or cEVR incurred significantly higher costs per SVR than their counterparts. The cost/SVR was extremely high among patients without RVR and in patients without cEVR. CONCLUSION We investigated the real-world cost effectiveness data for different subgroups of treatment-naïve HCV patients with PegIFN/RBV therapies, which could provide useful, informative evidence for making decisions regarding future therapeutic strategies comprising costly direct-acting antivirals.
Collapse
Affiliation(s)
- Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Ta-Wei Liu
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Yi-Shan Tsai
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Yu-Min Ko
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Kuan-Yu Chen
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Ching-Chih Lin
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
| | - Nai-Jen Hou
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| |
Collapse
|
|
27
|
Abstract
PURPOSE OF REVIEW Direct-acting antiviral agents (DAAs) have markedly improved the prognosis of hepatitis C virus (HCV)-genotype 3 (GT3), a highly prevalent infection worldwide. However, in patients with hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), GT3 infection presents a treatment challenge compared with other genotypes. The dependence of the HCV life cycle on host lipid metabolism suggests the possible utility of targeting host cellular factors for combination anti-HCV therapy. We discuss current and emergent DAA regimens for HCV-GT3 treatment. We then summarize recent research findings on the reliance of HCV entry, replication, and virion assembly on host lipid metabolism. RECENT FINDINGS Current HCV treatment guidelines recommend the use of daclatasvir plus sofosbuvir (DCV/SOF) or sofosbuvir plus velpatasvir (SOF/VEL) for the management of GT3 based upon clinical efficacy [≥88% overall sustained virological response (SVR)] and tolerability. Potential future DAA options, such as SOF/VEL co-formulated with GS-9857, also look promising in treating cirrhotic GT3 patients. However, HCV resistance to DAAs will likely continue to impact the therapeutic efficacy of interferon-free treatment regimens. Disruption of HCV entry by targeting required host cellular receptors shows potential in minimizing HCV resistance and broadening therapeutic options for certain subpopulations of GT3 patients. The use of cholesterol biosynthesis and transport inhibitors may also improve health outcomes for GT3 patients when used synergistically with DAAs. Due to the morbidity and mortality associated with HCV-GT3 infection compared to other genotypes, efforts should be made to address current limitations in the therapeutic prevention and management of HCV-GT3 infection.
Collapse
|
|
28
|
Shen J, Huang CK, Yu H, Shen B, Zhang Y, Liang Y, Li Z, Feng X, Zhao J, Duan L, Cai X. The role of exosomes in hepatitis, liver cirrhosis and hepatocellular carcinoma. J Cell Mol Med 2017; 21:986-992. [PMID: 28224705 PMCID: PMC5387156 DOI: 10.1111/jcmm.12950] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 06/29/2016] [Indexed: 12/21/2022] Open
Abstract
Exosomes are small vesicles that were initially thought to be a mechanism for discarding unneeded membrane proteins from reticulocytes. Their mediation of intercellular communication appears to be associated with several biological functions. Current studies have shown that most mammalian cells undergo the process of exosome formation and utilize exosome‐mediated cell communication. Exosomes contain various microRNAs, mRNAs and proteins. They have been reported to mediate multiple functions, such as antigen presentation, immune escape and tumour progression. This concise review highlights the findings regarding the roles of exosomes in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. However, further elucidation of the contributions of exosomes to intercellular information transmission is needed. The potential medical applications of exosomes in liver diseases seem practical and will depend on the ingenuity of future investigators and their insights into exosome‐mediated biological processes.
Collapse
Affiliation(s)
- Jiliang Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Chiung-Kuei Huang
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Hong Yu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Bo Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Yaping Zhang
- Department of Anesthesiology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Yuelong Liang
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Zheyong Li
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Xu Feng
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Jie Zhao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Lian Duan
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
29
|
Stahmeyer JT, Rossol S, Liersch S, Guerra I, Krauth C. Cost-Effectiveness of Treating Hepatitis C with Sofosbuvir/Ledipasvir in Germany. PLoS One 2017; 12:e0169401. [PMID: 28046099 PMCID: PMC5207688 DOI: 10.1371/journal.pone.0169401] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/30/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany. MATERIAL AND METHODS We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness. RESULTS Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses. CONCLUSIONS Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.
Collapse
Affiliation(s)
- Jona T. Stahmeyer
- Institute for Epidemiology, Social Medicine and Health Systems Research; Hannover Medical School; Hannover; Germany
| | - Siegbert Rossol
- Department of Internal Medicine; Krankenhaus Nordwest; Steinbacher Hohl 2–26; Frankfurt am Main; Germany
| | - Sebastian Liersch
- Institute for Epidemiology, Social Medicine and Health Systems Research; Hannover Medical School; Hannover; Germany
| | - Ines Guerra
- Real World Strategy and Analytics; MAPI Group; 3rd Floor Beaufort House; Uxbridge, Middlesex; United Kingdom
| | - Christian Krauth
- Institute for Epidemiology, Social Medicine and Health Systems Research; Hannover Medical School; Hannover; Germany
| |
Collapse
|
|
30
|
HCV Integrated Care: A Randomized Trial to Increase Treatment Initiation and SVR with Direct Acting Antivirals. Int J Hepatol 2017; 2017:5834182. [PMID: 28819570 PMCID: PMC5551521 DOI: 10.1155/2017/5834182] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Revised: 06/10/2017] [Accepted: 06/12/2017] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND AND AIMS Psychiatric or substance use disorders are barriers to successful HCV antiviral treatment. In a randomized, controlled trial (RCT), the effects of HCV Integrated Care (IC) for increasing treatment rates and sustained viral response (SVR) were studied with direct acting antivirals (DAA). METHODS In 2012-13, VA patients, whose screening was positive for depression, PTSD, or substance use (N = 79), were randomized to IC or Usual Care (UC). IC consisted of brief psychological interventions and case management. The primary endpoint was SVR among patients followed for an average of 16.6 months. RESULTS 42% of the study participants were previously homeless and 79% had HCV genotype 1. Twice as many IC participants (45%) initiated treatment compared with UC participants (23%) (χ2 = 4.59, p = 0.032). Among those treated, SVR rates did not significantly differ (IC: 12/18 = 67%; UC: 5/9 = 55%; p = 0.23). Among all randomized participants, IC participants trended toward better SVR rates (30.0% versus 12.8% in UC; p = 0.07). CONCLUSIONS Although first-generation DAAs are no longer used, this smaller RCT helps confirm the results of a larger multisite RCT showing that Integrated Care results in higher treatment initiation and SVR rates among HCV-infected persons with comorbid psychological disorders. Integrated mental health services can facilitate treatment among the most challenging HCV patients, many of whom have not been successfully treated. This trial is registered with ClinicalTrials.gov number NCT00722423.
Collapse
|
|
31
|
Morales AL, Junga Z, Singla MB, Sjogren M, Torres D. Hepatitis C eradication with sofosbuvir leads to significant metabolic changes. World J Hepatol 2016; 8:1557-1563. [PMID: 28050236 PMCID: PMC5165269 DOI: 10.4254/wjh.v8.i35.1557] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control.
METHODS This is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis.
RESULTS Two hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P < 0.005). Those treated with SOF/LDV had a lower HbA1C response than those treated with other regimens (0.26% ± 0.53% vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P < 0.001; TC: 171.6 ± 32.5 mg/dL vs 199.7 ± 40.0 mg/dL, P < 0.001). Pre-treatment body-mass index (BMI) did not differ from post-treatment BMI (P = 0.684).
CONCLUSION Eradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.
Collapse
|
|
32
|
Abstract
Type-III interferons (IFN-λ), the most recently discovered family of IFNs, shares common features with other family members, but also has many distinctive activities. IFN-λ uniquely has a different receptor complex, and a more focused pattern of tissue expression and signaling effects, from other classes of IFNs. Multiple genome-wide association studies (GWAS) and subsequent validation reports suggest a pivotal role for polymorphisms near the IFNL3 gene in hepatitis C clearance and control, as also for several other epithelial cell tropic viruses. Apart from its antiviral activity, IFN-λ possesses anti-tumor, immune-inflammatory and homeostatic functions. The overlapping effects of IFN-λ with type I IFN, with a restricted tissue expression pattern renders IFN-λ an attractive therapeutic target for viral infection, cancer and autoimmune diseases, with limited side effects. Areas covered: This review will summarize the current and future therapeutic opportunities offered by this most recently discovered family of interferons. Expert opinion: Our knowledge on IFN-λ is rapidly expanding. Though there are many remaining questions and challenges that require elucidation, the unique characteristics of IFN-λ increases enthusiasm that multiple therapeutic options will emerge.
Collapse
Affiliation(s)
- Mohammed Eslam
- a Storr Liver Centre, Westmead Institute for Medical Research , Westmead Hospital and University of Sydney , Sydney , Australia
| | - Jacob George
- a Storr Liver Centre, Westmead Institute for Medical Research , Westmead Hospital and University of Sydney , Sydney , Australia
| |
Collapse
|
|
33
|
Chen SR, Wang AQ, Lin LG, Qiu HC, Wang YT, Wang Y. In Vitro Study on Anti-Hepatitis C Virus Activity of Spatholobus suberectus Dunn. Molecules 2016; 21:E1367. [PMID: 27754461 PMCID: PMC6274077 DOI: 10.3390/molecules21101367] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 10/07/2016] [Accepted: 10/09/2016] [Indexed: 12/18/2022] Open
Abstract
Hepatitis C virus (HCV) infects 200 million people worldwide, and 75% of HCV cases progress into chronic infections, which consequently cause cirrhosis and hepatocellular carcinoma. HCV infection is treated with currently considered standard drugs, including direct anti-viral agents (DAAs), alone or in combination with peginterferon-α plus ribavirin. However, sustained viral responses vary in different cohorts, and high costs limit the broad use of DAAs. In this study, the ethanol and water extracts of 12 herbs from Lingnan in China were examined in terms of their inhibitory effect on HCV replication. Among the examined extracts, Spatholobus suberectus ethanol extracts suppressed HCV replication. By comparison, Extracts from Fructus lycii, Radix astragali (root), Rubus chingii Hu (fruit), Flos chrysanthemi Indici (flower), Cassia obtusifolia (seed), Lonicera japonica Thunb (flower), Forsythia suspense Thunb (fruit), Poria cocos (sclerotia), Carthamus tinctorius L. (flower), Crataegus pinnatifida Bge. (fruit), and Leonurus japonicas Houtt. (leaf) extracts failed to show a similar activity. Active S. suberectus fractions containing tannins as the major component also inhibited the in vitro translation of HCV RNA. The combination treatments of single compounds, such as epigallocatechin gallate and epicatechin gallate, were not as potent as crude S. suberectus fractions; therefore, crude S. suberectus extract may be a potential alternative treatment against HCV either alone or in combination with other agents.
Collapse
Affiliation(s)
- Shao-Ru Chen
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR 999078, China.
| | - An-Qi Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR 999078, China.
| | - Li-Gen Lin
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR 999078, China.
| | - Hong-Cong Qiu
- Guangxi Institute of Traditional Medical and Pharmaceutical Sciences and Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Nanning 530022, China.
| | - Yi-Tao Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR 999078, China.
| | - Ying Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR 999078, China.
| |
Collapse
|
|
34
|
Henry L, Younossi Z. Patient-reported and economic outcomes related to sofosbuvir and ledipasvir treatment for chronic hepatitis C. Expert Rev Pharmacoecon Outcomes Res 2016; 16:659-665. [PMID: 27710134 DOI: 10.1080/14737167.2016.1244007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION We used published literature from 2013-2016, to review data regarding the new all oral interferon and ribavirin free direct acting antiviral (DAA's) treatment regimens. Areas covered: Specifically, this paper will address DAA's clinical efficacy, their associated patient reported outcomes, their adherence to treatment, and their cost-effectiveness of treatment using studies from the United States. Expert commentary: The current data suggest that cure and elimination of HCV appears to be on the horizon; however, more research is needed to verify similar results from real world practices. Further, research is also needed to overcome the barriers to treatment (lack of education and awareness of HCV, inadequate diagnosis technology, and lack of access and link to care) in order for the elimination of HCV to be obtained.
Collapse
Affiliation(s)
- Linda Henry
- a Betty and Guy Beatty Center for Integrated Research , Inova Health Systems , Falls Church , VA , USA.,b Center for Outcomes Research in Liver Disease , Washington , D.C. , USA
| | - Zobair Younossi
- a Betty and Guy Beatty Center for Integrated Research , Inova Health Systems , Falls Church , VA , USA.,c Center for Liver Diseases, Department of Medicine , Inova Fairfax Hospital , Falls Church , VA , USA
| |
Collapse
|
|
35
|
Sundaram V, Kowdley KV. Dual daclatasvir and sofosbuvir for treatment of genotype 3 chronic hepatitis C virus infection. Expert Rev Gastroenterol Hepatol 2016; 10:13-20. [PMID: 26560449 DOI: 10.1586/17474124.2016.1116937] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is one of the most common etiologies of liver-related mortality throughout the world. Traditionally, therapy has been focused on pegylated interferon in combination with ribavirin, with clinical trials demonstrating that HCV genotype 1 had the lowest response rate (40-50%), while genotype 3 had an intermediate response rate (60-70%). Recently, significant advances have been made with all-oral direct-acting antiviral (DAA) therapy, which have significantly improved cure rates for HCV genotype 1. Accordingly, HCV genotype 3 is now potentially the most difficult to treat. One of the most potent DAA medications is sofosbuvir, a pan-genotypic nucleotide analogue that inhibits the NS5B polymerase of HCV. Daclatasvir, a pan-genotypic inhibitor of the HCV NS5A replication complex, was recently approved in the United States for treatment of HCV genotype 3 in conjunction with sofosbuvir. This combination may provide a powerful tool in the treatment of HCV genotype 3.
Collapse
Affiliation(s)
- Vinay Sundaram
- a Department of Medicine and Comprehensive Transplant Center , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | | |
Collapse
|
|
36
|
Deenen MJ, de Kanter CTMM, Dofferhoff ASM, Grintjes-Huisman KJT, van der Ven AJAM, Fleuren HWHA, Gisolf EH, Koopmans PP, Drenth JPH, Burger DM. Lower Ribavirin Plasma Concentrations in HCV/HIV-Coinfected Patients Than in HCV-Monoinfected Patients Despite Similar Dosage. Ther Drug Monit 2016; 37:751-5. [PMID: 26102531 DOI: 10.1097/ftd.0000000000000226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV)/HIV-coinfected patients respond worse to dual therapy with ribavirin (RBV)/peginterferon compared with HCV-monoinfected patients. Several trials found that lower RBV plasma concentrations are associated with impaired virological response rates. The aim of this study was to determine RBV plasma concentrations in a cohort of HCV-monoinfected and HCV/HIV-coinfected patients. Our hypothesis is that HCV/HIV-coinfected patients have lower RBV plasma concentrations, which may in part explain their inferior response to dual therapy. METHODS A retrospective cohort study was performed in chronic HCV-monoinfected and HCV/HIV-coinfected patients who received peginterferon and weight-based RBV. Plasma RBV concentrations were determined at weeks 4 and 12 by a validated high-performance liquid chromatography assay. RBV concentrations were compared between monoinfected and coinfected patients. We calculated the proportion of patients with a subtherapeutic RBV plasma concentration defined as <2.0 mg/L. RESULTS A total of 61 HCV-infected patients were included, of whom 21 (34%) were coinfected with HIV. Although there was no difference in the weight-based dose of RBV between monoinfected and coinfected patients, RBV exposure was significantly lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients: the mean ± SD RBV plasma concentrations were 1.82 ± 0.63 mg/L versus 2.25 ± 0.80 mg/L (P = 0.04) at week 4 and 2.14 ± 0.65 mg/L versus 2.62 ± 0.81 mg/L (P = 0.05) at week 12, respectively. The percentage of patients with subtherapeutic plasma concentrations of RBV in coinfected patients versus monoinfected patients was 62% versus 46% (P = 0.240) at week 4 and 50% versus 16% (P = 0.01) at week 12 of treatment, respectively. CONCLUSIONS HIV/HCV-coinfected patients yield significantly lower plasma concentrations of RBV than HCV-monoinfected patients. This puts them at an increased risk of not achieving sustained virological response.
Collapse
Affiliation(s)
- Maarten J Deenen
- *Department of Pharmacy, Radboud University Medical Center, Nijmegen; †Department of Clinical Pharmacy, Rijnstate Hospital, Arnhem; ‡Nijmegen Institute for Health Sciences, Radboud University Medical Center, Nijmegen; §Department of General Internal Medicine, Radboud University Medical Center, Nijmegen; ¶Department of Internal Medicine, Canisius Wilhelmina Hospital, Nijmegen; ‖Department of Clinical Pharmacy, Canisius Wilhelmina Hospital, Nijmegen; **Department of Internal Medicine, Rijnstate Hospital, Arnhem; and ††Department of Internal Medicine, Division of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Bourhill T, Arbuthnot P, Ely A. Successful disabling of the 5' UTR of HCV using adeno-associated viral vectors to deliver modular multimeric primary microRNA mimics. J Virol Methods 2016; 235:26-33. [PMID: 27181212 DOI: 10.1016/j.jviromet.2016.05.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 04/16/2016] [Accepted: 05/11/2016] [Indexed: 02/05/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is a major health concern and is strongly associated with cirrhosis, hepatocellular carcinoma and liver-related mortality. The HCV genome is the template for both protein translation and viral replication and, being RNA, is amenable to direct genetic silencing by RNA interference (RNAi). HCV is a highly mutable virus and is capable of escaping RNAi-mediated silencing. This has highlighted the importance of developing RNAi-based therapy that simultaneously targets multiple regions of the HCV genome. To develop a multi-targeting RNAi activator, a novel approach for the generation of anti-HCV gene therapy was investigated. Five artificial primary miRNA (pri-miR) were each designed to mimic the naturally occurring monomeric pri-miR-31. Potent knockdown of an HCV reporter was seen with four of the five constructs and were processed according to the intended design. The design of the individual pri-miR mimics enabled the modular assembly into multimeric mimics of any possible conformation. Consequently the four potent pri-miR mimics were used to generate polycistronic cassettes, which showed impressive silencing of an HCV target. To further their application as a gene therapy, recombinant adeno-associated viral (rAAV) vectors that express the polycistronic pri-miR mimics were generated. All AAV-delivered anti-HCV pri-miR mimics significantly knocked down the expression of an HCV target and showed inhibition of HCV replicon replication. Here we describe a protocol for the generation of therapeutic rAAVs that express modular polycistronic pri-miR cassettes allowing for rapid alteration and generation of tailored therapeutic constructs against HCV.
Collapse
Affiliation(s)
- Tarryn Bourhill
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa
| | - Abdullah Ely
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa.
| |
Collapse
|
|
38
|
Asselah T, Hézode C, Qaqish RB, ElKhashab M, Hassanein T, Papatheodoridis G, Feld JJ, Moreno C, Zeuzem S, Ferenci P, Yu Y, Redman R, Pilot-Matias T, Mobashery N. Ombitasvir, paritaprevir, and ritonavir plus ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a multicentre, phase 3, randomised open-label trial. Lancet Gastroenterol Hepatol 2016; 1:25-35. [PMID: 28404108 DOI: 10.1016/s2468-1253(16)30001-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 03/31/2016] [Accepted: 04/07/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotype 4 infection is most commonly reported in sub-Saharan Africa and the Middle East; however, prevalence is increasing worldwide through immigration. HCV genotype 4 accounts for 20% of all infections, but clinical trial data for treatment remain limited. We assessed the combination of two direct-acting antivirals, ombitasvir (NS5A inhibitor) and paritaprevir (NS3/4A protease inhibitor; co-dosed with ritonavir) plus ribavirin in patients with HCV genotype 4 infection and compensated cirrhosis. METHODS In this multicentre, randomised, open-label phase 3 trial (AGATE-I), treatment-naive and interferon or pegylated interferon and ribavirin treatment-experienced patients with HCV genotype 4 infection and compensated cirrhosis were recruited from academic, public, and private hospitals in Austria, Belgium, Canada, France, Germany, Greece, Italy, and the USA. Key eligibility criteria were age 18 years or older, with chronic HCV infection assessed by the presence of anti-HCV antibodies or HCV RNA. Patients were randomly assigned (1:1) to receive 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir once daily, with weight-based ribavirin dosed twice daily for either 12 weeks or 16 weeks. Randomisation was stratified by HCV treatment history (treatment-experienced vs treatment-naive patients) and further stratified by type of non-response to previous HCV treatment (null responders, partial responders, or relapsers) for treatment-experienced patients. Treatments were assigned by an interactive response technology system with computer-generated randomisation lists prepared by personnel from the study's funding sponsor who were not involved with the conduct of the study or with data analysis. The primary outcome was the proportion of patients with a sustained virological response (HCV RNA <25 IU/mL) at post-treatment week 12 (SVR12) in the intention-to-treat population, with the lower 97·5% CI compared with a clinically relevant threshold (67%; based on SVR reported for pegylated interferon and ribavirin) to achieve superiority. The safety population included all patients who received at least one dose of study drug, and safety analyses were done by the treatment duration received (12 weeks or 16 weeks). Data presented are from the planned primary interim analysis of part one of the study when all patients enrolled in part one had reached post-treatment week 12 or prematurely discontinued from the study. This trial is registered with ClinicalTrials.gov, number NCT02265237, and part two of the trial is ongoing but closed to new participants. FINDINGS Between Nov 18, 2014, and May 19, 2015, we enrolled 120 eligible patients, with 59 patients assigned to receive 12 weeks of treatment and 61 patients assigned to receive 16 weeks of treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. One patient in the 12-week group experienced virological breakthrough and one discontinued prematurely after the first day of treatment. One patient missed the post-treatment week 12 visit in the 16-week group. SVR12 was achieved in 57 (97%; 97·5% CI 86·7-99·2) of 59 patients in the 12-week group and 60 (98%; 89·6-99·8) of 61 in the 16-week group. Adverse events in more than 10% of all patients were asthenia (11 [18%] of 60 in the 12-week group; 19 [32%] of 60 in the 16-week group), fatigue (ten [17%] in the 12-week group; 20 [33%] in the 16-week group), headache (14 [23%] in the 12-week group; 14 [23%] in the 16-week group), anaemia (nine [15%] in the 12-week group; 12 [20%] in the 16-week group), pruritus (five [8%] in the 12-week group; 14 [23%] in the 16-week group), nausea (six [10%] in the 12-week group; eight [13%] in the 16-week group), and dizziness (four [7%] in the 12-week group; nine [15%] in the 16-week group). INTERPRETATION With SVR12 achieved in a high proportion of patients, no post-treatment relapses, and a similar adverse event profile for the 12-week and 16-week treatment groups, extending treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin beyond 12 weeks seems to have no additional benefit for patients with HCV genotype 4 infection and compensated cirrhosis and might not be necessary for this patient group. FUNDING AbbVie.
Collapse
Affiliation(s)
- Tarik Asselah
- Centre de Recherche sur l'Inflammation, Inserm UMR 1149, Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France.
| | - Christophe Hézode
- Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | | | - Magdy ElKhashab
- Toronto Liver Centre, University of Toronto, Toronto, ON, Canada
| | - Tarek Hassanein
- Southern California Liver Centers and Southern California Research Center, Coronado, CA, USA
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada
| | - Christophe Moreno
- CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | | | | | - Yao Yu
- AbbVie Inc, North Chicago, IL, USA
| | | | | | | |
Collapse
|
|
39
|
Alavian SM, Hajarizadeh B, Bagheri Lankarani K, Sharafi H, Ebrahimi Daryani N, Merat S, Mohraz M, Mardani M, Fattahi MR, Poustchi H, Nikbin M, Nabavi M, Adibi P, Ziaee M, Behnava B, Rezaee-Zavareh MS, Colombo M, Massoumi H, Bizri AR, Eghtesad B, Amiri M, Namvar A, Hesamizadeh K, Malekzadeh R. Recommendations for the Clinical Management of Hepatitis C in Iran: A Consensus-Based National Guideline. HEPATITIS MONTHLY 2016; 16:e40959. [PMID: 27799966 PMCID: PMC5075356 DOI: 10.5812/hepatmon.guideline] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 07/31/2016] [Indexed: 02/07/2023]
Abstract
CONTEXT Hepatitis C virus (HCV) infection is a major public health issue worldwide, including Iran. The new direct-acting antiviral agents (DAAs) with high efficacy have changed the landscape of HCV treatment. This guideline provides updated recommendations for clinical management of HCV infection in Iran. EVIDENCE ACQUISITION The recommendations of this guideline are based on international and national scientific evidences and consensus-based expert opinion. Scientific evidences were collected through a systematic review of studies that evaluated efficacy and safety of DAA regimens, using PubMed, Scopus and Web of Science. Expert opinion was based on the consensus of Iran Hepatitis Scientific Board (IHSB) in the 3rd national consensus on management of Hepatitis C in Iran, held on 22nd of July 2016. RESULTS Pegylated Interferon alpha (PegIFN), Ribavirin (RBV), Sofosbuvir (SOF), Ledipasvir (LDV) and Daclatasvir (DCV) are currently available in Iran. Pre-treatment assessments include HCV RNA level, HCV genotype and resistance testing, assessment of liver fibrosis, and underlying diseases. In HCV genotype 1 and 4, DCV/SOF and LDV/SOF are recommended. In HCV genotype 2, SOF plus RBV and in HCV genotype 3, DCV/SOF is recommended. Additional care for underlying diseases should be considered. CONCLUSIONS Affordable new HCV treatment regimens are available in Iran, providing an opportunity for HCV elimination. Recommendations provided in this current national guideline can facilitate evidence-based management of HCV infection.
Collapse
Affiliation(s)
- Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, The Kirby Institute, The University of New South Wales (UNSW Australia), Sydney, Australia
| | | | - Heidar Sharafi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | | | - Shahin Merat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Minoo Mohraz
- Iranian Research Center for HIV/AIDS (IRCHA), Tehran University of Medical Sciences, Tehran, IR Iran
| | - Masoud Mardani
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Mohamad Reza Fattahi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mehri Nikbin
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Mahmood Nabavi
- Department of Infectious Diseases and Tropical Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Peyman Adibi
- Department of Gastroenterology and Hepatology, Isfahan University of Medical Sciences, Isfahan, IR Iran
| | - Masood Ziaee
- Hepatitis Research Center, Birjand University of Medical Sciences, Birjand, IR Iran
| | - Bita Behnava
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Mohammad Saeid Rezaee-Zavareh
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
- Student’s Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Massimo Colombo
- Department of Medicine, Gastroenterology Division 1, AM and A Migliavacca Center for the Study of Liver Disease, Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Hatef Massoumi
- New York Associates in Gastroenterology, Bronx, New York, USA
| | - Abdul Rahman Bizri
- Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Majid Amiri
- Gastroenterology and Hepatology Department, Gouin Hospital, Clichy, France
| | - Ali Namvar
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
| | - Khashayar Hesamizadeh
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Reza Malekzadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| |
Collapse
|
|
40
|
Abstract
Chronic hepatitis C virus (HCV) infection is one of the most common etiologies of liver-related mortality throughout the world. Among the six HCV genotypes, genotype 1 was significantly more aggressive when utilizing the combination of pegylated interferon and ribavirin, as genotype 1-infected patients had the lowest likelihood of achieving cure (40%-50%) and required twice as long duration of treatment, as compared to genotypes 2 and 3. Recently, however, significant advances have been made with the advent of all-oral direct-acting antiviral agents, which have significantly improved the safety, efficacy, and tolerability of the treatment of HCV genotype 1. Among the available treatments for HCV genotype 1, the combination therapy of ledipasvir/sofosbuvir provides several advantages compared to other regimens, including use of a single-pill regimen, possibility to shorten the duration of treatment to 8 weeks, efficacy in patients exposed to protease inhibitors, safety in decompensated cirrhosis, and potential to avoid ribavirin. In this review, we discuss the pharmacotherapy of the combination of ledipasvir/sofosbuvir therapy and summarize the results of the Phase III clinical trials for this treatment in HCV genotype 1 patients. We will also discuss the data for special populations, including decompensated cirrhosis, human immunodeficiency virus (HIV) coinfected patients, African-Americans, the elderly, and those who failed sofosbuvir-containing regimens.
Collapse
Affiliation(s)
- Vinay Sundaram
- Department of Medicine and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Kris V Kowdley
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
| |
Collapse
|
|
41
|
Hessel MHM, Cohen AF, Rissmann R. Sofosbuvir and daclatasvir. Br J Clin Pharmacol 2016; 82:878-9. [PMID: 27198488 PMCID: PMC5111747 DOI: 10.1111/bcp.13011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 04/06/2016] [Accepted: 05/11/2016] [Indexed: 12/26/2022] Open
Affiliation(s)
| | - Adam F Cohen
- Leiden University Medical Center, Leiden.,Center for Human Drug Research, Leiden, the Netherlands
| | - Robert Rissmann
- Leiden University Medical Center, Leiden.,Center for Human Drug Research, Leiden, the Netherlands
| |
Collapse
|
|
42
|
Abstract
Little is known about the tolerance and effectiveness of novel oral direct acting antivirals (DAA) in hepatitis C patients with decompensated cirrhosis. To examine the studies relevant to the treatment of hepatitis C virus(HCV)-related decompensated liver disease, we performed computer-based searches for English articles between 1947 and August 2015. Fourteen articles including HCV patients with decompensated cirrhosis were reviewed. The combinations of ledipasvir(LDV)/sofosbuvir(SOF)/ribavirin(RBV) for 12 weeks, or daclatasvir/SOF/RBV for 12 weeks are safe and effective for HCV genotype 1 or 4 infection, and daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks might be effective and safe for HCV genotype 2 or 3 infection. In conclusion, current evidence supports the use of all oral DAA regimens in HCV patients with decompensated cirrhosis.
Collapse
Affiliation(s)
- Ching-Sheng Hsu
- a Division of Gastroenterology, Department of Internal Medicine , Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation , Taipei , Taiwan.,b School of Post-Baccalaureate Chinese Medicine , Tzu Chi University , Hualien , Taiwan.,c School of Medicine , Tzu Chi University , Hualien , Taiwan
| | - Jia-Horng Kao
- d Graduate Institute of Clinical Medicine , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Internal Medicine , National Taiwan University Hospital , Taipei , Taiwan.,f Department of Medical Research , National Taiwan University Hospital , Taipei , Taiwan.,g Hepatitis Research Center , National Taiwan University Hospital , Taipei , Taiwan
| |
Collapse
|
|
43
|
Resistance to direct-acting antiviral agents: clinical utility and significance. Curr Opin HIV AIDS 2016; 10:381-9. [PMID: 26248125 DOI: 10.1097/coh.0000000000000177] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW This article examines the dynamics and factors underlying hepatitis C virus (HCV) resistance, along with their impact on daily clinical management of HCV-infected patients. RECENT FINDINGS Across available treatment-regimens, GT-3 is the most difficult-to-cure genotype, but also genotype-1a may show lower success-rates compared with genotype-1b. Natural resistance to NS3, NS5A and NS5B inhibitors may contribute to treatment failures. The Q80K NS3-protease mutation affects sensibility to simeprevir + peg-interferon/ribavirin combinations. It reaches up to 48% prevalence in genotype-1a in some studies (but it is lower in other). Resistant variants (particularly in NS5A) developed at failure can persist, in a substantial proportion of patients, even 3 years after treatment-discontinuation, potentially affecting readministration of the same direct-acting antiviral agent (DAA)-class. This will become an issue for those patients failing all-oral regimens with multiple-resistant viruses. SUMMARY Recent data support the importance of an accurate genotype and genotype-1 subtype (1a/1b) assignment prior therapy. Resistance testing at baseline has no clear indication so far in clinical practice for all-DAA regimens selection, while it remains a valuable option at the retreatment of patients who failed DAA-containing regimens, provided that data are generated to inform treatment decisions based on the results of resistance testing. In this context, long-term RAVs persistence after failure should be taken into account.
Collapse
|
|
44
|
Buti M, Domínguez-Hernández R, Oyagüez I, Casado MÁ. [Cost-effectiveness analysis of sofosbuvir, peginterferon and ribavirin in patients with chronic hepatitis C: Early treatment in the initial stage of fibrosis vs. delayed treatment in advanced fibrosis]. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:449-57. [PMID: 27084669 DOI: 10.1016/j.gastrohep.2016.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 02/26/2016] [Accepted: 03/07/2016] [Indexed: 01/16/2023]
Abstract
AIMS Cost-effectiveness analysis of sofosbuvir combined with peginterferon alpha-2a and ribavirin (SOF/Peg-IFN/RBV) in early versus advanced fibrosis in previously untreated patients with chronic hepatitis C genotype 1 (CHC-GT1), from the perspective of the Spanish National Health System (NHS). METHODS A Markov model was developed to compare lifetime costs and outcomes (life years gained [LYGs] and quality-adjusted life years [QALYs]) of 2 treatment strategies: SOF/Peg-IFN/RBV administered during early fibrosis (mild-moderate fibrosis; F2-F3) or advanced fibrosis (cirrhosis; F4). Efficacy (sustained virologic response), annual transition probabilities, disease management costs and utilities were obtained from the literature. Costs and outcomes were discounted annually at 3%. Direct costs were considered, expressed in Euros (€, 2014). Probabilistic sensitivity analysis (PSA) was also performed. RESULTS SOF/Peg-IFN/RBV therapy at F2-F3 was more effective (19.12 LYGs and 14.14 QALYs) compared to F4. In a cohort of 1,000 patients, SOF/Peg-IFN/RBV prevented 66 cases of decompensated cirrhosis, 60 hepatocellular carcinomas and 4 liver transplantations compared with therapy in advanced fibrosis. The total lifetime cost of early therapy (€43,263) was less than the cost of treatment in the advanced stage (€49,018). Early therapy was a dominant strategy, more effective and less costly in all simulations. In the PSA analysis, administration of SOF/PEG-IFN/RBV at F2-F3 was dominant in all simulations. CONCLUSIONS Starting SOF/Peg-IFN/RBV therapy at F2-F3, compared with therapy at F4, reduced the incidence of liver disease complications and was associated with cost savings for the Spanish NHS in CHC-GT1 patients.
Collapse
Affiliation(s)
- María Buti
- Unidad de Hepatología, Hospital Universitario Vall d'Hebron, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), España
| | | | - Itziar Oyagüez
- Pharmacoeconomics & Outcomes Research Iberia, Madrid, España
| | | |
Collapse
|
|
45
|
Thong VD, Poovorawan K, Tangkijvanich P, Wasitthankasem R, Vongpunsawad S, Poovorawan Y. Influence of Host and Viral Factors on Patients with Chronic Hepatitis C Virus Genotype 6 Treated with Pegylated Interferon and Ribavirin: A Systematic Review and Meta-Analysis. Intervirology 2016; 58:373-381. [PMID: 27010195 DOI: 10.1159/000444366] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 01/31/2016] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES We conducted a systematic review and meta-analysis of the influence of host and viral factors on the sustained virologic response (SVR) in hepatitis C virus genotype 6 (HCV-6) patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). METHODS Data were retrieved from Medline, Embase, PubMed and the Cochrane Library for 'genotype 6' studies published up to December 2014 and for abstracts from international scientific meetings. Inclusion criteria were efficacy of PEG-IFN+RBV based on SVR, 24- or 48-week therapy and treatment-naïve patients. Patients with hepatitis B, D and E and HIV coinfection or another concurrent liver disease were excluded. Pooled standard difference, odds ratio and confidence intervals (CIs) were calculated using a random-effect model with STATA 11. RESULTS Fourteen studies were included in the meta-analysis. The pooled SVR rate was 80% (95% CI: 0.78-0.83, p < 0.0001; I2 = 71.2%). SVR of the PEG-IFN+RBV-treated HCV-6 patients was markedly higher than that of HCV-1 patients (80.1 vs. 55.3%). The SVR rate was significantly higher for the 48- than the 24-week treatment, but not different among HCV-infected patients with rs12979860 and ss469415590 polymorphisms of the ILFN4 gene (80.6% CC vs. 66.7% non-CC, p = 0.593; 81.1% TT/TT vs. 60% non-TT/TT, p = 0.288). Gender and type of PEG-IFN did not affect SVR rates. CONCLUSIONS Treatment outcomes for HCV-6 patients are superior to those for HCV-1 patients and comparable to those of HCV-2 and HCV-3 patients, especially at 48 weeks. The level of fibrosis affects treatment outcome, but SVR rates are not significantly different between genders. IL28B and IFNL4 polymorphisms are not significantly associated with HCV-6 treatment outcome.
Collapse
Affiliation(s)
- Vo Duy Thong
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | | | | |
Collapse
|
|
46
|
Scherer ML, Sammons C, Nelson B, Hammer SM, Verna E. Anti-Hepatitis Virus Agents. CLINICAL VIROLOGY 2016:239-270. [DOI: 10.1128/9781555819439.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
47
|
Ederth J, Jern C, Norder H, Magnius L, Alm E, Rognsvåg BK, Sundin CG, Brytting M, Esbjörnsson J, Mild M. Molecular characterization of HCV in a Swedish county over 8 years (2002-2009) reveals distinct transmission patterns. Infect Ecol Epidemiol 2016; 6:30670. [PMID: 26854010 PMCID: PMC4744866 DOI: 10.3402/iee.v6.30670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 01/13/2016] [Accepted: 01/13/2016] [Indexed: 02/06/2023] Open
Abstract
Background Hepatitis C virus (HCV) is a major public health concern and data on its molecular epidemiology in Sweden is scarce. We carried out an 8-year population-based study of newly diagnosed HCV cases in one of Sweden's centrally situated counties, Södermanland (D-county). The aim was to characterize the HCV strains circulating, analyze their genetic relatedness to detect networks, and in combination with demographic data learn more about transmission. Methods Molecular analyses of serum samples from 91% (N=557) of all newly notified cases in D-county, 2002–2009, were performed. Phylogenetic analysis (NS5B gene, 300 bp) was linked to demographic data from the national surveillance database, SmiNet, to characterize D-county transmission clusters. The linear-by-linear association test (LBL) was used to analyze trends over time. Results The most prevalent subtypes were 1a (38%) and 3a (34%). Subtype 1a was most prevalent among cases transmitted via sexual contact, via contaminated blood, or blood products, while subtype 3a was most prevalent among people who inject drugs (PWIDs). Phylogenetic analysis revealed that the subtype 3a sequences formed more and larger transmission clusters (50% of the sequences clustered), while the 1a sequences formed smaller clusters (19% of the sequences clustered), possibly suggesting different epidemics. Conclusion We found different transmission patterns in D-county which may, from a public health perspective, have implications for how to control virus infections by targeted interventions.
Collapse
Affiliation(s)
- Josefine Ederth
- Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden;
| | - Camilla Jern
- Stockholm South General Hospital, Stockholm, Sweden
| | - Helené Norder
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lars Magnius
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Erik Alm
- Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden
| | | | | | - Mia Brytting
- Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden
| | - Joakim Esbjörnsson
- Department of Microbiology Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.,Nuffield Department Medicine, University of Oxford, Oxford, United Kingdom
| | - Mattias Mild
- Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden
| |
Collapse
|
|
48
|
Tong MJ, Chang PW, Huynh TT, Rosinski AA, Tong LT. Adverse events associated with ribavirin in sofosbuvir-based therapies for patients with chronic hepatitis C: A community practice experience. J Dig Dis 2016; 17:113-21. [PMID: 26749171 DOI: 10.1111/1751-2980.12313] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 12/22/2015] [Accepted: 12/27/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Due to high sustained virological response (SVR) rates, sofosbuvir-based regimens are currently a mainstay for hepatitis C virus (HCV) therapies. The addition of pegylated interferon (PEG-IFN) and ribavirin impacts patients' quality of life during treatment. This study aimed to compare severe adverse events (SAEs) amongst therapeutic combinations for HCV in a community clinic setting. METHODS From December 2013 to July 2014, 128 chronic HCV-infected patients were treated with sofosbuvir, ribavirin and weekly PEG-IFN for 12 weeks (cohort 1), 12 or 24 weeks of sofosbuvir and ribavirin (cohorts 2 and 3) or sofosbuvir plus simeprevir for 12 weeks (cohort 4). Adverse events were recorded from baseline to 12 or 24 weeks of treatment. RESULTS SAEs appeared in 15.6-53.8% of ribavirin-inclusive treated patients compared to 4.8% of the ribavirin-free regimen. PEG-IFN, sofosbuvir plus ribavirin had the highest frequencies of fatigue, headache and rash compared to either 12 or 24 weeks of ribavirin and sofosbuvir. However, sofosbuvir and ribavirin regimens led to significant increases in dyspnea, need for ribavirin dose reductions and withdrawal from treatment due to SAEs. Anemia was also more frequent in ribavirin-inclusive combinations (P < 0.001). Conversely, sofosbuvir plus simeprevir reached similar SVR rates at week 12 post-treatment compared to all ribavirin-containing regimens, but with significantly fewer adverse events (P = 0.006). At week 12 post-treatment, cirrhotic patients experienced a higher virological relapse rate than non-cirrhotic patients (P = 0.019). CONCLUSIONS Ribavirin-inclusive HCV therapies increased the frequencies of SAEs, had higher dropout rates and increased patient morbidity.
Collapse
Affiliation(s)
- Myron John Tong
- Liver Center, Huntington Medical Research Institutes, Pasadena.,Pfleger Liver Institute and the Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | | | | | | | | |
Collapse
|
|
49
|
Patel K, Tillmann HL, Matta B, Sheridan MJ, Gardner SD, Shackel NA, McHutchison JG, Goodman ZD. Longitudinal assessment of hepatitis C fibrosis progression by collagen and smooth muscle actin morphometry in comparison to serum markers. Aliment Pharmacol Ther 2016; 43:356-63. [PMID: 26560052 DOI: 10.1111/apt.13471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/21/2015] [Accepted: 10/21/2015] [Indexed: 01/14/2023]
Abstract
BACKGROUND Assessment of fibrosis progression in chronic liver disease relies upon non-invasive tools and changes in semi-quantitative histopathology scores that may not be reliable. AIM To assess the diagnostic performance of the FibroSURE (FS) index and collagen/alpha smooth muscle actin (α-SMA) morphometry in relation to longitudinal changes in fibrosis on paired biopsies. METHODS The study cohort included 201 chronic hepatitis C (CHC) nonresponders enrolled in a prior phase II anti-fibrotic study. Serum FS and paired biopsies, with both collagen and α-SMA morphometry, were evaluated at baseline and week 52. RESULTS Study patients were mostly male (67%) and Caucasian (77%), with Ishak stages 2 (n = 79), 3 (n = 88) and 4 (n = 30), excluded (n = 4 stage 1 or 5). Mean biopsy length was 22.9 mm. For baseline Ishak 2/3 vs. 4, there were no significant differences in AUROCs for collagen (0.71), SMA (0.66) or FS (0.70). At week 52, 62% of patients had no change in Ishak stage, but collagen/α-SMA increased by 34-51% (P < 0.0001), and FS decreased by 5% (P = 0.008). Among the 33% of patients with +/-1 Ishak stage change, FS changes were not significant, but α-SMA increased 29-72%, and collagen increased by 12-38% (P = 0.01 for +1 only). CONCLUSIONS Longitudinal changes in collagen and α-SMA morphometry are apparent prior to change in histological stage or FibroSURE in CHC nonresponders with intermediate fibrosis. This likely reflects quantitative morphological differences that are not detected by routine histological staging or serum markers such as FibroSURE.
Collapse
Affiliation(s)
- K Patel
- Duke Clinical Research Institute, Durham, NC, USA.,Duke University Medical Center, Durham, NC, USA.,Liver Cell Biology, Centenary Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - H L Tillmann
- Duke Clinical Research Institute, Durham, NC, USA.,Duke University Medical Center, Durham, NC, USA
| | - B Matta
- Duke University Medical Center, Durham, NC, USA
| | - M J Sheridan
- Inova Research Center, Inova Fairfax Medical Campus, Falls Church, VA, USA
| | - S D Gardner
- Infectious Diseases Therapeutic Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA
| | - N A Shackel
- Liver Cell Biology, Centenary Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | | | - Z D Goodman
- Hepatic Pathology Consultation and Research, Inova Fairfax Hospital, Falls Church, VA, USA
| |
Collapse
|
|
50
|
Saeed N, Gurakar A. Tackling HCV-3 in Asia: Breakthroughs for Efficient and Cost-effective Treatment Strategies. Euroasian J Hepatogastroenterol 2016; 6:35-42. [PMID: 29201722 PMCID: PMC5578556 DOI: 10.5005/jp-journals-10018-1163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/18/2015] [Indexed: 11/23/2022] Open
Abstract
Hepatitis C virus (HCV) is known to cause chronic hepatitis C, and its sequelae of cirrhosis and hepatocellular carcinoma. Hepatitis C genotype 3 (HCV-3) in particular is notorious for causing accelerated liver fibrosis, cardiovascular, and metabolic effects, thus increasing morbidity and mortality. It is the commonest variant in Asian countries like India and Pakistan. It is also one of the hardest-to-treat genotypes, especially among treatment-experienced and cirrhotic patients. Due to limited health care affordability and accessibility in these areas, many patients remain untreated. Until recently, the established therapy for HCV had been a combination of pegylated interferon + ribavirin. However, it was only effective in about half of patients and had severe adverse effects; hence a more efficacious option needed to be found. Recent advances have led to the development of sofosbuvir, an NS5B inhibitor that is fast becoming the standard of care, in combination with other novel drugs. It was initially marketed at $1,000 per pill, a cost that was too high for most. Thus, it has not been utilized as a global therapy as yet. Formulation of effective interferon-free regimens is a huge milestone, and awareness needs to be raised regarding these new highly effective options in both the physician and the patient population. This article discusses the newest drugs and combinations that have been developed in the fight against HCV-3, as a treatment outline for HCV-3-dominant areas. It also highlights recent breakthroughs in cost reductions of these drugs and the effort to make them globally accessible. HOW TO CITE THIS ARTICLE Saeed N, Gurakar A. Tackling HCV-3 in Asia: Breakthroughs for Efficient and Cost-effective Treatment Strategies. Euroasian J Hepato-Gastroenterol 2016;6(1):35-42.
Collapse
Affiliation(s)
- Naba Saeed
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ahmet Gurakar
- Department of Transplant Hepatology, Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore Maryland, USA
| |
Collapse
|