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Barry MP, Corcorran MA, Tsui JI, Moreno C, Buskin SE, Guthrie BL, Glick SN. High Seroprevalence of Hepatitis C Virus Among Cisgender Women Who Exchange Sex in the Seattle, Washington Area. SUBSTANCE USE & ADDICTION JOURNAL 2024; 45:81-90. [PMID: 38258855 DOI: 10.1177/29767342231208936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
BACKGROUND Injection drug use (IDU) is a risk factor for hepatitis C virus (HCV) acquisition and occurs disproportionately among women who exchange sex (WES). However, little is known about HCV epidemiology in this population. We estimated HCV seroprevalence, identified correlates of HCV seropositivity, and characterized social networks by HCV serostatus and IDU history among WES in the Seattle, Washington, area. METHODS This was a secondary analysis of data from the 2016 National HIV Behavioral Surveillance survey in the Seattle, Washington area, a cross-sectional survey that used respondent-driven sampling (RDS) to enroll WES for money or drugs (N = 291). All participants were offered rapid HCV-antibody testing. We estimated HCV seropositivity and used log regression methods to estimate crude and adjusted prevalence ratios (PRs) for correlates of HCV seropositivity among WES. Using RDS recruitment chain data, we computed homophily indices to estimate the extent to which participants were likely to recruit another participant with the same HCV serostatus and IDU history. RESULTS In the study sample of WES in the Seattle, Washington area, 79% reported lifetime IDU and 60% were HCV seropositive. HCV seropositivity was strongly associated with ever injecting drugs (PRadj: 7.7 [3.3, 18.0]). The RDS homophily scores for HCV seropositivity (0.07) and ever injecting drugs (0.02) suggested that participants did not tend to recruit others with the same characteristics beyond what would be expected by chance. CONCLUSION Among this sample of WES in Seattle, Washington area, HCV seroprevalence was high and strongly associated with a history of IDU. The high burden of HCV among WES suggests this marginalized group would benefit from additional harm reduction services and targeted HCV treatment campaigns to reduce forward transmission. We saw little evidence of preferential recruitment among WES who were HCV seropositive or reported a history of IDU, suggesting the potential futility of peer-based referrals for HCV treatment.
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Affiliation(s)
- Michael P Barry
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- HIV/STD Program, Public Health-Seattle & King County, Seattle, WA, USA
| | - Maria A Corcorran
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Judith I Tsui
- Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Courtney Moreno
- HIV/STD Program, Public Health-Seattle & King County, Seattle, WA, USA
| | - Susan E Buskin
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- HIV/STD Program, Public Health-Seattle & King County, Seattle, WA, USA
| | - Brandon L Guthrie
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Department of Global Health, University of Washington, Seattle, WA, USA
| | - Sara N Glick
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- HIV/STD Program, Public Health-Seattle & King County, Seattle, WA, USA
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA
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Wu G, Zhou A, Kwon S. Integrating hepatitis C virus screening of baby boomers at a community hospital emergency department. J Viral Hepat 2022; 29:263-270. [PMID: 35152523 DOI: 10.1111/jvh.13654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 01/22/2022] [Accepted: 01/31/2022] [Indexed: 01/24/2023]
Abstract
Approximately 2.4 million Americans are infected with hepatitis C virus (HCV), and persons born from 1945 through 1965 (i.e. baby boomers) account for nearly three-fourths of all HCV infections. The purpose of this study was to implement HCV screening for baby boomers presenting to a community hospital emergency department (ED) and to facilitate linkage to care. We developed a process within our electronic medical record system to screen patients for HCV testing eligibility, link eligible patients to laboratory orders, notify patients of HCV test results (via patient navigator) and track follow-up care. We tracked performance from February 2016 to December 2018. Sociodemographic compositions and linkage to care rates of all participants were evaluated. A total of 14,927 patients from the birth cohort of 1945-1965 were screened for HCV. Of those tested, 555 (3.7%) had a positive HCV antibody test and 147 were HCV RNA-positive patients (1.0%) demonstrating that only 27% of HCV antibody-positive individuals were chronically infected. Males, black race and USA-born baby boomers had a higher prevalence of HCV antibody and viral load positivity (p < 0.05). Initially, only 17.6% of patients were ultimately linked to care, which improved to over 94% after the implementation of patient navigation support. There is a need for HCV screening protocol in the community. The cost of implementing an HCV screening programme must include information technology and a team of care coordinators to improve screening rates and facilitate linkage to continual care using the four pillars framework.
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Affiliation(s)
- Gregory Wu
- Department of Surgery, Holy Name Medical Center, Teaneck, New Jersey, USA
| | - Aiqi Zhou
- Data Science Institute, Columbia University, New York, New York, USA
| | - Steve Kwon
- Department of Surgery, Holy Name Medical Center, Teaneck, New Jersey, USA.,Department of Surgery, Columbia University Medical Center, New York, New York, USA
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3
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Choobin H, Bamdad T, Shekarabi M. The pattern of antiviral protein expression induced by interferon λ1 in peripheral blood mononuclear cells of patients with chronic hepatitis C virus infection. Arch Virol 2020; 165:583-592. [PMID: 31927635 DOI: 10.1007/s00705-019-04438-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/12/2019] [Indexed: 12/28/2022]
Abstract
Interferon lambda was discovered in recent years to be an antiviral agent, and research on different aspects of this antiviral factor in viral infection and investigations of its effectiveness are also progressing. The immunological effects of interferon lambda on different cell populations is not precisely known, which may be due to its use of a heterodimeric receptor consisting of IL-10R2 and IFN-λR1, which are not broadly expressed in all types of cells. In the present study, signaling by interferon lambda and its effect on the expression of hepatitis C virus (HCV) proteins were measured, and the expression pattern of some antiviral proteins and IL-10 levels were investigated in peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 50 patients with chronic genotype 1a HCV infection and 10 healthy individuals as controls. The PBMCs were treated with various doses of interferon lambda at different times of cultivation. Real-time PCR was used for relative quantification of Mxa, PKR, OAS, ISG15 and HCV core mRNAs. Expression of the NS5A protein was measured by flow cytometry, and IL-10 production was assessed by ELISA. A significant increase in the expression of mRNA encoding antiviral proteins and a decrease in the expression of mRNAs encoding the HCV core protein were observed when cells were treated with interferon lambda in an intermittent manner. The expression of HCV NS5A protein and interleukin 10 levels were also lower than in the control group. It was shown that the maximum antiviral effect of interferon lambda in PBMCs is dependent on the dose and treatment time.
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Affiliation(s)
- Hamzeh Choobin
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Taravat Bamdad
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehdi Shekarabi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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4
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Hu K, Zhu Z, Mathahs MM, Tran H, Bommer J, Testa CA, Schmidt WN. Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure-Activity Relationships. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:757-771. [PMID: 32158194 PMCID: PMC7048954 DOI: 10.2147/dddt.s201089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022]
Abstract
Background Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure-activity relationships that may be useful for future drug design of HCV and related Flaviviruses. Methods Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC50 values in low micromolar ranges [CoPP (1.4 µM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 µM) = protoporphyrin]. Results Lineweaver-Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC50 and IC50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protoporphyrins, suggesting that the planar, vinyl side chains are important for protease active site binding. MPPs were also active against three common protease mutants (T54A, A156T, and V36M) with equivalent or better IC50 values as compared to wild type enzyme. Conclusion These findings document the versatility of MPPs as antiviral agents with an expanded sensitivity for HCV genotypes and resistance to some common viral mutations. The results also suggest that further study of MPP structure and function will be useful for the development of new antiviral agents.
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Affiliation(s)
- Katherine Hu
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Zhaowen Zhu
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Meleah M Mathahs
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Huy Tran
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Jerry Bommer
- Frontier Scientific, Logan, UT 84321, USA.,Echelon Biosciences Inc, Salt Lake City, UT 84108, USA
| | | | - Warren N Schmidt
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
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Abstract
Many microbes, toxins, autoimmune diseases, and neoplastic diseases may cause liver inflammation; however, 5 viruses whose main pathogenesis is liver disease are referred to as hepatitis A, B, C, D, and E viruses. These viruses cause a significant burden of global illness. With the exception of hepatitis A virus, all may cause chronic infection potentially leading to cirrhosis and hepatocellular carcinoma. Excellent serologic and nucleic acid detection methods are available for determining the precise cause and, in some cases, the duration of infection. Diagnostics are critical for identifying individuals needing treatment and for monitoring the treatment success.
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Affiliation(s)
- Kunatum Prasidthrathsint
- Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Division of Clinical Microbiology, Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; University of Iowa Hospitals and Clinics, SW54, GH, 200 Hawkins Drive, Iowa City, IA 52242, USA; Medicine and Research Services, Iowa City Veterans Administration Health Care Center, Iowa City, IA, USA
| | - Jack T Stapleton
- Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; University of Iowa Hospitals and Clinics, SW54, GH, 200 Hawkins Drive, Iowa City, IA 52242, USA; Medicine and Research Services, Iowa City Veterans Administration Health Care Center, Iowa City, IA, USA.
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Ničković V, Katanić R, Katanić N, Kocić I. CHRONIC HEPATITIS B. ACTA MEDICA MEDIANAE 2017. [DOI: 10.5633/amm.2017.0408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Mansy SS, El-Ahwany E, Mahmoud S, Hassan S, Seleem MI, Abdelaal A, Helmy AH, Zoheiry MK, AbdelFattah AS, Hassanein MH. Potential ultrastructure predicting factors for hepatocellular carcinoma in HCV infected patients. Ultrastruct Pathol 2017; 41:209-226. [PMID: 28494215 DOI: 10.1080/01913123.2017.1316330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus represents one of the rising causes of hepatocellular carcinoma (HCC). Although the early diagnosis of HCC is vital for successful curative treatment, the majority of lesions are diagnosed in an irredeemable phase. This work deals with a comparative ultrastructural study of experimentally gradually induced HCC, surgically resected HCC, and potential premalignant lesions from HCV-infected patients, with the prospect to detect cellular criteria denoting premalignant transformation. Among the main detected pathological changes which are postulated to precede frank HCC: failure of normal hepatocyte regeneration with star shape clonal fragmentation, frequent elucidation of hepatic progenitor cells and Hering canals, hepatocytes of different electron density loaded with small sized rounded monotonous mitochondria, increase junctional complexes bordering bile canaliculi and in between hepatocyte membranes, abundant cellular proteinaceous material with hypertrophied or vesiculated rough endoplasmic reticulum (RER), sequestrated nucleus with proteinaceous granular material or hypertrophied RER, formation of lipolysosomes, large autophagosomes, and micro-vesicular fat deposition. In conclusion, the present work has visualized new hepatocytic division or regenerative process that mimic splitting or clonal fragmentation that occurs in primitive creature. Also, new observations that may be of value or assist in predicting HCC and identifying the appropriate patient for surveillance have been reported. Moreover, it has pointed to the possible malignant potentiality of liver stem/progenitor cells. For reliability, the results can be subjected to cohort longitudinal study.
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Affiliation(s)
- Soheir S Mansy
- a Electron Microscopy Research Department (Pathology) , Theodor Bilharz Research Institute , Giza , Egypt
| | - Eman El-Ahwany
- b Immunology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Soheir Mahmoud
- c Parasitology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Sara Hassan
- a Electron Microscopy Research Department (Pathology) , Theodor Bilharz Research Institute , Giza , Egypt
| | - Mohammed I Seleem
- d Hepatobiliary Surgery and Liver Transplantation , National Hepatology and Tropical Medicine Research Institute , Cairo , Egypt
| | - Amr Abdelaal
- e Surgery Department , Faculty of Medicine, Ain Shams University , Cairo , Egypt
| | - Ahmed H Helmy
- f Surgery Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Mona K Zoheiry
- b Immunology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Ahmed S AbdelFattah
- g Hepatogastroenterology Department , Theodor Bilharz Research Institute , Giza , Egypt
| | - Moataz H Hassanein
- g Hepatogastroenterology Department , Theodor Bilharz Research Institute , Giza , Egypt
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8
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Zhu Z, Tran H, Mathahs MM, Moninger TO, Schmidt WN. HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes. PLoS One 2017; 12:e0166853. [PMID: 28056029 PMCID: PMC5215869 DOI: 10.1371/journal.pone.0166853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 10/17/2016] [Indexed: 01/09/2023] Open
Abstract
Introduction Telomerase repairs the telomeric ends of chromosomes and is active in nearly all malignant cells. Hepatitis C virus (HCV) is known to be oncogenic and potential interactions with the telomerase system require further study. We determined the effects of HCV infection on human telomerase reverse transcriptase (TERT) expression and enzyme activity in primary human hepatocytes and continuous cell lines. Results Primary human hepatocytes and Huh-7.5 hepatoma cells showed early de novo TERT protein expression 2–4 days after infection and these events coincided with increased TERT promoter activation, TERT mRNA, and telomerase activity. Immunoprecipitation studies demonstrated that NS3-4A protease-helicase, in contrast to core or NS5A, specifically bound to the C-terminal region of TERT through interactions between helicase domain 2 and protease sequences. Increased telomerase activity was noted when NS3-4A was transfected into cells, when added to reconstituted mixtures of TERT and telomerase RNA, and when incubated with high molecular weight telomerase ‘holoenzyme’ complexes. The NS3-4A catalytic effect on telomerase was inhibited with primuline or danoprevir, agents that are known to inhibit NS3 helicase and protease activities respectively. In HCV infected cells, NS3-4A could be specifically recovered with telomerase holoenzyme complexes in contrast to NS5A or core protein. HCV infection also activated the effector caspase 7 which is known to target TERT. Activation coincided with the appearance of lower molecular weight carboxy-terminal fragment(s) of TERT, chiefly sized at 45 kD, which could be inhibited with pancaspase or caspase 7 inhibitors. Conclusions HCV infection induces TERT expression and stimulates telomerase activity in addition to triggering Caspase activity that leads to increased TERT degradation. These activities suggest multiple points whereby the virus can influence neoplasia. The NS3-4A protease-helicase can directly bind to TERT, increase telomerase activity, and thus potentially influence telomere repair and host cell neoplastic behavior.
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Affiliation(s)
- Zhaowen Zhu
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, United States of America
- Department of Internal Medicine Roy G. and Lucille A. Carver College of Medicine, University of Iowa Iowa City, IA, United States of America
| | - Huy Tran
- Department of Internal Medicine Roy G. and Lucille A. Carver College of Medicine, University of Iowa Iowa City, IA, United States of America
| | - M. Meleah Mathahs
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, United States of America
| | - Thomas O. Moninger
- Central Microscopy Research Facility Roy G. and Lucille A. Carver College of Medicine, University of Iowa Iowa City, IA, United States of America
| | - Warren N. Schmidt
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, United States of America
- Department of Internal Medicine Roy G. and Lucille A. Carver College of Medicine, University of Iowa Iowa City, IA, United States of America
- * E-mail:
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El-Serag HB, Kramer J, Duan Z, Kanwal F. Epidemiology and outcomes of hepatitis C infection in elderly US Veterans. J Viral Hepat 2016; 23:687-96. [PMID: 27040447 DOI: 10.1111/jvh.12533] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 02/17/2016] [Indexed: 12/14/2022]
Abstract
The chronic hepatitis C (CHC) cohort in the United States is getting older. Elderly patients with CHC may be at a high risk of cirrhosis and hepatocellular carcinoma (HCC), but also other nonhepatic comorbidities that negatively impact their likelihood of receiving or responding to antiviral treatment. There is little information on the clinical epidemiology or outcomes of CHC and its treatment in the elderly. We conducted a retrospective cohort study of 1 61 744 patients with a positive Hepatitis C virus RNA in the Veterans Health Administration Hepatitis C Clinical Case Registry to examine the association between age subgroups (20-49, 50-64, 65-85 years) and risk of cirrhosis, HCC or death using Cox proportional hazards models. We also examined the effect of treatment with a sustained viral response (SVR) on these outcomes in each age subgroup. The age distribution was 36.8% 20- to 49-year-olds, 57.6% 50- to 64-year-olds and 5.6% 65- to 85-year-olds (i.e. elderly). Risk of cirrhosis, HCC and death was significantly elevated in elderly patients [HR cirrhosis = 1.14 (1.00-1.29), HR HCC = 2.44 (1.99-2.99); HR death 2.09 (1.98-2.22)] compared with younger patients. The incidence of HCC was than 8.4 per 1000 PY in the elderly compared with 2.6 per 1000 PY and 5.7 per 1000 PY, among the 20-49 and 50-64 age groups, respectively. Elderly patients were significantly less likely to receive antiviral treatment (3.8% vs 14.8% and 19.1%, P < 0.0001), but among those who received treatment SVR was not different among the age groups (33.5% vs 33.2% and 32.1%). In an analysis limited to those who received treatment, SVR compared to treatment receipt with no SVR was associated with a reduction in risk of developing cirrhosis (HR = 0.34; 0.18-0.66) and HCC (HR = 0.60; 0.22-1.61) and all-cause mortality risk (HR = 0.52, 0.33-0.82). Elderly patients with CHC are more likely to develop HCC than younger patients but have traditionally received less antiviral treatment than younger patients. However, receipt of curative treatment is associated with a benefit in reducing cirrhosis, HCC and overall mortality, irrespective of age.
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Affiliation(s)
- H B El-Serag
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - J Kramer
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.,Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Z Duan
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - F Kanwal
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
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El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. Hepatology 2016; 64:130-7. [PMID: 26946190 PMCID: PMC4917456 DOI: 10.1002/hep.28535] [Citation(s) in RCA: 290] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 02/17/2016] [Accepted: 03/03/2016] [Indexed: 12/24/2022]
Abstract
UNLABELLED The long-term prognosis in terms of risk or predictors of developing hepatocellular carcinoma (HCC) among patients with sustained virological response (SVR) remains unclear. We conducted a retrospective cohort study using data from the Veterans Affairs VA hepatitis C virus (HCV) Clinical Case Registry in patients with positive HCV RNA between October 1999 and August 2009 and follow-up through December 2010. HCV treatment (interferon with or without ribavirin) and SVR (RNA test negative at least 12 weeks after the end of treatment) were determined. We used Cox's proportional hazards models to calculate hazard ratios (HRs) for potential predictors (demographic, virological, and clinical) associated with HCC development post-SVR. We identified 33,005 HCV-infected individuals who received treatment, of whom 10,817 achieved SVR. Among these patients, 100 developed new HCC during a total follow-up of 30,562 person-years for an overall incidence rate of 0.33% per year. Annual risk of HCC remained considerably high among patients with cirrhosis (1.39%) and those cured after age 64 (0.95%). Patients with diabetes (adjusted HR = 1.88; 1.21-2.91) or genotype 3 infection (adjusted HR = 1.62; 0.96-2.734) were significantly more likely to develop HCC. CONCLUSIONS Risk of HCC after HCV cure, though considerably reduced, remains relatively high at 0.33% per year. Older age and/or presence of cirrhosis at the time of SVR are associated with a high enough risk to warrant surveillance. Diabetes is also a risk factor for post-SVR HCC. (Hepatology 2016;64:130-137).
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Affiliation(s)
- Hashem B. El-Serag
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Fasiha Kanwal
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Peter Richardson
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jennifer Kramer
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
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12
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Tsertsvadze T, Sharvadze L, Chkhartishvili N, Dzigua L, Karchava M, Gatserelia L, Abutidze A, Nelson KE. The natural history of recent hepatitis C virus infection among blood donors and injection drug users in the country of Georgia. Virol J 2016; 13:22. [PMID: 26843145 PMCID: PMC4739321 DOI: 10.1186/s12985-016-0478-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/27/2016] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatitis C virus (HCV) infection is a serious health problem in Georgia. Methods We conducted a prospective study to identify and characterize the natural history of recent HCV infection since very first days of infection. Recent HCV infection was defined as detectable plasma HCV RNA in the absence of anti-HCV antibodies. Results A total of 7600 HCV seronegative blood donors and 3600 HCV seronegative drug users were screened for recent HCV infection. Among them 7 (0.09 %) blood donors and 10 (0.28 %) drug users tested positive for HCV RNA and were classified as having recent HCV infection. Of these 17 patients 4 (23.5 %) spontaneously cleared the virus by the end of 24 week follow-up. Five clinical forms of recent HCV infection were identified during the follow-up. Four patients had symptomatic disease, including 3 patients with jaundice and other clinical symptoms (2 of them cleared virus) and 1 patient only had other symptoms without jaundice. All symptomatic patients had ALT elevation. Three distinct variants of asymptomatic disease were identified in 13 patients: 9 patients had ALT elevation and none cleared the virus; 2 patients developed chronic disease without ALT elevation; 2 patients cleared virus without anti-HCV seroconversion and without ALT elevation; this form can be described as transitory HCV viremia. Conclusion Additional studies are needed to define clinical and public health implications of transitory HCV viremia. Our study suggests the need for implementing nucleic acid testing of blood donors and key populations in order to more effectively identify HCV infected persons.
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Affiliation(s)
- Tengiz Tsertsvadze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Lali Sharvadze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Nikoloz Chkhartishvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Lela Dzigua
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Marine Karchava
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Lana Gatserelia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Akaki Abutidze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Kenrad E Nelson
- Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Room E7638, Baltimore, Maryland, 21205, USA.
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Abstract
PURPOSE OF REVIEW Combined pegylated interferon-α and ribavirin remains the standard therapy for pediatric hepatitis C virus (HCV) infections in 2016, but direct-acting antivirals (DAAs) with greatly improved efficacy and safety are now approved for adults. Here we review the major classes of DAAs and their anticipated use for treatment and potentially prevention of HCV in children. RECENT FINDINGS Currently approved DAAs target the viral protease, polymerase, and NS5A, a protein involved in viral replication and assembly. In combination, DAAs have lifted sustained virologic response rates in adults to more than 90% for multiple HCV genotypes, and the rich DAA pipeline promises further improvements. Clinical trials of interferon-free DAA regimens have been initiated for children ages 3-17 years. In 2016, the first efficacy trial of a preventive HCV vaccine is also underway. While awaiting a vaccine, there is hope that increased DAA utilization may prevent pediatric HCV infections by shrinking the pool of infectious persons. SUMMARY Interferon-free DAA regimens have revolutionized therapy for HCV-infected adults and, pending results of pediatric trials, will likely do the same for HCV-infected children. If widely deployed, DAA therapies may also help to reduce the number of new vertically and horizontally acquired pediatric infections.
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Abstract
Since the discovery that certain small viral membrane proteins, collectively termed as viroporins, can permeabilize host cellular membranes and also behave as ion channels, attempts have been made to link this feature to specific biological roles. In parallel, most viroporins identified so far are virulence factors, and interest has focused toward the discovery of channel inhibitors that would have a therapeutic effect, or be used as research tools to understand the biological roles of viroporin ion channel activity. However, this paradigm is being shifted by the difficulties inherent to small viral membrane proteins, and by the realization that protein-protein interactions and other diverse roles in the virus life cycle may represent an equal, if not, more important target. Therefore, although targeting the channel activity of viroporins can probably be therapeutically useful in some cases, the focus may shift to their other functions in following years. Small-molecule inhibitors have been mostly developed against the influenza A M2 (IAV M2 or AM2). This is not surprising since AM2 is the best characterized viroporin to date, with a well-established biological role in viral pathogenesis combined the most extensive structural investigations conducted, and has emerged as a validated drug target. For other viroporins, these studies are still mostly in their infancy, and together with those for AM2, are the subject of the present review.
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Abdel-Ghaffar TY, Sira MM, El Naghi S. Hepatitis C genotype 4: The past, present, and future. World J Hepatol 2015; 7:2792-2810. [PMID: 26668691 PMCID: PMC4670951 DOI: 10.4254/wjh.v7.i28.2792] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 08/02/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) genotype (GT) 4 represents 12%-15% (15-18 million) of total global HCV infection. It is prevalent in Northern and Equatorial Africa and the Middle East, and is also present in some countries in Europe. GT-4 (and subtype 4a in particular) dominates the HCV epidemic in Egypt. In underdeveloped countries, risk factors associated with HCV infection may be due to unsafe medical practices or other factors such as familial transmission, mother’s HCV status, or illiteracy. HCV prevention and control programs should include health education, increased community awareness towards the disease, controlling infection distribution in health-care centers, proper sterilization of medical and dental instruments, and ensuring safe supply of blood and blood-products. Response rates to a 48-wk combined pegylated-interferon (PEG-IFN) and ribavirin (RBV) treatment range from 40%-69%, and HCV-GT-4 has been considered better than GT-1 but worse than GT-2 and GT-3 in treatment with PEG-IFN/RBV. However, with the introduction of the HCV-GT-1 effective protease inhibitors boceprevir and telaprevir in 2011, HCV-GT-4 became the “most difficult (GT) to treat”. Recently, the direct-acting antivirals (DAAs) with pan- genotypic activities simeprevir, sofosbuvir, and daclatasvir have been recommended in triple regimens with PEG-IFN/RBV for the treatment of HCV-GT-4. An IFN-free regimen will be available for treatment of all genotypes of HCV in the near future. To date, several DAAs have been developed and are currently being evaluated in various combinations in clinical trials. As new regimens and new agents are being approved by the Food and Drug Administration, we can expect the guidelines for HCV treatment to be changed. The availability of shorter, simpler, and more tolerable treatment regimens can reduce the morbidity and mortality associated with HCV infection. With such a large number of therapeutic agents available, we can end up with a range of choices that we can select from to treat patients.
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16
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El-Shamy A, Eng FJ, Doyle EH, Klepper AL, Sun X, Sangiovanni A, Iavarone M, Colombo M, Schwartz RE, Hoshida Y, Branch AD. A cell culture system for distinguishing hepatitis C viruses with and without liver cancer-related mutations in the viral core gene. J Hepatol 2015; 63:1323-33. [PMID: 26220749 PMCID: PMC4654634 DOI: 10.1016/j.jhep.2015.07.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 07/14/2015] [Accepted: 07/15/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Although patients infected by genotype 1b hepatitis C virus (HCV) with Q(70) and/or M(91)core gene mutations have an almost five-fold increased risk of developing hepatocellular carcinoma (HCC) and increased insulin resistance, the absence of a suitable experimental system has precluded direct experimentation on the effects of these mutations on cellular gene expression. METHODS HuH7 cells were treated long-term with human serum to induce differentiation and to produce a model system for testing high-risk and control HCV. For clinical validation, profiles of infected cells were compared to each other and to those of liver biopsies of patients with early-stage HCV-related cirrhosis followed prospectively for up to 23 years (n=216). RESULTS Long-term culture in human serum produced growth-arrested, hepatocyte-like cells whose gene profile overlapped significantly with that of primary human hepatocytes. High-risk (Q(70)/M(91)) and control (R(70)/L(91)) viruses had dramatically different effects on gene expression of these cells. The high-risk virus enhanced expression of pathways associated with cancer and type II diabetes, while the control virus enhanced pathways associated with oxidative phosphorylation. Of special clinical relevance, the transcriptome of cells replicating the high-risk virus correlated significantly with an HCC high-risk profile in patients (Bonferroni-corrected p=0.03), whereas no such association was observed for non-HCC-related clinical outcomes. CONCLUSIONS The cell-based system allowed direct head-to-head comparison of HCV variants, and provided experimental support for previous clinical data indicating an oncogenic effect of core gene mutations. This simple experimental system distinguished HCV variants and will enable future mechanistic analysis and exploration of interventional approaches.
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Affiliation(s)
- Ahmed El-Shamy
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Francis J. Eng
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Erin H. Doyle
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Arielle L. Klepper
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Xiaochen Sun
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Angelo Sangiovanni
- M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Massimo Iavarone
- M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Massimo Colombo
- M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Robert E. Schwartz
- Department of Medicine, Weill Cornell Medical College, Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medical College, New York, NY
| | - Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Andrea D. Branch
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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17
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Chacko KR, Gaglio PJ. Meet the Classes of Directly Acting Antiviral Agents: Strengths and Weaknesses. Clin Liver Dis 2015; 19:605-17, v. [PMID: 26466650 DOI: 10.1016/j.cld.2015.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
This article discusses direct-acting antiviral agents that target hepatitis C virus replication, their mechanism of action, strengths, and weaknesses. In addition, varying strategies using combinations of these agents are discussed.
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Affiliation(s)
- Kristina R Chacko
- Division of Hepatology, Department of Medicine, Montefiore Einstein Liver Center, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street Rosenthal 2 Red Zone, Bronx, NY 10467, USA
| | - Paul J Gaglio
- Division of Hepatology, Department of Medicine, Montefiore Einstein Liver Center, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street Rosenthal 2 Red Zone, Bronx, NY 10467, USA.
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18
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Swadling L, Capone S, Antrobus RD, Brown A, Richardson R, Newell EW, Halliday J, Kelly C, Bowen D, Fergusson J, Kurioka A, Ammendola V, Del Sorbo M, Grazioli F, Esposito ML, Siani L, Traboni C, Hill A, Colloca S, Davis M, Nicosia A, Cortese R, Folgori A, Klenerman P, Barnes E. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci Transl Med 2015; 6:261ra153. [PMID: 25378645 DOI: 10.1126/scitranslmed.3009185] [Citation(s) in RCA: 263] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.
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Affiliation(s)
- Leo Swadling
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
| | - Stefania Capone
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy
| | - Richard D Antrobus
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK
| | - Anthony Brown
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
| | - Rachel Richardson
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
| | - Evan W Newell
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Singapore Immunology Network, Singapore 138648, Singapore
| | - John Halliday
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. National Institute for Health Research Oxford Biomedical Research Centre, and Translational Gastroenterology Unit, Oxford OX3 7LE, UK
| | - Christabel Kelly
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. National Institute for Health Research Oxford Biomedical Research Centre, and Translational Gastroenterology Unit, Oxford OX3 7LE, UK
| | - Dan Bowen
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
| | - Joannah Fergusson
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
| | - Ayako Kurioka
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
| | | | | | - Fabiana Grazioli
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy
| | | | - Loredana Siani
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy
| | - Cinzia Traboni
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy
| | - Adrian Hill
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK
| | - Stefano Colloca
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy
| | - Mark Davis
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Alfredo Nicosia
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy. CEINGE, via Gaetano Salvatore 486, 80145 Naples, Italy. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
| | | | - Antonella Folgori
- ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy
| | - Paul Klenerman
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. National Institute for Health Research Oxford Biomedical Research Centre, and Translational Gastroenterology Unit, Oxford OX3 7LE, UK
| | - Eleanor Barnes
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK. National Institute for Health Research Oxford Biomedical Research Centre, and Translational Gastroenterology Unit, Oxford OX3 7LE, UK.
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Murira A, Lapierre P, Lamarre A. Evolution of the Humoral Response during HCV Infection: Theories on the Origin of Broadly Neutralizing Antibodies and Implications for Vaccine Design. Adv Immunol 2015; 129:55-107. [PMID: 26791858 DOI: 10.1016/bs.ai.2015.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Similar to human immunodeficiency virus (HIV)-1, vaccine-induced elicitation of broadly neutralizing (bNt) antibodies (Abs) is gaining traction as a key goal toward the eradication of the hepatitis C virus (HCV) pandemic. Previously, the significance of the Ab response against HCV was underappreciated given the prevailing evidence advancing the role of the cellular immune response in clearance and overall control of the infection. However, recent findings have driven growing interest in the humoral arm of the immune response and in particular the role of bNt responses due to their ability to confer protective immunity upon passive transfer in animal models. Nevertheless, the origin and development of bNt Abs is poorly understood and their occurrence is rare as well as delayed with emergence only observed in the chronic phase of infection. In this review, we characterize the interplay between the host immune response and HCV as it progresses from the acute to chronic phase of infection. In addition, we place these events in the context of current hypotheses on the origin of bNt Abs against the HIV-1, whose humoral immune response is better characterized. Based on the increasing significance of the humoral immune response against HCV, characterization of these events may be critical in understanding the development of the bNt responses and, thus, provide strategies toward effective vaccine design.
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Affiliation(s)
- Armstrong Murira
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
| | - Pascal Lapierre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada
| | - Alain Lamarre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
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20
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Trooskin SB, Poceta J, Towey CM, Yolken A, Rose JS, Luqman NL, Preston TWL, Chan PA, Beckwith C, Feller SC, Lee H, Nunn AS. Results from a Geographically Focused, Community-Based HCV Screening, Linkage-to-Care and Patient Navigation Program. J Gen Intern Med 2015; 30:950-7. [PMID: 25680353 PMCID: PMC4471023 DOI: 10.1007/s11606-015-3209-6] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 10/27/2014] [Accepted: 01/16/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Many of the five million Americans chronically infected with hepatitis C (HCV) are unaware of their infection and are not in care. OBJECTIVE We implemented and evaluated HCV screening and linkage-to-care interventions in a community setting. DESIGN We developed a comprehensive, community-based HCV screening and linkage-to-care program in a medically underserved neighborhood with high rates of HCV infection in Philadelphia, Pennsylvania. We provided patient navigation services to enroll uninsured patients in insurance programs, facilitate referrals from primary care physicians and link patients to an HCV infectious disease specialist with intention to treat and cure. PATIENTS Philadelphia residents were recruited through street outreach. MAIN MEASURES We measured anti-HCV seroprevalence and diagnosis, linkage and retention in care outcomes for chronically infected patients. KEY RESULTS We screened 1,301 participants for HCV; anti-HCV seroprevalence was 3.9 % and 2.8% of all patients were chronically infected. Half of chronically infected patients were newly diagnosed; the remaining patients were aware of infection but not in care. We provided confirmatory RNA testing and results, assisted patients with attaining insurance and linked most chronically infected patients to a primary care provider. The biggest barrier to retaining patients in care was obtaining referrals for subspecialty providers; however, we obtained referrals for 64% of chronically infected participants and have retained most in subspecialty HCV care. Several have commenced treatment. CONCLUSIONS Non-clinical screening programs with patient navigator services are an effective means to diagnose, link, retain and re-engage patients in HCV care. Eliminating referral requirements for subspecialty care might further enhance retention in care for patients chronically infected with HCV.
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Affiliation(s)
- Stacey B. Trooskin
- />Division of Infectious Diseases, Drexel University College of Medicine, Philadelphia, PA USA
| | - Joanna Poceta
- />Division of Infectious Diseases, Miriam Hospital, Providence, RI USA
- />Rhode Island Public Health Institute, Providence, RI USA
| | - Caitlin M. Towey
- />Department of Behavioral and Social Sciences, Brown University School of Public Health, Box G-S121-8, Providence, RI 02912 USA
- />Rhode Island Public Health Institute, Providence, RI USA
| | - Annajane Yolken
- />Department of Behavioral and Social Sciences, Brown University School of Public Health, Box G-S121-8, Providence, RI 02912 USA
- />Rhode Island Public Health Institute, Providence, RI USA
| | - Jennifer S. Rose
- />Department of Psychology, Wesleyan University, Middletown, CT USA
| | | | | | - Philip A. Chan
- />Division of Infectious Diseases, Miriam Hospital, Providence, RI USA
- />Brown University Warren Alpert Medical School, Providence, RI USA
| | - Curt Beckwith
- />Division of Infectious Diseases, Miriam Hospital, Providence, RI USA
- />Brown University Warren Alpert Medical School, Providence, RI USA
| | - Sophie C. Feller
- />Division of Infectious Diseases, Jefferson Medical College, Philadelphia, PA USA
| | - Hwajin Lee
- />Department of Behavioral and Social Sciences, Brown University School of Public Health, Box G-S121-8, Providence, RI 02912 USA
- />Rhode Island Public Health Institute, Providence, RI USA
| | - Amy S. Nunn
- />Department of Behavioral and Social Sciences, Brown University School of Public Health, Box G-S121-8, Providence, RI 02912 USA
- />Rhode Island Public Health Institute, Providence, RI USA
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21
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De Clercq E. Development of antiviral drugs for the treatment of hepatitis C at an accelerating pace. Rev Med Virol 2015; 25:254-67. [DOI: 10.1002/rmv.1842] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/04/2015] [Accepted: 05/05/2015] [Indexed: 02/06/2023]
Affiliation(s)
- Erik De Clercq
- Rega Institute for Medical Research; KU Leuven; Leuven Belgium
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22
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Chang KC, Tseng PL, Wu YY, Hung HC, Huang CM, Lu SN, Wang JH, Lee CM, Chen CH, Tsai MC, Yen YH, Lin MT, Wu CK, Huang CC, Chen HH, Hu TH. A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. Clin Gastroenterol Hepatol 2015; 13:1017-24. [PMID: 25460552 DOI: 10.1016/j.cgh.2014.10.035] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 10/12/2014] [Accepted: 10/17/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. METHODS In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. RESULTS The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. CONCLUSIONS Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.
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Affiliation(s)
- Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Ying Wu
- Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Hung-Chao Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Min Huang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsiu-Hsi Chen
- Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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Peter J, Nelson DR. Optimal interferon-free therapy in treatment-experienced chronic hepatitis C patients. Liver Int 2015; 35 Suppl 1:65-70. [PMID: 25529089 DOI: 10.1111/liv.12718] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Over the past year, interferon (IFN) free dosing regimens have become available to treat chronic hepatitis C. Offering high rates of sustained virological response (SVR), short treatment and improved tolerability, IFN-free treatment now represents the paradigm for both treatment-naïve and -experienced patients. Patients with prior treatment failure, in particular those with cirrhosis, still represent some of the most difficult to treat, but the availability of multiple agents that can interrupt several steps of the HCV lifecycle affords providers and patients with options that can be combined and individually tailored to each patient's unique needs to obtain high rates of SVR.
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Affiliation(s)
- Joy Peter
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Florida, Gainesville, FL, USA
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24
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Kayali Z, Schmidt WN. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med 2014; 7:387-98. [PMID: 25540594 PMCID: PMC4270038 DOI: 10.2147/pgpm.s52629] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance.
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Affiliation(s)
- Zeid Kayali
- Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, CA, USA
| | - Warren N Schmidt
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, USA
- Roy G and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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25
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Kruse R, Kramer JR, Tyson GL, Duan Z, Chen L, El-Serag HB, Kanwal F. Clinical outcomes of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients. Hepatology 2014; 60:1871-8. [PMID: 25065513 PMCID: PMC4245372 DOI: 10.1002/hep.27337] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Accepted: 07/24/2014] [Indexed: 12/19/2022]
Abstract
UNLABELLED The effect of hepatitis B virus (HBV) coinfection in patients with hepatitis C virus (HCV) remains unclear. We used the National Veterans Affairs HCV Clinical Case Registry to identify patients with confirmed HCV viremia during 1997-2005. We defined HBV coinfection as a positive test for hepatitis B surface antigen, HBV DNA, or hepatitis B e antigen. We defined cirrhosis and hepatocellular carcinoma (HCC) based on the validated ICD-9 codes and determined mortality through the end of 2009. We performed Cox proportional hazard regression analyses to examine the effect of HBV coinfection stratified by HBV DNA status (positive or negative) on the risk of cirrhosis, HCC, and death adjusting for patients' age, gender, race, human immunodeficiency virus (HIV) infection, alcohol or drug use, Deyo Score, and antiviral treatment. Among 99,548 patients with HCV infection, 1,370 patients (1.4%) had HBV coinfection. Of the coinfected patients, 677 (49.4%) patients had at least one HBV DNA test done and 303 patients (44.7%) tested positive for HBV DNA. The incidence rates of cirrhosis, HCC, and death were significantly higher in patients with HBV coinfection and detectable HBV DNA compared to HCV monoinfection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1,000 person-years, respectively; P < 0.05 for all comparisons). After adjustment for demographic, clinical, and treatment factors, patients with detectable HBV DNA had a significantly higher risk for cirrhosis (hazard ratio [HR] = 1.89 95% confidence interval [CI] = 1.46-2.45), HCC (HR = 2.12, 95% CI = 1.26-3.60), and death (HR = 1.62, 95% CI = 1.33-1.99) compared to HCV monoinfected patients. There were no differences in the risk of cirrhosis, HCC, or overall mortality between coinfected patients with undetectable HBV DNA and those with HCV monoinfection (HR = 1.18, 95% CI = 0.90-1.55; 1.54, 95% CI = 0.93-2.56; 1.08, 95% CI = 0.88-1.33, respectively). CONCLUSION We found that while only a small number of HCV patients were coinfected with HBV, patients with documented HBV viremia were at a significantly higher risk for cirrhosis, HCC, and overall death than HCV monoinfected patients. Absence of HBV replication was associated with a clinical course similar to that of HCV monoinfected patients.
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Affiliation(s)
- Robert Kruse
- Interdepartmental Program in Translational Biology and Molecular Medicine,
Baylor College of Medicine, Houston, Texas
| | - Jennifer R. Kramer
- Center for Innovations in Quality, Effectiveness, and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs Medical Center
| | - Gia L. Tyson
- Center for Innovations in Quality, Effectiveness, and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs Medical Center,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor
College of Medicine, Houston, TX,Section of Health Services Research, Department of Medicine, Baylor College
of Medicine, Houston, TX
| | - Zhigang Duan
- Center for Innovations in Quality, Effectiveness, and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs Medical Center,Section of Health Services Research, Department of Medicine, Baylor College
of Medicine, Houston, TX
| | - Liang Chen
- Center for Innovations in Quality, Effectiveness, and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs Medical Center,Section of Health Services Research, Department of Medicine, Baylor College
of Medicine, Houston, TX
| | - Hashem B. El-Serag
- Center for Innovations in Quality, Effectiveness, and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs Medical Center,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor
College of Medicine, Houston, TX,Section of Health Services Research, Department of Medicine, Baylor College
of Medicine, Houston, TX
| | - Fasiha Kanwal
- Center for Innovations in Quality, Effectiveness, and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs Medical Center,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor
College of Medicine, Houston, TX,Section of Health Services Research, Department of Medicine, Baylor College
of Medicine, Houston, TX,Interdepartmental Program in Translational Biology and Molecular Medicine,
Baylor College of Medicine, Houston, Texas
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26
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Dunkelberg JC, Berkley EMF, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for care. J Perinatol 2014; 34:882-91. [PMID: 25233195 PMCID: PMC4777346 DOI: 10.1038/jp.2014.167] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 07/31/2014] [Accepted: 08/06/2014] [Indexed: 12/17/2022]
Abstract
Our objective was to provide a comprehensive review of the current knowledge regarding pregnancy and hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as well as recent efforts to reduce the rate of mother-to-child transmission (MTCT). Maternal infection with either HBV or HCV has been linked to adverse pregnancy and birth outcomes, including MTCT. MTCT for HBV has been reduced to approximately 5% overall in countries including the US that have instituted postpartum neonatal HBV vaccination and immunoprophylaxis with hepatitis B immune globulin. However, the rate of transmission of HBV to newborns is nearly 30% when maternal HBV levels are greater than 200 000 IU ml(-1) (>6 log10 copies ml(-1)). For these patients, new guidelines from the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL) indicate that, in addition to neonatal vaccination and immunoprophylaxis, treating with antiviral agents such as tenofovir disoproxil fumarate or telbivudine during pregnancy beginning at 32 weeks of gestation is safe and effective in preventing MTCT. In contrast to HBV, no therapeutic agents are yet available or recommended to further decrease the risk of MTCT of HCV, which remains 3 to 10%. HCV MTCT can be minimized by avoiding fetal scalp electrodes and birth trauma whenever possible. Young women with HCV should be referred for treatment post delivery, and neonates should be closely followed to rule out infection. New, better-tolerated treatment regimens for HCV are now available, which should improve outcomes for all infected individuals.
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Affiliation(s)
- JC Dunkelberg
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - EMF Berkley
- Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA
| | - KW Thiel
- Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - KK Leslie
- Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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27
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Sulkowski MS. Management of acute and chronic HCV infection in persons with HIV coinfection. J Hepatol 2014; 61:S108-19. [PMID: 25443339 DOI: 10.1016/j.jhep.2014.08.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/10/2014] [Accepted: 08/12/2014] [Indexed: 01/13/2023]
Abstract
Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection.
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Affiliation(s)
- Mark S Sulkowski
- Johns Hopkins University, School of Medicine, Baltimore, MD, United States.
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28
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Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol 2014; 61:S79-90. [PMID: 25443348 PMCID: PMC4435677 DOI: 10.1016/j.jhep.2014.07.010] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 07/03/2014] [Accepted: 07/10/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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Affiliation(s)
- Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, United States.
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, United States
| | - Nabeel Bardeesy
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, United States
| | - Thomas F Baumert
- INSERM Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, France; Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States.
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29
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Yang HC, Kao JH. Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. Emerg Microbes Infect 2014; 3:e64. [PMID: 26038757 PMCID: PMC4185362 DOI: 10.1038/emi.2014.64] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/17/2014] [Accepted: 07/21/2014] [Indexed: 02/06/2023]
Abstract
Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV). Extensive research over the past decades has unveiled the important role of cccDNA in the natural history and antiviral treatment of chronic HBV infection. cccDNA can persist in patients recovering from acute HBV infection for decades. This explains why HBV reactivation occasionally occurs in patients with resolved hepatitis B receiving intensive immunosuppressive agents. In addition, although advances in antiviral treatment dramatically improve the adverse outcomes of chronic hepatitis B (CHB), accumulating evidence demonstrates that current antiviral treatments alone, be they nucleos(t)ide analogs (NAs) or interferon (IFN), fail to cure most CHB patients because of the persistent cccDNA. NA suppresses HBV replication by directly inhibiting viral polymerase, while IFN enhances host immunity against HBV infection. Viral rebound often occurs after discontinuation of antiviral treatment. The loss of cccDNA can be induced by non-cytolytic destruction of cccDNA or immune-mediated killing of infected hepatocytes. It is known that NA has no direct effect on viral transcription or cccDNA stability. Therefore, the long half-life of hepatocytes leads to a very slow decline in cccDNA in patients under antiviral therapy. Novel antiviral agents targeting cccDNA or cccDNA-containing hepatocytes are thus required for curing chronic HBV infection.
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Affiliation(s)
- Hung-Chih Yang
- Department of Microbiology, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China ; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China ; Department of Internal Medicine, National Taiwan University Hospital , Taipei 10002, Taiwan, China
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China ; Department of Internal Medicine, National Taiwan University Hospital , Taipei 10002, Taiwan, China ; Hepatitis Research Center, National Taiwan University Hospital , Taipei 10002, Taiwan, China ; Department of Medical Research, National Taiwan University Hospital , Taipei 10002, Taiwan, China
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30
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Toshikuni N, Arisawa T, Tsutsumi M. Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality. World J Gastroenterol 2014; 20:2876-2887. [PMID: 24659879 PMCID: PMC3961980 DOI: 10.3748/wjg.v20.i11.2876] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 01/13/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.
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31
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Recent Advances in Targeting Dengue and West Nile Virus Proteases Using Small Molecule Inhibitors. TOPICS IN MEDICINAL CHEMISTRY 2014. [DOI: 10.1007/7355_2014_46] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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32
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Pockros PJ. Interferon-free regimens and direct-acting antiviral agents. Gastroenterol Hepatol (N Y) 2013; 9:653-655. [PMID: 24764779 PMCID: PMC3992059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Affiliation(s)
- Paul J Pockros
- Director of the Center for Liver Diseases Division of Gastroenterology and Hepatology Scripps Clinic Director of Clinical Research Scripps Translational Science Institute La jolla, California
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