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Chen L, Liu CH, Kang S, Du L, Ma F, Li C, Bai L, Li H, Tang H. Determinants of suboptimal immune recovery among a Chinese Yi ethnicity population with sustained HIV suppression. BMC Infect Dis 2022; 22:137. [PMID: 35135485 PMCID: PMC8827152 DOI: 10.1186/s12879-022-07113-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 01/28/2022] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES Despite sustained viral suppression with effective antiretroviral therapy (ART), HIV-infected patients with suboptimal immune recovery are still at high risk of both non-AIDS-related and AIDS-related events. The aim of this study was to investigate determinants potentially associated with suboptimal CD4 + T cell count recovery during free ART with sustained viral suppression among an HIV-infected Yi ethnicity population in Liangshan Prefecture, an area in China with high HIV prevalence. METHODS This retrospective study included HIV-infected Yi adults (≥ 18 years and baseline CD4 + T cell count less than 500 cells/μL) for whom ART supported by National Free Antiretroviral Treatment Program was initiated between January 2015 and December 2018 in Zhaojue County, Liangshan Prefecture. Virological suppression (viral load < 50 copies/mL) was achieved within 12 months after ART initiation, and sustained virological suppression was maintained. Multivariate log-binomial regression analysis was used to assess determinants of suboptimal immune recovery. RESULTS There were 140 female and 137 male patients in this study, with a mean age of 36.57 ± 7.63 years. Most of the Yi patients were infected through IDU (48.7%) or heterosexual contact (49.8%), and the anti-HCV antibody prevalence was high (43.7%, 121/277). Of the 277 patients with a mean ART duration of 3.77 ± 1.21 years, complete immune recovery occurred in only 32.9%. The baseline CD4 + T cell count in patients with suboptimal and intermediate immune recovery was 248.64 ± 108.10 and 288.59 ± 108.86 cells/μL, respectively, which was much lower than the baseline 320.02 ± 123.65 cells/μL in patients who achieved complete immune recovery (p < 0.001). Multivariable analysis demonstrated that low pre-ART CD4 + cell count and coinfection with HCV were associated with immune recovery of the HIV patients. CONCLUSIONS Our study suggests that for HIV-infected Yi patients in Liangshan Prefecture, prompt ART initiation after diagnosis of HIV infection should be applied, and curative HCV treatment should be given to patients with HCV/HIV coinfection to improve the immunological effectiveness of ART. Trial registration None.
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Affiliation(s)
- Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Center of Antiretroviral Treatment, People's Hospital of Zhaojue County, 616150, Liangshan, Yi Autonomous Prefecture, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Shuang Kang
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Fanghua Ma
- Center of Antiretroviral Treatment, People's Hospital of Zhaojue County, 616150, Liangshan, Yi Autonomous Prefecture, China
| | - Changmin Li
- Center of Antiretroviral Treatment, People's Hospital of Zhaojue County, 616150, Liangshan, Yi Autonomous Prefecture, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
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Epidemiological Features and Risk Factors for Acquiring Hepatitis B, Hepatitis C, and Syphilis in HIV-Infected Patients in Shaanxi Province, Northwest China. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17061990. [PMID: 32197326 PMCID: PMC7143838 DOI: 10.3390/ijerph17061990] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 03/12/2020] [Accepted: 03/16/2020] [Indexed: 01/01/2023]
Abstract
Human immunodeficiency virus (HIV)-infected patients are at a higher risk for co-infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Treponema pallidum (TP; the agent causing syphilis) than the general population. The prevalence of HBV, HCV, and syphilis has geographic differences and varies from region to region among HIV-positive individuals. A retrospective study was carried out on HIV-positive individuals between June 2011 and June 2016 in Shaanxi Province. Univariate and multivariate logistic regression analyses using stepwise regression analysis regarding risk factors for HIV–HBV, HIV–HCV, and HIV–syphilis co-infection. HBV–HCV, HCV–syphilis, HBV–syphilis, and HBV–HCV–syphilis co-infection rates were 1.7%, 2.2%, 2.6%, and 0.1%, respectively. The rate of ineffective hepatitis B vaccine immunization was as high as 30.2% among HIV-positive individuals. Ethnicity (OR = 31.030, 95% CI: 11.643–82.694) and HIV transmission routes (OR = 134.024, 95% CI: 14.328–1253.653) were the risk factors for HCV infection in HIV-positive individuals. Among the HIV-positive individuals with the antibodies of TP, the rate of homosexual transmission was also higher, but heterosexual transmission was lower (OR = 0.549 95% CI: 0.382–0.789) The HIV-infected patients in Shaanxi Province had the characteristics of low active detection rate and late diagnosis. The high rate of ineffective vaccination against HBV suggests a need for improved vaccination services.
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Dultz G, Müller T, Petersen J, Mauss S, Zimmermann T, Muche M, Simon KG, Berg T, Zeuzem S, Hüppe D, Böker K, Wedemeyer H, Welzel TM. Effectiveness and Safety of Direct-Acting Antiviral Combination Therapies for Treatment of Hepatitis C Virus in Elderly Patients: Results from the German Hepatitis C Registry. Drugs Aging 2018; 35:843-857. [PMID: 30084012 DOI: 10.1007/s40266-018-0572-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND With the aging of the hepatitis C virus (HCV)-infected patient cohort and the availability of highly effective and tolerable treatment regimens, an increasing number of elderly patients are now eligible for HCV therapy. This study investigated clinical and epidemiologic characteristics of elderly HCV-infected patients as well as the effectiveness and safety of available therapies. METHODS Patients were enrolled into the German Hepatitis C Registry (DHC-R), a prospective, multicenter, real-world cohort study. Patients were treated at the discretion of the physician, and data were collected by a web-based system. RESULTS Of 7133 patients who initiated treatment, 686 (9.6%) were > 70 years of age. In patients > 70 years, intent-to-treat (ITT) SVR12 was 92.6% (514/555) compared to 90.7% (4521/4985) in patients ≤ 70 years of age. Overall, adverse events (AEs) were reported in 374 (54.5%) and 3435 patients (53.3%) > 70 or ≤ 70 years of age; 7.6% (52) and 3.6% (235) in the respective age groups had a serious AE. Twenty-two (3.2%) and 62 (1.0%) of the patients > 70 or ≤ 70 years discontinued treatment due to AEs. Death was reported in 34 patients, of whom eight were > 70 years of age. Frequent comorbidities in patients > 70 years of age were cardiac disease, renal disease and diabetes. Psychiatric disorders, substance abuse and viral co-infection were more frequent in younger patients. CONCLUSION Direct-acting antiviral therapies were well tolerated in patients older than 70 years. SVR12 rates in the elderly patient group were similar to those observed in younger patients. Differences in the prevalence of comorbidities between age groups warrant individualized attention with respect to drug-drug interactions and therapy adherence. The study was registered in the German Clinical Trials Register, DRKS-ID: DRKS00009717.
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Affiliation(s)
- Georg Dultz
- Department of Medicine 1, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
| | - Tobias Müller
- Charité Campus Virchow-Klinikum (CVK), Berlin, Germany
| | - Jörg Petersen
- ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
| | - Tim Zimmermann
- University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marion Muche
- Charité Campus Virchow-Klinikum (CVK), Berlin, Germany
| | | | - Thomas Berg
- University Hospital Leipzig, Leipzig, Germany
| | - Stefan Zeuzem
- Department of Medicine 1, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany
| | | | | | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg Essen, Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Leberstiftungs-GmbH Deutschland, Hannover, Germany
| | - Tania M Welzel
- Department of Medicine 1, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany
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Hepatitis C following liver transplantation: current approach and future research opportunities. Curr Opin Infect Dis 2018; 29:346-52. [PMID: 27191202 DOI: 10.1097/qco.0000000000000274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW The treatment of hepatitis C virus infection (HCV) in liver transplant recipients was very limited until direct-acting antivirals became widely available. We review the current approach to HCV treatment following liver transplantation and future research opportunities. RECENT FINDINGS Current treatment of HCV infection with all oral new direct-acting antivirals in the postliver transplant setting is easier, shorter, tolerable, and more effective with high-sustained virological response rates. However, some challenges remain, including the optimal timing of therapy, drug-drug interactions, renal insufficiency, and HIV coinfection. SUMMARY Patients with recurrent HCV following liver transplant will significantly benefit from all oral new direct acting antivirals. Ongoing studies will determine the optimal timing and combination in this unique population.
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Pinato DJ, Sharma R, Citti C, Platt H, Ventura-Cots M, Allara E, Chen TY, Dalla Pria A, Jain M, Mínguez B, Kikuchi L, Kaufman West E, Merli M, Kaplan DE, Hasson H, Marks K, Nelson M, Núñez M, Aytaman A, Bower M, Bräu N. The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma. Aliment Pharmacol Ther 2018; 47:95-103. [PMID: 29034998 DOI: 10.1111/apt.14356] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/19/2017] [Accepted: 09/11/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease. AIM To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection. METHODS Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded. RESULTS A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001). CONCLUSIONS In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.
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McGinty T, Mallon P. Protecting bone in long-term HIV positive patients receiving antiretrovirals. Expert Rev Anti Infect Ther 2017; 14:587-99. [PMID: 27189695 DOI: 10.1080/14787210.2016.1184570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION As the population of people living with HIV ages, the increase in non-AIDs morbidities is expected to increase in parallel. Maintaining bone health in those with HIV will be an important area of focus for the HIV clinician to prevent the morbidity and mortality associated with fragility fractures, the principal clinical sequela of low bone mineral density (BMD). Rates of fractures and prevalence of low bone mineral density, a risk factor for future fragility fractures, are already increased in the HIV positive population. AREAS COVERED This review examines the strategies to maintain bone health in those living with HIV from screening through to managing those with established low BMD or fracture, including the role for choice of or modification of antiretroviral therapy to maintain bone health. Expert commentary: The increasing complexity of managing bone health in the age of succesful antiretroviral therapy and an aging patient population as well as future perspectives which may help achieve the long term aim of minimising the impact of low BMD in those with HIV are discussed and explored.
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Affiliation(s)
- Tara McGinty
- a School of Medicine , University College Dublin , Dublin , Ireland
| | - Patrick Mallon
- a School of Medicine , University College Dublin , Dublin , Ireland
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Hepatitis C virus drives increased type I interferon-associated impairments associated with fibrosis severity in antiretroviral treatment-treated HIV-1-hepatitis C virus-coinfected individuals. AIDS 2017; 31:1223-1234. [PMID: 28492391 DOI: 10.1097/qad.0000000000001455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Viral coinfections might contribute to the increased immune activation and inflammation that persist in antiretroviral treatment (ART)-treated HIV-1 patients. We investigated whether the hepatitis C virus (HCV) coinfection contributes to such alterations by impairing the plasmacytoid dendritic cell (pDC) IFNα/TLR7 pathway in a highly homogeneous group of ART-treated HIV-1-HCV-coinfected patients. METHODS Twenty-nine HIV-1-infected patients with fully suppressive ART were included, 15 of whom being HCV-coinfected with mild-to-moderate fibrosis and matched for their HIV-1 disease, and 13 control healthy donors. Cellular activation, plasma levels of inflammatory cytokines and pDC transcriptome associated with IFNα/TLR7 pathway were characterized. RESULTS Higher plasma levels of type-I interferon (IFN)-associated cytokines [interferon gamma-induced protein 10 (IP-10), MIP-1β, IL-8 and IFN-inducible T-cell alpha chemoattractant) were observed in HIV-1-HCV-coinfected than in HIV-1-monoinfected patients (P = 0.0007, 0.028, 0.028 and 0.035, respectively). The pDCs and T cells displayed a more exhausted (LAG-3+ and CD57+, respectively) phenotype. The pDC IFNα pathway (defined by phosphorylated STAT1 expression) was constitutively activated in all patients, irrespective of HCV coinfection. Expression of interferon-stimulated genes (ISGs) EI2AK2, ISG15, Mx1 and IFI44 was increased in pDCs from HIV-1-HCV-coinfected individuals and was correlated with fibrosis score (Fibroscan, www.echosens.com, Paris, France and aspartate-aminotransferase/platelet-ratio index score, P = 0.026 and 0.019, respectively). Plasma levels of IP-10, STAT1 expression in pDCs and Mx1 mRNA levels in pDCs decreased after interferon-free anti-HCV treatment. CONCLUSION HCV replication appears to drive increases in type-I IFN-associated inflammation and ISGs expression in pDCs, in association with fibrosis severity in ART-treated HIV-1-infected patients with mild-to-moderate fibrosis. Preliminary results indicate reduction of these alterations with earlier interferon-free anti-HCV treatment in those patients.
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Bruno G, Saracino A, Fabrizio C, Scudeller L, Milano E, Dell'Acqua R, Ladisa N, Fasano M, Minniti S, Buccoliero G, Tartaglia A, Giammario A, Milella M, Angarano G. Safety and effectiveness of a 12-week course of sofosbuvir and simeprevir ± ribavirin in HCV-infected patients with or without HIV infection: a multicentre observational study. Int J Antimicrob Agents 2017; 49:296-301. [PMID: 28163136 DOI: 10.1016/j.ijantimicag.2016.11.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/03/2016] [Accepted: 11/25/2016] [Indexed: 12/15/2022]
Abstract
The combination of sofosbuvir and simeprevir ± ribavirin (SOF + SMV ± RBV) for hepatitis C virus (HCV) treatment has been associated with high rates of sustained virological response (SVR). Few data are available regarding this regimen in HIV/HCV co-infected patients. This study evaluated the effectiveness and safety of a 12-week course of SOF + SMV ± RBV in a cohort of HCV monoinfected and HIV/HCV co-infected individuals. HCV-infected patients, with or without HIV infection, receiving a 12-week course of SOF + SMV ± RBV in four Italian centres from February to October 2015, were included in this retrospective observational study. Clinical and biochemical data were retrieved for all patients. A total of 88 individuals were evaluated: 29 (33.0%) HIV/HCV co-infected and 59 (67.0%) monoinfected. Most patients were males with HCV genotype 1b (62.5%) and 1a (25%) infection. RBV was used in 41 HCV monoinfected and 6 HIV/HCV co-infected patients. Cirrhosis was found in 67 patients (76.1%). The most common adverse events (AEs) were rash and/or pruritus (23.9%), fatigue (13.6%) and anaemia (9.1%). Serious AEs occurred in three patients (3.4%). No treatment discontinuations were observed. RBV use was associated with multiple AEs (P = 0.02). An overall SVR12 of 93.2% was achieved; 96.6% in HCV monoinfected and 86.2% in HIV/HCV co-infected individuals, without significance both in univariate (P = 0.09) and multivariate analyses (P = 0.12). A baseline platelet count ≥90 000/mm3 was associated with higher rates of SVR (P = 0.005). A 12-week course of SOF + SMV ± RBV was associated with good safety and high SVR12 rate both in HCV monoinfected and HIV-HCV co-infected individuals.
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Affiliation(s)
- Giuseppe Bruno
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Annalisa Saracino
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Claudia Fabrizio
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Luigia Scudeller
- Scientific Direction, Clinical Epidemiology Unit, IRCCS San Matteo Foundation, Pavia, Italy
| | - Eugenio Milano
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Raffaele Dell'Acqua
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Nicoletta Ladisa
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Massimo Fasano
- Clinic of Infectious Diseases, University of Foggia, Foggia, Italy
| | - Salvatore Minniti
- Infectious Diseases Unit, 'A. Perrino' Hospital, ASL Brindisi, Brindisi, Italy
| | - Giovanni Buccoliero
- Oncohaematologic Department, Infectious Diseases, 'San G. Moscati' Hospital, ASL Taranto, Taranto, Italy
| | | | - Adele Giammario
- Clinic of Infectious Diseases, University of Foggia, Foggia, Italy
| | - Michele Milella
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Gioacchino Angarano
- Clinic of Infectious Diseases, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
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Debes JD, Bohjanen PR, Boonstra A. Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection. J Clin Transl Hepatol 2016; 4:328-335. [PMID: 28097102 PMCID: PMC5225153 DOI: 10.14218/jcth.2016.00034] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/14/2016] [Accepted: 10/21/2016] [Indexed: 12/23/2022] Open
Abstract
With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis. In addition, mitochondrial toxicity, triggered by both ART and HIV, contributes to intrahepatic damage, which is even more severe in patients co-infected with viral hepatitis. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review.
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Affiliation(s)
- Jose D. Debes
- Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA
- *Correspondence to: Jose D. Debes, Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA. Tel: +1-612-624-6353, Fax: +1-612-301-1292, E-mail:
| | - Paul R. Bohjanen
- Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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Natural occurrence of NS5B inhibitor resistance-associated variants in Brazilian patients infected with HCV or HCV and HIV. Arch Virol 2016; 162:165-169. [PMID: 27704215 DOI: 10.1007/s00705-016-3094-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 09/29/2016] [Indexed: 01/08/2023]
Abstract
Resistance-associated variants (RAVs) represent a challenge to the success of new HCV therapies. The aim of this study was to describe the prevalence of naturally occurring NS5B RAVs in Brazilian direct acting antivirals (DAA)-naïve patients infected with HCV genotype 1, or co-infected with HIV. Patient enrollment and sample collection were performed between 2011 and 2013. Using Sanger-based sequencing, 244 sequences were obtained. RAVs detected in HCV-1a sequences were V321A (1.6 %), M414V (1.3 %), A421V (21.4-23.7 %), A421G (1.3 %) and Y448H (1.3 %); and in HCV-1b sequences were L159F (16.1 %), C316N (7.1-16.3 %) and A421V (3.2-6.3 %). Understanding the real RAVs scenario in patients is fundamental to establishing the most effective therapeutic strategy and in minimizing the risks for their selection.
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Medrano LM, Rallón N, Berenguer J, Jiménez-Sousa MA, Soriano V, Aldámiz-Echevarria T, Fernández-Rodríguez A, García M, Tejerina F, Martínez I, Benito JM, Resino S. Relationship of TRIM5 and TRIM22 polymorphisms with liver disease and HCV clearance after antiviral therapy in HIV/HCV coinfected patients. J Transl Med 2016; 14:257. [PMID: 27590274 PMCID: PMC5010694 DOI: 10.1186/s12967-016-1005-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 08/16/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND AIMS TRIM5 and TRIM22 are restriction factors involved in innate immune response and exhibit anti-viral activity. Single nucleotide polymorphisms (SNPs) at TRIM5 and TRIM22 genes have shown to influence several viral infections such as human immunodeficiency virus (HIV), hepatitis B, as well as measles and rubella vaccination. The aim of this study is to analyze whether TRIM5 and TRIM22 polymorphisms are associated with liver fibrosis inflammation-related biomarkers and response to pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) therapy in HIV/hepatitis C virus (HCV) coinfected patients. METHODS A retrospective study was performed in 319 patients who started pegIFNα/RBV therapy. Liver fibrosis stage was characterized in 288 patients. TRIM5 rs3824949 and TRIM22 polymorphisms (rs1063303, rs7935564, and rs7113258) were genotyped using the GoldenGate assay. The primary outcomes were: a) significant liver fibrosis (≥F2) evaluated by liver biopsy or transient elastography (liver stiffness values ≥7.1 Kpa); b) sustained virological response (SVR) defined as no detectable HCV viral load (<10 IU/mL) at week 24 after the end of the treatment. The secondary outcome variable was plasma chemokine levels. RESULTS Patients with TRIM5 rs3824949 GG genotype had higher SVR rate than patients with TRIM5 rs3824949 CC/CG genotypes (p = 0.013), and they had increased odds of achieving SVR (adjusted odds ratio (aOR = 2.58; p = 0.012). Patients with TRIM22 rs1063303 GG genotype had higher proportion of significant liver fibrosis than patients with rs1063303 CC/CG genotypes (p = 0.021), and they had increased odds of having significant hepatic fibrosis (aOR = 2.19; p = 0.034). Patients with TRIM22 rs7113258 AT/AA genotype had higher SVR rate than patients with rs7113258 TT genotypes (p = 0.013), and they had increased odds of achieving SVR (aOR = 1.88; p = 0.041). The TRIM22 haplotype conformed by rs1063303_C and rs7113258_A was more frequent in patients with SVR (p = 0.018) and was significantly associated with achieving SVR (aOR = 2.80; p = 0.013). The TRIM5 rs3824949 GG genotype was significantly associated with higher levels of GRO-α (adjusted arithmetic mean ratio ((aAMR) = 1.40; p = 0.011) and MCP-1 (aAMR = 1.61; p = 0.003). CONCLUSIONS TRIM5 and TRIM22 SNPs are associated to increased odds of significant liver fibrosis and SVR after pegIFNα/RBV therapy in HIV/HCV coinfected patients. Besides, TRIM5 SNP was associated to higher baseline levels of circulating biomarkers GRO and MCP-1.
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Affiliation(s)
- Luz M. Medrano
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220 Majadahonda Madrid, Spain
| | - Norma Rallón
- Instituto de Investigación Sanitaria de La Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, Madrid, Spain
- Hospital Universitario Rey Juan Carlos, Móstoles, Spain
| | - Juan Berenguer
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - María A. Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220 Majadahonda Madrid, Spain
| | - Vicente Soriano
- Unidad de Enfermedades Infecciosas, Hospital Universitario La Paz, Madrid, Spain
| | - Teresa Aldámiz-Echevarria
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220 Majadahonda Madrid, Spain
| | - Marcial García
- Instituto de Investigación Sanitaria de La Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, Madrid, Spain
- Hospital Universitario Rey Juan Carlos, Móstoles, Spain
| | - Francisco Tejerina
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Isidoro Martínez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220 Majadahonda Madrid, Spain
| | - José M. Benito
- Instituto de Investigación Sanitaria de La Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, Madrid, Spain
- Hospital Universitario Rey Juan Carlos, Móstoles, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220 Majadahonda Madrid, Spain
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Del Bello D, Cha A, Sorbera M, Bichoupan K, Levine C, Doyle E, Harty A, Patel N, Ng M, Gardenier D, Odin J, Schiano TD, Fierer DS, Berkowitz L, Perumalswami PV, Dieterich DT, Branch AD. Real-World Sustained Virologic Response Rates of Sofosbuvir-Containing Regimens in Patients Coinfected With Hepatitis C and HIV. Clin Infect Dis 2016; 62:1497-1504. [PMID: 26936665 PMCID: PMC4885645 DOI: 10.1093/cid/ciw119] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/24/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Patients with hepatitis C virus (HCV) with or without human immunodeficiency virus (HIV) achieve high sustained virological response (SVR) rates on sofosbuvir (SOF)-containing regimens in clinical trials. Real world data on patients coinfected with HCV and HIV treated with SOF-based regimens are lacking. METHODS This observational cohort study included HIV/HCV-coinfected adults with genotype 1 HCV who initiated treatment with a SOF-containing regimen between December 2013 and December 2014 (n = 89) at the Mount Sinai Hospital or the Brooklyn Hospital Center. The primary outcome was SVR at 12 weeks after the end of treatment. The secondary outcomes were risk factors for treatment failure, serious adverse events, and side effects. A post hoc per protocol analysis of SVR was performed on patients who completed treatment and follow-up. RESULTS In an intention-to-treat analysis, SVR rates were 76% (31/41) for simeprevir (SMV)/SOF, 94% (16/17) for SMV/SOF/ribavirin (RBV), and 52% (16/31) for SOF/RBV. The SVR rates of SMV/SOF/RBV and SMV/SOF did not differ significantly in this small study (P = .15). However the SVR rate of SMV/SOF/RBV was higher than that of SOF/RBV (P < .01). In a per protocol analysis, SMV/SOF/RBV had a higher SVR rate than SOF/RBV: 100% (16/16) vs 57% (16/28) (P < .01). The most commonly reported adverse effects were rash, pruritus, fatigue, and insomnia. One patient who had decompensated cirrhosis prior to treatment initiation died after receiving SMV/SOF. CONCLUSIONS SMV/SOF ± RBV is an effective option with minimal adverse effects for most HIV-positive patients with genotype 1 HCV. SMV should be used with caution in patients with decompensated cirrhosis.
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Affiliation(s)
- David Del Bello
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai
| | - Agnes Cha
- Department of Pharmacotherapy, Brooklyn Hospital Center
| | - Maria Sorbera
- Department of Pharmacotherapy, Brooklyn Hospital Center
| | | | - Calley Levine
- Department of Medicine, Icahn School of Medicine at Mount Sinai
| | | | - Alyson Harty
- Faculty Practice Associates, Mount Sinai Hospital
| | | | - Michel Ng
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai
| | | | | | | | - Daniel S Fierer
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai
| | | | | | - Douglas T Dieterich
- Division of Liver Diseases, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York
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Liver transplantation for hepatitis C virus in the era of direct-acting antiviral agents. Curr Opin HIV AIDS 2016; 10:361-8. [PMID: 26185921 DOI: 10.1097/coh.0000000000000186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation is widely used to treat HIV patients with an end-stage liver disease, mainly decompensated cirrhosis and hepatocellular carcinoma. The results are good especially in non-hepatitis C virus (HCV)-coinfected patients. In HIV-HCV-coinfected patients, 5-year post-liver transplantation survival is around 50-55%, negatively impacted by HCV recurrence. The results of PEG-IFN/RBV are poor in terms of efficacy and safety. In patients with genotype 1 infection, triple therapy (boceprevir or telaprevir) has increased sustained virological response (SVR) rate, but drug-drug interactions (DDIs) with immunosuppressive agents and high rates of adverse events lead to forsake these combinations. Herein, we provide new data and practical management regarding HIV-HCV liver transplantation patients using new direct-acting antiviral agents (DAA). RECENT FINDINGS The second-generation DAA have good safety profile. In patients who are candidates for liver transplantation or are already recipients, the optimal therapeutic option is to combine the new DAA. Efficacy results have dramatically improved with greater than 90% of SVR rate in many studies enrolling HCV-monoinfected liver transplant recipients. Some concerns persist in terms of DDI. SUMMARY Even sparse, data regarding efficacy and safety of these regimens in HCV-HIV-coinfected liver transplantation will radically change the prognosis of this peculiar population.
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Abstract
The management of hepatitis C virus (HCV) infection in special populations is challenging. The efficacy and safety data of the currently approved all-oral direct-acting antiviral combinations, including sofosbuvir, ledipasvir, daclatasvir, paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D), and ribavirin, is compelling for use in special HCV populations, as has recently been recommended by expert guidelines. The treatment regimens and sustained virological response rates for special populations are nearly similar to those of the general HCV population. Sofosbuvir is not recommended in patients with severe renal impairment, and simeprevir and 3D regimen are not recommended for those with decompensated liver disease.
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Cachay ER, Wyles D, Hill L, Ballard C, Torriani F, Colwell B, Kuo A, Schooley R, Mathews CW. The Impact of Direct-Acting Antivirals in the Hepatitis C-Sustained Viral Response in Human Immunodeficiency Virus-Infected Patients With Ongoing Barriers to Care. Open Forum Infect Dis 2015; 2:ofv168. [PMID: 26697509 PMCID: PMC4683297 DOI: 10.1093/ofid/ofv168] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 11/03/2015] [Indexed: 12/13/2022] Open
Abstract
Using an inclusive HCV treatment protocol that encourages prospective engagement in care, HIV-infected patients with and without ongoing barriers to care had similar chances of HCV sustained viral response irrespective of which HCV treatment regimen was used. Background. Access to hepatitis C virus (HCV) medications for human immunodeficiency virus (HIV)-infected patients with ongoing barriers to care is restricted by healthcare payers in the absence of HCV treatment outcomes data in the era of direct-acting antivirals (DAA). Methods. Retrospective analysis of HCV treatment outcomes using interferon (IFN)-free DAA regimens and an inclusive treatment protocol in an urban HIV clinic where ongoing barriers to care (drug or alcohol use, psychiatric disease, and/or unstable housing) are common. Then, using logistic regression analysis, we compared the proportion of HIV-infected patients who achieved HCV sustained viral response (SVR) in the pegylated-IFN plus ribavirin (PEG-IFN/RBV, 2008–2011), pegylated-IFN plus ribavirin and telaprevir (PEG-IFN/RBV/PI, 2011–2013), and IFN-free DAA therapy eras (2014). Results are displayed using forest plots. Results. The proportion of patients who achieved HCV SVR in the PEG-IFN/RBV, PEG-IFN/RBV/PI, and IFN-free DAA therapy eras increased from 38.4% (95% confidence interval [CI], 23.2–53.7) and 48% (95% CI, 28.4–67.6) to 83.3% (95% CI, 70.0–96.7), respectively. Similar proportions of patients with ongoing barriers to care were treated during the PEG-IFN/RBV (25 of 39 [64%]), PEG-IFN/RBV/PI (14 of 25 [56%]), and IFN-free DAA (16 of 30 [53%]) eras. Hepatitis C virus SVR among patients with ongoing barriers to care improved from 40% (95% CI, 21–59) to 76.5% (95% CI, 56–97) in the PEG-IFN/RBV and IFN-free DAA eras, respectively. After stratification for factors associated with HCV SVR such as HCV genotype and cirrhosis, HCV SVR were similar in patients regardless of the presence of ongoing barriers to care. Conclusions. Using IFN-free DAA and an inclusive HCV treatment protocol, 76.5% of HIV/HCV-treated patients with ongoing barriers to care achieved HCV SVR.
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Affiliation(s)
- Edward R Cachay
- Department of Medicine , Owen Clinic ; Department of Medicine, Division of Infectious Diseases
| | - David Wyles
- Department of Medicine , Owen Clinic ; Department of Medicine, Division of Infectious Diseases
| | - Lucas Hill
- Skaggs School of Pharmacy and Pharmaceutical Sciences
| | - Craig Ballard
- Department of Medicine , Owen Clinic ; Skaggs School of Pharmacy and Pharmaceutical Sciences
| | - Francesca Torriani
- Department of Medicine , Owen Clinic ; Department of Medicine, Division of Infectious Diseases
| | - Bradford Colwell
- Department of Medicine , Owen Clinic ; Skaggs School of Pharmacy and Pharmaceutical Sciences
| | - Alexander Kuo
- Department of Medicine, Division of Gastroenterology and Hepatology , University of California San Diego
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Jansen K, Thamm M, Bock CT, Scheufele R, Kücherer C, Muenstermann D, Hagedorn HJ, Jessen H, Dupke S, Hamouda O, Gunsenheimer-Bartmeyer B, Meixenberger K. High Prevalence and High Incidence of Coinfection with Hepatitis B, Hepatitis C, and Syphilis and Low Rate of Effective Vaccination against Hepatitis B in HIV-Positive Men Who Have Sex with Men with Known Date of HIV Seroconversion in Germany. PLoS One 2015; 10:e0142515. [PMID: 26555244 PMCID: PMC4640863 DOI: 10.1371/journal.pone.0142515] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 10/22/2015] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Men who have sex with men (MSM) are at higher risk for coinfection with hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis than the general population. HIV infection and these coinfections accelerate disease progression reciprocally. This study evaluated the prevalence and incidence of these coinfections in HIV1-positive MSM in Germany. MATERIALS AND METHODS As part of a nationwide, multicenter, prospective cohort study of HIV-infected MSM, plasma samples collected yearly were screened for HBsAg and antibodies to HBc, HBs, HCV, and syphilis. Samples with indications of active HBV or HCV infection were confirmed by polymerase chain reaction. Prevalence and incidence of each infection and incidence rates per study participant were calculated, and incidences over 4-year time intervals compared. RESULTS This study screened 5,445 samples from 1,843 MSM. Median age at HIV seroconversion was 33 years. Prevalences of active, cleared, and occult HBV, and of active/cleared HCV were 1.7%, 27.1%, 0.2%, and 8.2%, respectively, and 47.5% had been effectively vaccinated against HBV. Prevalence of antibodies to Treponema pallidum and of triple or quadruple sexually transmitted infections (STIs) were 39.6% and 18.9%, respectively. Prevalence of STI, cleared HBV, HBV vaccination, and history of syphilis differed significantly among age groups. Incidences of HBV, HCV, and syphilis were 2.51, 1.54, and 4.06 per 100 person-years, respectively. Incidences of HCV and syphilis increased over time. HCV incidence was significantly higher in MSM coinfected with syphilis and living in Berlin, and syphilis incidence was significantly higher for MSM living in Berlin. DISCUSSION Despite extensive HBV vaccination campaigns, fewer than 50% of screened MSM were effectively vaccinated, with a high proportion of HIV-positive MSM coinfected with HBV. High rates of STI coinfections in HIV-positive MSM and increasing incidences emphasize the need for better tailored campaigns for HBV vaccination and STI prevention.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Stephan Dupke
- Medical Care Centre Driesener Strasse, Berlin, Germany
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Ohkoshi S, Hirono H, Yamagiwa S. Direct antiviral agent treatment of decompensated hepatitis C virus-induced liver cirrhosis. World J Gastrointest Pharmacol Ther 2015; 6:114-119. [PMID: 26558145 PMCID: PMC4635151 DOI: 10.4292/wjgpt.v6.i4.114] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 07/15/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023] Open
Abstract
Recently, direct antiviral agents (DAAs) have been increasingly used for the treatment of chronic hepatitis C virus (HCV) infections, replacing interferon-based regimens that have severe adverse effects and low tolerability. The constant supply of new DAAs makes shorter treatment periods with enhanced safety possible. The efficacy of DAAs for treatment of compensated liver cirrhosis (LC) is not less than that for treatment of non-cirrhotic conditions. These clinical advantages have been useful in pre- and post-liver transplantation (LT) settings. Moreover, DAAs can be used to treat decompensated HCV-induced LC in elderly patients or those with severe complications otherwise having poor prognosis. Although encouraging clinical data are beginning to appear, the actual efficacy of DAAs for suppressing disease progression, allowing delisting for LT and, most importantly, improving prognosis of patients with decompensated HCV-LC remains unknown. Case-control studies to examine the short- or long-term effects of DAAs for treatment of decompensated HCV-LC are urgently need.
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Abstract
The hepatitis C virus (HCV) treatment landscape has rapidly changed over the past 5 years. The development of direct-acting antiviral (DAA) agents that specifically target various steps in the HCV lifecycle has revolutionized therapeutic options for patients with HCV, with the development of highly effective and well-tolerated oral interferon-free regimens. There are many DAAs that are currently in development or have recently been approved, which target different nonstructural HCV proteins and host targets that are essential for HCV replication. This review will focus on the different classes of DAAs and the various combinations that are in advanced development for the treatment of chronic HCV infection and will focus on the different regimens in specific patient populations.
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Affiliation(s)
- Jacinta A Holmes
- Department of Gastroenterology, St Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria, Australia
| | - Alexander J Thompson
- Department of Gastroenterology, St Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria, Australia
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Abstract
HIV Attachment. In this cross section, HIV is shown at the top and a target cell is shown at the bottom in blues. HIV envelope protein (A) has bound to the receptor CD4 (B) and then to coreceptor CCR5 (C), causing a change in conformation that inserts fusion peptides into the cellular membrane Antiretroviral therapy changed the face of HIV/AIDS from that of soon and certain death to that of a chronic disease in the years following introduction of highly active antiretroviral therapy in 1995-1996 (initially termed HAART, but now most often abbreviated to ART since not all combinations of regimens are equally active). Since then, many new agents have been developed and introduced in response to problems of resistance, toxicity, and tolerability, and great advances have been achieved in accessibility of HIV drugs in resource-poor global regions. Potential challenges that providers of HIV therapy will face in the coming decade include continuing problems with resistance, especially where access to drugs is inconsistent, determining how best to combine new and existing agents, defining the role of preventive treatment (pre-exposure prophylaxis or PrEP), and evaluating the potential of strategies for cure in some populations.
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