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Magri A, Manfredi GF, Smirne C, Pigni S, Burlone ME, Bellan M, Vercellino N, Minisini R, Pirisi M. Impact of Age and Sex on Viral Load in Hepatitis C Virus Infection. Viruses 2024; 17:21. [PMID: 39861810 PMCID: PMC11769058 DOI: 10.3390/v17010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/27/2025] Open
Abstract
The determinants of hepatitis C virus (HCV) viral load remain incompletely understood and may differ in females, who are relatively protected from the consequences of HCV infection during their reproductive years. We aimed to evaluate how age affects the relationship between sex and viral load. n = 922 patients (males n = 497, median age 62 years), all naïve to direct antiviral agents, were studied. Females were older (median age 68 vs. 57, p < 0.001) and had a higher prevalence of genotype 2 (33% vs. 20%, p < 0.001) than males; there was no difference between sexes regarding the METAVIR stage. The median HCV RNA concentration was 1.017 × 106 IU/mL (interquartile range, 0.286-2.400). Among males, the METAVIR stage was the strongest independent predictor of a high viral load (defined as the highest two quartiles), with advanced stages inversely associated with viral load (p = 0.008). In females, age was the only independent predictor, with women aged ≥55 years exhibiting higher loads (p = 0.009). These findings are consistent with data showing that estrogens exert an antiviral effect in in vitro models of HCV. Their declining levels after the menopause may explain the "catch-up" phase of HCV-related liver disease, observed in older women.
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Affiliation(s)
- Andrea Magri
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7JT, UK
| | - Giulia Francesca Manfredi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Silvia Pigni
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Michela Emma Burlone
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
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2
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Rana U, Driedger M, Sereda P, Pan S, Ding E, Wong A, Walmsley S, Klein M, Kelly D, Loutfy M, Thomas R, Sanche S, Kroch A, Machouf N, Roy-Gagnon MH, Hogg R, Cooper CL. Clinical and demographic predictors of antiretroviral efficacy in HIV-HBV co-infected patients. JOURNAL OF THE ASSOCIATION OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASE CANADA = JOURNAL OFFICIEL DE L'ASSOCIATION POUR LA MICROBIOLOGIE MEDICALE ET L'INFECTIOLOGIE CANADA 2021; 6:137-148. [PMID: 36341035 PMCID: PMC9608701 DOI: 10.3138/jammi-2020-0011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 10/22/2020] [Indexed: 06/16/2023]
Abstract
BACKGROUND The clinical and demographic characteristics that predict antiretroviral efficacy among patients co-infected with HIV and hepatitis B virus (HBV) remain poorly defined. We evaluated HIV virological suppression and rebound in a cohort of HIV-HBV co-infected patients initiated on antiretroviral therapy. METHODS A retrospective cohort analysis was performed with Canadian Observation Cohort Collaboration data. Cox proportional hazards models were used to determine the factors associated with time to virological suppression and time to virological rebound. RESULTS HBV status was available for 2,419 participants. A total of 8% were HBV co-infected, of whom 95% achieved virological suppression. After virological suppression, 29% of HIV-HBV co-infected participants experienced HIV virological rebound. HBV co-infection itself did not predict virological suppression or rebound risk. The rate of virological suppression was lower among patients with a history of injection drug use or baseline CD4 cell counts of <199 cells per cubic millimetre. Low baseline HIV RNA and men-who-have-sex-with-men status were significantly associated with a higher rate of virological suppression. Injection drug use and non-White race predicted viral rebound. CONCLUSIONS HBV co-infected HIV patients achieve similar antiretroviral outcomes as those living with HIV mono-infection. Equitable treatment outcomes may be approached by targeting resources to key subpopulations living with HIV-HBV co-infection.
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Affiliation(s)
- Urvi Rana
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States
| | - Matt Driedger
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Paul Sereda
- BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Shenyi Pan
- BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Erin Ding
- BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Alex Wong
- Regina Qu’Appelle Health Region, Regina, Saskatchewan, Canada
| | | | - Marina Klein
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Deborah Kelly
- Memorial University of Newfoundland, Saint John’s, Newfoundland, Canada
| | - Mona Loutfy
- Maple Leaf Medical Clinic, Toronto, Ontario, Canada
| | - Rejean Thomas
- Clinique Medicale l’Actuel, Montreal, Quebec, Canada
| | - Stephen Sanche
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Abigail Kroch
- Ontario HIV Treatment Network, Toronto, Ontario, Canada
| | - Nima Machouf
- Clinique de Médicine Urbaine du Quartier Latin, Montreal, Quebec, Canada
| | | | - Robert Hogg
- BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
- Simon Fraser University, Burnaby, British Columbia, Canada
| | - Curtis L Cooper
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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3
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Prevalence of Hepatitis C Virus Infection in a Surgical Population of Southeast China: A Large-Scale Multicenter Study. Can J Gastroenterol Hepatol 2020; 2020:8219536. [PMID: 32377514 PMCID: PMC7180502 DOI: 10.1155/2020/8219536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 01/30/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Chronic HCV infection affects 80 million people globally and may progress to advanced liver disease. The present study aims to investigate the present epidemiology of HCV infection in a southeastern Chinese surgical patient cohort. METHODS Blood samples obtained from 78,484 surgical patients from 18 different city and county hospitals were enrolled. The incidence of serum HCV antibody positivity, HCV RNA load, and HCV genotyping, as well as demographics and relevant clinical history, were investigated. Data were stratified using the multistage cluster random sampling method and further analyzed using the SPSS-20 package. RESULTS HCV antibody positivity was detected in 0.15% of the population (95% confidence interval (CI): 0.12%-0.18%). Genotype 1b (55.74%) was the dominant type. The HCV infection peaked in the age groups of 16-20, 41-50, and 61-65 years, and it was higher in males than in females (0.19% vs. 0.13%, P < 0.05). The geographical distribution of infection rates differed: 0.19% (95% CI: 0.14%-0.24%), 0.18% (95% CI: 0.13%-0.23%), and 0.06% (95% CI: 0.03-0.09%) in plain areas, islands, and valley regions, respectively. Patients with transfusion history and urban residence were associated with high HCV RNA levels (adjusted odds ratio = 11.24 and 6.20, P < 0.05). CONCLUSION The prevalence of HCV infection in this cohort from southeast China was 0.17%, which is lower than the reported 0.43% infection rate in China in 2006. This result can be (partially) explained by the improvement of blood donor screening and the successful campaign for the use of disposable syringes and needles.
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4
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Sridhar S, Yip CCY, Chew NFS, Wu S, Leung KH, Chan JFW, Cheng VCC, Yuen KY. Epidemiological and Clinical Characteristics of Human Hepegivirus 1 Infection in Patients With Hepatitis C. Open Forum Infect Dis 2019; 6:ofz329. [PMID: 31660385 PMCID: PMC6735942 DOI: 10.1093/ofid/ofz329] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 07/11/2019] [Indexed: 12/13/2022] Open
Abstract
Background Transmission of human hepegivirus 1 (HHpgV-1), a novel human pegivirus, is closely associated with hepatitis C virus (HCV). The impact of HHpgV-1 viremia on HCV infection is unknown. This study aimed to (a) evaluate the impact of HHpgV-1 viremia on HCV viral load and liver injury and (b) elucidate the clinical and molecular epidemiology of HHpgV-1 infection. Methods Individuals with HHpgV-1 viremia (cases) were identified by screening plasma from 655 HCV-infected adults. HHpgV-1 isolates were sequenced for phylogenetic analysis, and viral load was quantified. Cases were age- and sex-matched to HCV-infected individuals without HHpgV-1 viremia (controls) in a 1:3 ratio. A retrospective case–control analysis was performed to identify differences in HCV viral load and parameters of liver injury. Results Among HCV-infected adults, 16/655 (2.4%) had HHpgV-1 viremia. Risk groups for HHpgV-1 infection included intravenous drug users, blood product recipients, tattoo recipients, and men who have sex with men. Viral sequences clustered into 2 distinct HHpgV-1 genogroups. Cases had a higher mean HCV viral load than controls, with difference between means of 0.58 log10 IU/mL (P = .009). Cases were more likely to have an HCV viral load >5 log10 IU/mL (P = .028). Multiple regression demonstrated the impact of HHpgV-1 viral load and infection status on HCV viral load. HHpgV-1 infection was not associated with higher liver function tests, fibrosis scores, or imaging abnormalities. Conclusions HHpgV-1 viremia is associated with a higher HCV viral load in co-infected patients. HHpgV-1 infection does not affect progression of HCV-related liver disease.
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Affiliation(s)
- Siddharth Sridhar
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong - Shenzhen Hospital, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong
| | - Cyril C Y Yip
- Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Nicholas F S Chew
- Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Shusheng Wu
- Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Kit-Hang Leung
- Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Jasper F W Chan
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong - Shenzhen Hospital, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong
| | - Vincent C C Cheng
- Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Kwok-Yung Yuen
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong - Shenzhen Hospital, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong.,The Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong
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5
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Nijmeijer BM, Sarrami‐Forooshani R, Steba GS, Schreurs RRCE, Koekkoek SM, Molenkamp R, Schinkel J, Reiss P, Siegenbeek van Heukelom ML, van der Valk M, Ribeiro CMS, Geijtenbeek TBH. HIV-1 exposure and immune activation enhance sexual transmission of Hepatitis C virus by primary Langerhans cells. J Int AIDS Soc 2019; 22:e25268. [PMID: 30932366 PMCID: PMC6442005 DOI: 10.1002/jia2.25268] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 03/05/2019] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION The significant rise in incidence of Hepatitis C virus (HCV) infection among men-who-have-sex-with-men (MSM) living with HIV-1 suggests that HCV under specific circumstances is transmitted via sexual contact. During sexual transmission HCV has to cross the epithelial barrier to either directly enter the blood stream or indirectly via mucosal immune cells. However, the mechanisms of sexual transmission of HCV remain unclear. We investigated the role of Langerhans cells (LCs) in HCV susceptibility during sexual contact as LCs are among the first cells in mucosal tissues to encounter invading viruses. METHODS We investigated the phenotype of primary LCs in anal biopsies from MSM living with HIV-1. To investigate the role of primary LCs in HCV infection and transmission, we have used both isolated primary skin LCs and the ex vivo tissue transmission model. RESULTS Our data identified an important role for mucosal LCs in facilitating HCV transmission after HIV-1 exposure or immune activation. LCs were detected within mucosal anal tissues obtained from HIV-1 positive MSM biopsies. In order to perform functional studies, we used primary LCs from skin, which have a similar phenotype as mucosal LCs. Immature LCs were neither infected nor transmitted HCV to hepatocytes. Notably, exposure to HIV-1 significantly increased HCV transmission by LCs in the ex vivo transmission model. HIV-1 replication was crucial for the increased HCV transmission as HIV-1 inhibitors significantly reduced HIV-1-induced HCV transmission. Moreover, tissue immune activation of LCs also increased HCV transmission to target cells. CONCLUSIONS Thus, our data strongly indicate that HIV-1 or immune activation in MSM leads to capture of HCV by mucosal LCs, which might facilitate transmission to other cells or allow entry of HCV into the blood. This novel transmission mechanism by LCs also implicates that the activation state of LCs is an important cellular determinant for HCV susceptibility after sexual contact.
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Affiliation(s)
- Bernadien M Nijmeijer
- Department of Experimental ImmunologyAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Ramin Sarrami‐Forooshani
- Department of Experimental ImmunologyAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Gaby S Steba
- Department of Medical MicrobiologyClinical Virology LaboratoryAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Renée RCE Schreurs
- Department of Experimental ImmunologyAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Sylvie M Koekkoek
- Department of Medical MicrobiologyClinical Virology LaboratoryAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Richard Molenkamp
- Department of Medical MicrobiologyClinical Virology LaboratoryAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Janke Schinkel
- Department of Medical MicrobiologyClinical Virology LaboratoryAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Peter Reiss
- Department of Global HealthAmsterdam University Medical Centers, and Amsterdam Institute for Global Health and DevelopmentAmsterdam University Medical Centers HIV Monitoring FoundationAmsterdamThe Netherlands
- Division of Infectious DiseasesDepartment of Internal MedicineAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Matthijs L Siegenbeek van Heukelom
- Division of Infectious DiseasesDepartment of Internal MedicineAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
- Department of DermatologyAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Marc van der Valk
- Division of Infectious DiseasesDepartment of Internal MedicineAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Carla MS Ribeiro
- Department of Experimental ImmunologyAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Teunis BH Geijtenbeek
- Department of Experimental ImmunologyAmsterdam Infection and Immunity InstituteAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
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6
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MacGregor L, Martin NK, Mukandavire C, Hickson F, Weatherburn P, Hickman M, Vickerman P. Behavioural, not biological, factors drive the HCV epidemic among HIV-positive MSM: HCV and HIV modelling analysis including HCV treatment-as-prevention impact. Int J Epidemiol 2018; 46:1582-1592. [PMID: 28605503 DOI: 10.1093/ije/dyx075] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2017] [Indexed: 02/05/2023] Open
Abstract
Background Uncertainty surrounds why hepatitis C virus (HCV) is concentrated among HIV-positive men who have sex with men (MSM). We used mathematical modelling to explore reasons for these infection patterns, and implications for HCV treatment-as-prevention. Methods Using a joint MSM HIV/HCV transmission model parameterized with UK behavioural data, we considered how biological (heightened HCV infectivity and reduced spontaneous clearance among HIV-positive MSM) and/or behavioural factors (preferential sexual mixing by HIV status and risk heterogeneity) could concentrate HCV infection in HIV-positive MSM as commonly observed (5-20 times the HCV prevalence in HIV-negative MSM; defined as the HCV ratio). We explored how HCV treatment-as-prevention impact varies under differing HCV ratios. Results Biological factors produced low HCV ratios (< 3), not explaining the skewed epidemic. However, combining preferential mixing by HIV status with sexual risk behaviour heterogeneity produced high HCV ratios (> 10) that were highly sensitive to both factors. Irrespective of the HCV ratio or behavioural/biological factors, HCV treatment of HIV-diagnosed MSM markedly reduced the HCV prevalence among HIV-positive MSM, but less impact was achieved among all MSM for lower HCV ratios. Conclusions Sexual behaviour patterns likely drive observed HCV infection patterns among HIV-positive MSM. Changes in these patterns could disseminate HCV amongst HIV-negative MSM, limiting the impact of targeting HCV treatment to HIV-diagnosed MSM.
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Affiliation(s)
- Louis MacGregor
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Natasha K Martin
- School of Social and Community Medicine, University of Bristol, Bristol, UK.,Division of Global Public Health, University of California San Diego, La Jolla, CA, UK
| | | | - Ford Hickson
- London School of Hygiene and Tropical Medicine, London, UK
| | | | - Matthew Hickman
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Peter Vickerman
- School of Social and Community Medicine, University of Bristol, Bristol, UK
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7
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Abstract
HIV/hepatitis C virus (HCV) coinfection is estimated to affect 2 million individuals globally. The acceleration of HCV-associated complications, particularly hepatic fibrosis, because of HIV coinfection has been well established, whereas the impact of HCV on HIV progression remains unclear. In this review, we summarize the current evidence on the impact of coinfection on the transmission and clinical progression of each infection. We focus on the virological and immunological alterations that contribute to HIV and HCV pathogenesis in coinfection and also review the disease-modifying effects of antiretroviral therapy as they pertain to HCV.
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Abstract
Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining, but rates of cirrhosis and hepatocellular carcinoma are projected to increase. The outcome of chronic hepatitis C is variable. It is estimated that 20% to 25% will develop cirrhosis over a 25-year to 30-year period. The rate of disease progression is influenced by many host, viral, and environmental factors. Few can be modified.
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9
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Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M, Amin J, Schinkel J, Applegate T, Maher L, Hellard M, Lloyd AR, Prins M, Geskus RB, Dore GJ, Grebely J. Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study. J Viral Hepat 2015; 22:708-17. [PMID: 25580520 PMCID: PMC4496327 DOI: 10.1111/jvh.12384] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/09/2014] [Indexed: 02/06/2023]
Abstract
Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.
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Affiliation(s)
| | - Bart Grady
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Andrea L. Cox
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel Sacks-Davis
- Burnet Institute, Melbourne, VIC, Australia,Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Julie Bruneau
- CRCHUM, Université de Montréal, Montreal, QC, Canada
| | - Meghan Morris
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Janaki Amin
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | | | | | - Lisa Maher
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | - Margaret Hellard
- Burnet Institute, Melbourne, VIC, Australia,Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Andrew R. Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Maria Prins
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands,Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald B Geskus
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands,Academic Medical Center, Amsterdam, The Netherlands
| | | | - Jason Grebely
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
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10
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Heil EL, Hynicka LM, Kottilil S, Tang L. What does the pharmacological future of treating chronic hepatitis C look like? Expert Rev Clin Pharmacol 2015; 8:605-22. [PMID: 26289223 DOI: 10.1586/17512433.2015.1074859] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Development of direct acting antivirals has revolutionized the standard of care for the treatment of hepatitis C virus. New interferon-free regimens provide sustained virologic response rates of >90% in many genotype 1 patients with only 12 weeks of oral therapy. This review will provide a brief overview of current standards of care with a summary of the evidence supporting the recommended combinations of direct acting antivirals. We will discuss the direction of future therapies, with strategies for shorter durations of therapy and new all-oral combinations in the pipeline.
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Affiliation(s)
- Emily L Heil
- a 1 Department of Pharmacy, University of Maryland Medical Center, 29 S. Greene St, Room 400, Baltimore, MD 21201, USA
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11
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Treatment of hepatitis C in patients with HIV. Lancet HIV 2015; 2:e308-9. [PMID: 26423368 DOI: 10.1016/s2352-3018(15)00128-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 06/23/2015] [Indexed: 01/17/2023]
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12
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Bailey JR, Dowd KA, Snider AE, Osburn WO, Mehta SH, Kirk GD, Thomas DL, Ray SC. CD4+ T-Cell-Dependent Reduction in Hepatitis C Virus-Specific Neutralizing Antibody Responses After Coinfection With Human Immunodeficiency Virus. J Infect Dis 2015; 212:914-23. [PMID: 25754978 DOI: 10.1093/infdis/jiv139] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 02/26/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Human immunodeficiency virus (HIV) infection leads to lower rates of hepatitis C virus (HCV) clearance after acute infection, higher HCV viremia, and accelerated progression of HCV-related fibrosis. The mechanisms underlying this acceleration of HCV progression by HIV are poorly understood, but HIV-induced dysfunction in the anti-HCV humoral immune response may play a role. METHODS To define the effect of HIV coinfection on the anti-HCV antibody response, we measured anti-HCV envelope binding antibody titers, neutralizing antibody (nAb) titers, and nAb breadth of serum from HCV-infected subjects isolated longitudinally before and after incident HIV infection. RESULTS A significant reduction in HCV envelope-specific binding antibody and nAb titers was detected in subjects with CD4(+) T-cell counts <350/mm(3) after HIV infection, and subjects with CD4(+) T-cell counts <200/mm(3) also showed a reduction in nAb breadth. Subjects who maintained CD4(+) T-cell counts ≥350/mm(3) displayed little to no decline in antibody levels. CONCLUSIONS Depletion of CD4(+) T cells by HIV infection results in a global decline in the anti-HCV envelope antibody response, including binding antibody titers, nAb titers, and nAb breadth.
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Affiliation(s)
| | - Kimberly A Dowd
- Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Anna E Snider
- Division of Infectious Diseases, Department of Medicine
| | | | - Shruti H Mehta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
| | - Gregory D Kirk
- Division of Infectious Diseases, Department of Medicine Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
| | | | - Stuart C Ray
- Division of Infectious Diseases, Department of Medicine Department of Oncology, Johns Hopkins University School of Medicine
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13
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Grady BPX, Prins M, Rebers S, Molenkamp R, Geskus RB, Schinkel J. BMI, male sex and IL28B genotype associated with persistently high hepatitis C virus RNA levels among chronically infected drug users up to 23 years following seroconversion. J Viral Hepat 2015; 22:263-71. [PMID: 25174990 DOI: 10.1111/jvh.12303] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 07/16/2014] [Indexed: 01/06/2023]
Abstract
The natural course of serum HCV RNA levels during chronic infection remains unclear. We investigated HCV RNA levels and factors associated with HCV RNA levels for the entire course from HCV seroconversion. We measured HCV RNA levels of 54 HCV seroconverters from the Amsterdam Cohort Studies among drug users at yearly intervals up to 23 years using bDNA (VERSANT 3.0, lower limit of detection 615 IU/mL). Samples below the cut-off of the assay were tested by TMA (Siemens VERSANT, detection limit 5 IU/mL). We used a latent class linear mixed model to examine the HCV RNA patterns and factors associated with HCV RNA levels. The median follow-up time was 10.8 years (IQR 6.5-14.9). We found two distinct HCV RNA patterns characterized by 45/54 cases and 9/54 cases. In multivariable analyses, HCV RNA levels were 0.41 log(10) IU/mL (95% confidence interval (CI) 0.06-0.75) higher for males as compared to females. Individuals with the IL28B CC genotype had 0.40 log(10) IU/mL (95% 0.08-0.73) higher HCV RNA levels than individuals with IL28B CT/TT genotypes. Body mass index (BMI) was associated with higher HCV RNA levels, 0.055 log(10) IU/mL per BMI point (95% CI 0.027-0.083). In this unique study, which examines the HCV RNA patterns over an extended period and following seroconversion, male sex, IL28B CC genotype and BMI were independently associated with higher average HCV RNA levels. These results contribute to defining the natural history of HCV infection and could play an important part in clinical decision-making.
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Affiliation(s)
- B P X Grady
- Cluster of Infectious Diseases, Department of Research, Amsterdam Public Health Service, Amsterdam, The Netherlands; Center of Infectious Diseases and Immunology Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands
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14
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Wu JQ, Saksena MM, Soriano V, Vispo E, Saksena NK. Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection identified by transcriptome profiling of PBMCs. Virol J 2015; 12:4. [PMID: 25623235 PMCID: PMC4312599 DOI: 10.1186/s12985-014-0236-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 12/30/2014] [Indexed: 01/01/2023] Open
Abstract
Background Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono- and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups. Methods Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono- and co-infection. Results Forty-one, 262, and 44 DEGs with fold change > 1.5 and FDR (false discovery rate) <0.05 for the comparisons of HCV versus co-infection, HIV versus co-infection, and HIV versus HCV were identified, respectively. Significantly altered pathways (FDR < 0.05), featured by those involved in immune system, signaling transduction, and cell cycle, were detected. Notably, the differential regulation of cytotoxicity pathway discriminated between HIV, HCV mono- and co-infection (up-regulated in the former versus the latter group: co-infection versus HIV or HCV, HIV versus HCV; FDR <0.001 ~ 0.019). Conversely, the cytokine-cytokine receptor interaction pathway was down-regulated in co-infection versus either HCV (FDR = 0.003) or HIV (FDR = 0.028). For the comparison of HIV versus HCV, the cell cycle (FDR = 0.016) and WNT signaling (FDR = 0.006) pathways were up- and down-regulated in HIV, respectively. Conclusions Our study is the first to identify the differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection, which may reflect the distinct patterns of virus-host cell interactions underlying disease progression. Further inspection of cytotoxicity pathway has pinned down to the expression of the KIR genes to be associated with specific patterns of particular virus-host interactions. Between HIV and HCV, the altered cell cycle and WNT signaling pathways may suggest the different impact of HIV and HCV on cell proliferation and differentiation. Electronic supplementary material The online version of this article (doi:10.1186/s12985-014-0236-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jing Qin Wu
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, Newcastle, NSW, 2308, Australia.
| | - Monica Miranda Saksena
- Herpes Virus Pathogenesis Lab, Center for Virus Research, Westmead Millennium Institute, University of Sydney, Westmead, Sydney, NSW, 2145, Australia.
| | - Vincent Soriano
- Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029, Madrid, Spain.
| | - Eugenia Vispo
- Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029, Madrid, Spain.
| | - Nitin K Saksena
- Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute & Westmead Hospital, University of Sydney, Westmead, Sydney, NSW, 2145, Australia.
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15
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Jacka B, Applegate T, Krajden M, Olmstead A, Harrigan PR, Marshall BDL, DeBeck K, Milloy MJ, Lamoury F, Pybus OG, Lima VD, Magiorkinis G, Montoya V, Montaner J, Joy J, Woods C, Dobrer S, Dore GJ, Poon AF, Grebely J. Phylogenetic clustering of hepatitis C virus among people who inject drugs in Vancouver, Canada. Hepatology 2014; 60:1571-1580. [PMID: 25042607 PMCID: PMC4211947 DOI: 10.1002/hep.27310] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 07/08/2014] [Indexed: 12/20/2022]
Abstract
UNLABELLED Little is known about factors associated with hepatitis C virus (HCV) transmission among people who inject drugs (PWID). Phylogenetic clustering and associated factors were evaluated among PWID in Vancouver, Canada. Data were derived from the Vancouver Injection Drug Users Study. Participants who were HCV antibody-positive at enrolment and those with HCV antibody seroconversion during follow-up (1996 to 2012) were tested for HCV RNA and sequenced (Core-E2 region). Phylogenetic trees were inferred using maximum likelihood analysis and clusters were identified using ClusterPicker (90% bootstrap threshold, 0.05 genetic distance threshold). Factors associated with clustering were assessed using logistic regression. Among 655 eligible participants, HCV genotype prevalence was: G1a: 48% (n=313), G1b: 6% (n=41), G2a: 3% (n=20), G2b: 7% (n=46), G3a: 33% (n=213), G4a: <1% (n=4), G6a: 1% (n=8), G6e: <1% (n=1), and unclassifiable: 1% (n=9). The mean age was 36 years, 162 (25%) were female, and 164 (25%) were HIV+. Among 501 participants with HCV G1a and G3a, 31% (n=156) were in a pair/cluster. Factors independently associated with phylogenetic clustering included: age <40 (versus age≥40, adjusted odds ratio [AOR]=1.64; 95% confidence interval [CI] 1.03, 2.63), human immunodeficiency virus (HIV) infection (AOR=1.82; 95% CI 1.18, 2.81), HCV seroconversion (AOR=3.05; 95% CI 1.40, 6.66), and recent syringe borrowing (AOR 1.59; 95% CI 1.07, 2.36). CONCLUSION In this sample of PWID, one-third demonstrated phylogenetic clustering. Factors independently associated with phylogenetic clustering included younger age, recent HCV seroconversion, prevalent HIV infection, and recent syringe borrowing. Strategies to enhance the delivery of prevention and/or treatment strategies to those with HIV and recent HCV seroconversion should be explored, given an increased likelihood of HCV transmission in these subpopulations.
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Affiliation(s)
- B Jacka
- Viral Hepatitis Clinical Research Program, The Kirby Institute,
UNSW Australia, Sydney NSW, Australia
| | - T Applegate
- Viral Hepatitis Clinical Research Program, The Kirby Institute,
UNSW Australia, Sydney NSW, Australia
| | - M Krajden
- BC Centre for Disease Control, Vancouver BC
| | - A Olmstead
- BC Centre for Disease Control, Vancouver BC
| | - PR Harrigan
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC
| | - BDL Marshall
- Department of Epidemiology, Brown University, Providence, RI,
USA
| | - K DeBeck
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC,School of Public Policy, Simon Fraser University, Vancouver, BC,
Canada
| | - M-J Milloy
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC,Department of Family Practice, Faculty of Medicine, University of
British Columbia, Vancouver, BC
| | - F Lamoury
- Viral Hepatitis Clinical Research Program, The Kirby Institute,
UNSW Australia, Sydney NSW, Australia
| | - OG Pybus
- Department of Zoology, University of Oxford
| | - VD Lima
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC,Division of AIDS, Department of Medicine, Faculty of Medicine,
University of British Columbia, Vancouver, BC, Canada
| | - G Magiorkinis
- Department of Zoology, University of Oxford,Virus Reference Department, Public Health England, London,
UK
| | - V Montoya
- BC Centre for Disease Control, Vancouver BC
| | - J Montaner
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC,Division of AIDS, Department of Medicine, Faculty of Medicine,
University of British Columbia, Vancouver, BC, Canada
| | - J Joy
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC
| | - C Woods
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC
| | - S Dobrer
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC
| | - GJ Dore
- Viral Hepatitis Clinical Research Program, The Kirby Institute,
UNSW Australia, Sydney NSW, Australia
| | - AF Poon
- BC Centre for Excellence in HIV/AIDS, St Paul's Hospital,
Vancouver BC
| | - J Grebely
- Viral Hepatitis Clinical Research Program, The Kirby Institute,
UNSW Australia, Sydney NSW, Australia
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16
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Genome-wide mRNA and miRNA analysis of peripheral blood mononuclear cells (PBMC) reveals different miRNAs regulating HIV/HCV co-infection. Virology 2014; 450-451:336-49. [PMID: 24503097 DOI: 10.1016/j.virol.2013.12.026] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 10/24/2013] [Accepted: 12/19/2013] [Indexed: 12/12/2022]
Abstract
Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common due to shared transmission routes. The genomic basis of HIV/HCV co-infection and its regulation by microRNA (miRNA) is unknown. Therefore, our objective was to investigate genome-wide mRNA expression and its regulation by miRNA in primary PBMCs derived from 27 patients (5 HCV - mono-infected, 5 HIV-mono-infected, 12 HCV/HIV co-infected, and 5 healthy controls). This revealed 27 miRNAs and 476 mRNAs as differentially expressed (DE) in HCV/HIV co-infection when compared to controls (adj p<0.05). Our study shows the first evidence of miRNAs specific for co-infection, several of which are correlated with key gene targets demonstrating functional relationships to pathways in cancer, immune-function, and metabolism. Notable was the up regulation of HCV-specific miR-122 in co-infection (FC>50, p=4.02E-06), which may have clinical/biological implications.
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17
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Abstract
The hepatitis C virus (HCV) is a spherical enveloped RNA virus of the Flaviviridae family, classified within the Hepacivirus genus. Since its discovery in 1989, HCV has been recognized as a major cause of chronic hepatitis and hepatic fibrosis that progresses in some patients to cirrhosis and hepatocellular carcinoma. In the United States, approximately 4 million people have been infected with HCV, and 10,000 HCVrelated deaths occur each year. Due to shared routes of transmission, HCV and HIV co-infection are common, affecting approximately one third of all HIV-infected persons in the United States. In addition, HIV co-infection is associated with higher HCV RNA viral load and a more rapid progression of HCV-related liver disease, leading to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons because the incidence of infection is increased and the natural history of HCV infection is accelerated in co-infected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed among HIV/HCV co-infected individuals.
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Affiliation(s)
- Mark S Sulkowski
- Division of Infectious Diseases, Johns Hopkins Medical Institutions, 1830 East Monument Street, Room 319, 21287-0003, Baltimore, MD, USA,
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18
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Longitudinal changes in viral RNA concentration in patients with chronic hepatitis C and/or HIV infection in the absence of antiviral therapy. J Clin Virol 2013; 58:391-5. [DOI: 10.1016/j.jcv.2013.06.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 06/20/2013] [Accepted: 06/24/2013] [Indexed: 11/22/2022]
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19
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Rodríguez-Torres M. Challenges in the treatment of chronic hepatitis C in the HIV/HCV-coinfected patient. Expert Rev Anti Infect Ther 2013. [PMID: 23199398 DOI: 10.1586/eri.12.107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) and HIV are common coinfections that convey a shortened lifespan, mostly related to liver disease. Treatment against HCV in the coinfected patient is notoriously more complex and challenging. There are no optimal treatment algorithms for HIV/HCV coinfected patients as efficacy of approved anti-HCV therapies is low with relevant side effects. The use of direct-acting antivirals for anti-HCV therapy has the potential to improve therapeutic efficacy, but also increase side effects and drug-drug interactions. In spite of all of this, the most important and significant fact is that chronic hepatitis C is potentially curable, and the eradication of the HCV infection is a crucial outcome in this population. The establishment of a productive collaboration among the regulatory agencies, the medical community and the pharmaceutical industry could lead to faster access to more effective HCV therapies for the coinfected patient and eventually stop the progression of liver disease in these patients.
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20
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Focus on drug interactions: the challenge of treating hepatitis C virus infection with direct-acting antiviral drugs in the HIV-positive patient. Curr Opin Infect Dis 2013; 26:50-7. [PMID: 23242341 DOI: 10.1097/qco.0b013e32835c2027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE OF REVIEW Successful treatment of hepatitis C virus (HCV) infection is necessary for the survival of HIV-infected patients. This review covers the outcomes of current therapy, first-generation HCV direct-acting antivirals (DAAs) and their drug-to-drug interactions (DDIs). Understanding DDIs between HIV antiretroviral therapy (ART) and the DAAs in development is important to assure the best management of the HIV/HCV coinfected individuals. RECENT FINDINGS The two first-in-class DAAs were approved for clinical use in 2011. The first trials with boceprevir or telaprevir added to standard therapy in HIV/HCV coinfected patients revealed triple therapy to be efficacious with significantly improved sustained virological response rates. However, these DAAs were associated with more and worse adverse effects, as well as with significant DDIs with multiple drugs, including ART. Early data on DAAs in development suggest improved efficacy and safety and the potential for lesser DDIs. SUMMARY Anti-HCV therapy is fundamental in coinfected patients, but the approved therapies are suboptimal. The first-generation of approved HCV DAAs improved efficacy of therapy in coinfected patients, but have multiple safety concerns, including potentially serious drug interactions with ART. Early results from newer DAAs are promising.
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21
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Kirk GD, Mehta SH, Astemborski J, Galai N, Washington J, Higgins Y, Balagopal A, Thomas DL. HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. Ann Intern Med 2013; 158:658-66. [PMID: 23440167 PMCID: PMC3708651 DOI: 10.7326/0003-4819-158-9-201305070-00604] [Citation(s) in RCA: 139] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown. OBJECTIVE To investigate whether persons with HIV infection develop hepatitis C virus (HCV)-related liver disease at younger ages than similar persons without HIV. DESIGN Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol. SETTING Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study. PARTICIPANTS 1176 current and former injection drug users with antibodies to HCV. MEASUREMENTS Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels. RESULTS Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older. LIMITATION The process of liver fibrosis began before the study in most persons. CONCLUSION In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older. PRIMARY FUNDING SOURCE National Institute on Drug Abuse.
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Affiliation(s)
- Gregory D Kirk
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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22
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Parikh N, Nonnemacher MR, Pirrone V, Block T, Mehta A, Wigdahl B. Substance abuse, HIV-1 and hepatitis. Curr HIV Res 2013; 10:557-71. [PMID: 22973853 DOI: 10.2174/157016212803306023] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 07/16/2012] [Accepted: 09/05/2012] [Indexed: 02/06/2023]
Abstract
During the course of human immunodeficiency virus type 1 (HIV-1) disease, the virus has been shown to effectively escape the immune response with the subsequent establishment of latent viral reservoirs in specific cell populations within the peripheral blood (PB) and associated lymphoid tissues, bone marrow (BM), brain, and potentially other end organs. HIV-1, along with hepatitis B and C viruses (HBV and HCV), are known to share similar routes of transmission, including intravenous drug use, blood transfusions, sexual intercourse, and perinatal exposure. Substance abuse, including the use of opioids and cocaine, is a significant risk factor for exposure to HIV-1 and the development of acquired immune deficiency syndrome, as well as HBV and HCV exposure, infection, and disease. Thus, coinfection with HIV-1 and HBV or HCV is common and may be impacted by chronic substance abuse during the course of disease. HIV- 1 impacts the natural course of HBV and HCV infection by accelerating the progression of HBV/HCV-associated liver disease toward end-stage cirrhosis and quantitative depletion of the CD4+ T-cell compartment. HBV or HCV coinfection with HIV-1 is also associated with increased mortality when compared to either infection alone. This review focuses on the impact of substance abuse and coinfection with HBV and HCV in the PB, BM, and brain on the HIV-1 pathogenic process as it relates to viral pathogenesis, disease progression, and the associated immune response during the course of this complex interplay. The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point.
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Affiliation(s)
- Nirzari Parikh
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
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23
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Grint D, Peters L, Reekie J, Soriano V, Kirk O, Knysz B, Suetnov O, Lazzarin A, Ledergerber B, Rockstroh JK, Mocroft A. Stability of hepatitis C virus (HCV) RNA levels among interferon-naïve HIV/HCV-coinfected individuals treated with combination antiretroviral therapy. HIV Med 2013; 14:370-8. [PMID: 23534815 DOI: 10.1111/hiv.12033] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Infection with hepatitis C virus (HCV) is a major cause of chronic liver disease. High HCV RNA levels have been associated with poor treatment response. This study aimed to examine the natural history of HCV RNA in chronically HCV/HIV-coinfected individuals. METHODS Mixed models were used to analyse the natural history of HCV RNA changes over time in HIV-positive patients with chronic HCV infection. RESULTS A total of 1541 individuals, predominantly White (91%), male (73%), from southern (35%) and western central Europe (23%) and with HCV genotype 1 (58%), were included in the analysis. The median follow-up time was 5.0 years [interquartile range (IQR) 2.8 to 8.3 years]. Among patients not on combination antiretroviral therapy (cART), HCV RNA levels increased by a mean 27.6% per year [95% confidence interval (CI) 6.1-53.5%; P = 0.0098]. Among patients receiving cART, HCV RNA levels were stable, increasing by a mean 2.6% per year (95% CI -1.1 to 6.5%; P = 0.17). Baseline HCV RNA levels were 25.5% higher (95% CI 8.8 to 39.1%; P = 0.0044) in individuals with HCV genotype 1 compared with HCV genotypes 2, 3 and 4. A 1 log HIV-1 RNA copies/mL increase in HIV RNA was associated with a 10.9% increase (95% CI 2.3 to 20.2%; P = 0.012) in HCV RNA. CONCLUSIONS While HCV RNA levels increased significantly in patients prior to receiving cART, among those treated with cART HCV RNA levels remained stable over time.
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Affiliation(s)
- D Grint
- HIV Epidemiology & Biostatistics Group, Research Department of Infection and Population Health, University College London-Royal Free Campus, London, UK.
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24
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Scaggiante R, Chemello L, Rinaldi R, Bartolucci GB, Trevisan A. Acute hepatitis C virus infection in a nurse trainee following a needlestick injury. World J Gastroenterol 2013; 19:581-5. [PMID: 23382640 PMCID: PMC3558585 DOI: 10.3748/wjg.v19.i4.581] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 07/31/2012] [Accepted: 08/08/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection after biological accident (needlestick injury) is a rare event. This report describes the first case of acute HCV infection after a needlestick injury in a female nursing student at Padua University Hospital. The student nurse was injured on the second finger of the right hand when recapping a 23-gauge needle after taking a blood sample. The patient who was the source was a 72-year-old female with weakly positive anti-HCV test results. Three months after the injury, at the second step of follow-up, a relevant increase in transaminases with a low viral replication activity (350 IU/mL) was observed in the student, indicating HCV infection. The patient tested positive for the same genotype (1b) of HCV as the injured student. A rapid decline in transaminases, which was not accompanied by viral clearance, and persistently positive HCV-RNA was described 1 mo later. Six months after testing positive for HCV, the student was treated with pegylated interferon plus ribavirin for 24 wk. A rapid virological response was observed after 4 wk of treatment, and a sustained virological response (SVR) was evident 6 mo after therapy withdrawal, confirming that the patient was definitively cured. Despite the favourable IL28B gene (rs12979860) CC- polymorphism observed in the patient, which is usually predictive of a spontaneous clearance and SVR, spontaneous viral clearance did not take place; however, infection with this genotype was promising for a sustained virological response after therapy.
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25
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Meissner EG, Suffredini AF, Kottilil S. Opportunities in proteomics to understand hepatitis C and HIV coinfection. Future Virol 2012; 7:759-765. [PMID: 23105947 PMCID: PMC3480018 DOI: 10.2217/fvl.12.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Antiretroviral therapy has significantly reduced morbidity and mortality associated with HIV infection. However, coinfection with HCV results in a more complicated disease course for both infections. HIV infection dramatically impacts the natural history of chronic liver disease due to HCV. Coinfected patients not on antiretroviral therapy for HIV develop liver fibrosis and cirrhosis at a faster rate, clear acute infection less commonly and respond to IFN-α-based therapy for chronic infection less often than HCV-monoinfected patients. The interaction between these two viruses, the immune system and the fibrotic machinery of the liver remains incompletely understood. In this review, we discuss recent advances in proteomics as applied to HCV and HIV and highlight issues in coinfection that are amenable to further discovery through proteomic approaches. We focus on clinical predictors of liver fibrosis and treatment outcome as these have the greatest potential clinical applicability.
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Affiliation(s)
- Eric G Meissner
- Laboratory of Immunoregulation, National Institute of Allergy & Infectious Diseases, Bethesda, MD 20892, USA
| | - Anthony F Suffredini
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shyamasundaran Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy & Infectious Diseases, Bethesda, MD 20892, USA
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26
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Uccellini L, Tseng FC, Monaco A, Shebl FM, Pfeiffer R, Dotrang M, Buckett D, Busch MP, Wang E, Edlin BR, Marincola F, O’Brien TR. HCV RNA levels in a multiethnic cohort of injection drug users: human genetic, viral and demographic associations. Hepatology 2012; 56:86-94. [PMID: 22331649 PMCID: PMC3369001 DOI: 10.1002/hep.25652] [Citation(s) in RCA: 24] [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: 07/07/2011] [Accepted: 01/28/2012] [Indexed: 12/28/2022]
Abstract
UNLABELLED In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV enzyme immunoassay were tested for HCV viremia by a branched-chain DNA assay. HCV genotype was determined by sequencing the HCV nonstructural 5B protein region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1,701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). Human immunodeficiency virus type 1 (HIV-1) prevalence was 13.9%. The overall median HCV RNA level was 6.45 log(10) copies/mL. In unadjusted analyses, higher levels were found with older age, male gender, African-American ancestry, hepatitis B virus infection, HIV-1 infection, and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotypes 3 or 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype, and IL28B rs12979860 genotype were all independently associated with HCV RNA. CONCLUSION The level of HCV viremia is influenced by a large number of demographic, viral, and human genetic factors.
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Affiliation(s)
- Lorenzo Uccellini
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, NIH, Bethesda, Maryland
- Institute of Infectious and Tropical Diseases, University of Milan, L. Sacco Hospital, Milan, Italy
| | - Fan-Chen Tseng
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | - Alessandro Monaco
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, NIH, Bethesda, Maryland
| | - Fatma M. Shebl
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | - Ruth Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | | | - Dianna Buckett
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | - Michael P. Busch
- University of California, San Francisco, CA
- Blood Systems Research Institute, San Francisco, CA
| | - Ena Wang
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, NIH, Bethesda, Maryland
| | - Brian R. Edlin
- University of California, San Francisco, CA
- SUNY Downstate College of Medicine, Brooklyn, NY and Center for the Study of Hepatitis C, Weill Medical College of Cornell University, New York, NY
| | - Francesco Marincola
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, NIH, Bethesda, Maryland
| | - Thomas R. O’Brien
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
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Neukam K, García-Rey S, Cifuentes C, Macías J, Mira JA, Vázquez MJ, Parra-Sánchez M, Palomares JC, Merchante N, Di Lello FA, Pineda JA. HIV-coinfection leads to a modest increase in plasma HCV-RNA load in patients with chronic HCV infection. Antiviral Res 2012; 95:212-5. [PMID: 22750672 DOI: 10.1016/j.antiviral.2012.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 06/21/2012] [Accepted: 06/21/2012] [Indexed: 12/13/2022]
Abstract
The influence of HIV coinfection on plasma hepatitis C virus (HCV) RNA load has not been reliably evaluated. We analyzed plasma HCV RNA load in 396 HCV-monoinfected and 467 HIV/HCV-coinfected patients. Median HCV RNA concentrations (interquartile range) in HCV-monoinfected patients were 5.88 (5.3-6.2) log(10)IU/mL versus 5.96 (5.6-6.5) log(10)IU/mL in HIV/HCV-coinfected individuals (p=0.033) as determined with the Cobas Amplicor Test and 6.06 (5.4-5.7) log(10)IU/mL versus 6.3 (5.5-6.9) log(10)IU/mL (p=0.026) using the Cobas TaqMan System. The plasma HCV RNA load in patients with HIV infection and undetectable plasmatic HIV RNA was similar to that observed in HCV-monoinfected individuals [6.02 (5.45-6.61) log(10)IU/mL versus 6.01 (5.36-6.59) log(10)IU/mL, respectively (p=1.0)]. In conclusion, HIV coinfection tends to be associated with higher plasma HCV RNA load, however, the magnitude of the differences is small and this effect can be counterbalanced with antiviral therapy.
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Affiliation(s)
- Karin Neukam
- Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Avenida de Bellavista S/N, 41014 Seville, Spain
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28
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Boodram B, Hershow RC, Cotler SJ, Ouellet LJ. Chronic hepatitis C virus infection and increases in viral load in a prospective cohort of young, HIV-uninfected injection drug users. Drug Alcohol Depend 2011; 119:166-71. [PMID: 21724339 PMCID: PMC3206181 DOI: 10.1016/j.drugalcdep.2011.06.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 06/06/2011] [Accepted: 06/06/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND Chronic hepatitis C (HCV) infection, defined as persistent RNA (viral load) for at least 6 months, accounts for up to 50% of all cirrhosis, end-stage liver disease and liver cancer cases. Moreover, elevated HCV viral load is consistently associated with high infectivity and poor therapy response. This study aims to identify modifiable behavioral correlates both chronic HCV infection and increases in viral load over time among injection drug users (IDUs). METHODS Cross-sectional and longitudinal analyses were performed using self-interview and serological data from a prospective cohort study (2002-2006) among young (age 18-35), HIV-negative, HCV therapy-naïve IDUs (n=113) from metropolitan Chicago, Illinois, USA. RESULTS After adjustment for age, gender and race/ethnicity, using drugs measured or mixed in someone else's syringe (odds ratio=2.7, 95% confidence interval: 1.1, 6.7) was associated with chronic (n=75, 66%) versus resolved (n=38, 34%) HCV infection status. Among chronically-infected IDUs, injecting with a new, sterile syringe infrequently (<1/2 half the time when injecting) compared to frequently (1/2 the time or more when injecting) was associated with increases in viral load over time after adjusting for age, gender, race/ethnicity and time effects. CONCLUSIONS Reductions in risky injection-related practices among young IDUs may ameliorate both the burden of chronic HCV infection-related liver disease and elevated viral load-related poor treatment response.
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Affiliation(s)
- Basmattee Boodram
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street (M/C 923), Chicago, IL 60612, USA.
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29
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Thomas DL, Leoutsakas D, Zabransky T, Kumar MS. Hepatitis C in HIV-infected individuals: cure and control, right now. J Int AIDS Soc 2011; 14:22. [PMID: 21548988 PMCID: PMC3115833 DOI: 10.1186/1758-2652-14-22] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 05/08/2011] [Indexed: 01/25/2023] Open
Abstract
For persons living with HIV, hepatitis C is a major public health problem that must be controlled and could be eliminated. The challenge arises because the hepatitis C virus (HCV) is prevalent among HIV-infected persons in most parts of the world, because HIV worsens all HCV outcomes, and because HCV may add additional individual economic and psychosocial complications to HIV disease. Despite the major benefits of antiretroviral therapy on HIV outcomes, antiretroviral therapy is not sufficient to halt the complications of HCV. Nonetheless, HCV can be controlled at all stages, including prevention of infection and cure. Thus, HCV is an eradicable disease. There are significant inequalities worldwide in HCV control that could markedly constrain the impact of these measures.
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Affiliation(s)
| | | | - Tomas Zabransky
- Center for Addictology, Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague
| | - M Suresh Kumar
- Gaitonde Centre for AIDS Research and Education, Chennai, India
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30
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Gadalla SM, Preiss LR, Eyster ME, Goedert JJ. Correlates of high hepatitis C virus RNA load in a cohort of HIV-negative and HIV-positive individuals with haemophilia. J Viral Hepat 2011; 18:161-9. [PMID: 20337924 PMCID: PMC2929328 DOI: 10.1111/j.1365-2893.2010.01289.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Hepatitis C virus (HCV) treatment failure and disease progression are more likely with high HCV-RNA load. Correlates of high HCV-RNA load in individuals with haemophilia are largely unknown. Among 1266 interferon naïve HCV-infected individuals with haemophilia, we compared those with high (> 2 x 10⁶ HCV-RNA copies/mL) to lower viral load, overall and stratifying on HIV co-infection status using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Overall, high HCV load was independently associated with longer duration of HCV infection (P(trend)=0.0001), body mass index ≥ 25 kg/m² (OR=1.4, 95% CI=1.1-1.9), and HIV co-infection (OR=1.4, 95% CI=1.0-1.8). Among 795 HIV-negative participants, high HCV-RNA load was associated with older age at HCV acquisition (OR=1.9 for > 15 years vs ≤ 2 years, P(trend)=0.008), and lower AST/platelet ratio (P(trend)=0.01), in addition to longer duration of HCV infection (P(trend)=0.0008), and body mass index ≥ 25 kg/m² (OR=1.6, P=0.005). Among 471 HIV-positive individuals, anti-retroviral therapy (ART) was the only variable associated with high HCV-RNA load (OR=1.8, CI=1.1-2.9 for combination ART; OR=1.8, CI=0.9-3.4, for other ART vs no treatment). High HCV-RNA load with haemophilia is more likely with longer duration of infection, older age at infection, higher body mass index, and antiretroviral therapy. These findings may help identify individuals at increased risk of HCV treatment failure and progression to end-stage liver disease.
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Affiliation(s)
- Shahinaz M. Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
- Cancer Prevention Fellowship Program, National Institute of Heath, Bethesda, MD, 20892, USA
| | | | - M. Elaine Eyster
- Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - James J. Goedert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
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Abstract
The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.
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32
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Burbelo PD, Kovacs JA, Ching KH, Issa AT, Iadarola MJ, Murphy AA, Schlaak JF, Masur H, Polis MA, Kottilil S. Proteome-wide anti-hepatitis C virus (HCV) and anti-HIV antibody profiling for predicting and monitoring the response to HCV therapy in HIV-coinfected patients. J Infect Dis 2010; 202:894-8. [PMID: 20684729 PMCID: PMC2924471 DOI: 10.1086/655780] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
We quantified antibody responses to the hepatitis C virus (HCV) proteome that are associated with sustained virologic response (SVR) in human immunodeficiency virus (HIV)/HCV-coinfected patients treated with pegylated interferon and ribavirin. Analysis of pre- and posttreatment samples revealed significant decreases in the combined anti-core, anti-E1, and anti-NS4 HCV antibody titers in those with SVRs but not in those who experienced relapse or who did not respond. Furthermore, anti-HIV p24 antibody titers inversely correlated with treatment response. These results suggest that profiling anti-HCV antibody is useful for monitoring HCV therapy, especially in discriminating between those who experience relapse and those who have SVRs at 48 weeks.
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Affiliation(s)
- Peter D. Burbelo
- Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research
| | - Joseph A. Kovacs
- Critical Care Medicine Department, National Institutes of Health Clinical Center
| | - Kathryn H. Ching
- Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research
| | - Alexandra T. Issa
- Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research
| | - Michael J. Iadarola
- Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research
| | - Alison A Murphy
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892
| | | | - Henry Masur
- Critical Care Medicine Department, National Institutes of Health Clinical Center
| | - Michael A. Polis
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892
| | - Shyam Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892
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Liu L, Fisher BE, Dowd KA, Astemborski J, Cox AL, Ray SC. Acceleration of hepatitis C virus envelope evolution in humans is consistent with progressive humoral immune selection during the transition from acute to chronic infection. J Virol 2010; 84:5067-77. [PMID: 20200239 PMCID: PMC2863818 DOI: 10.1128/jvi.02265-09] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Accepted: 02/24/2010] [Indexed: 12/30/2022] Open
Abstract
During the transition from acute to chronic infection in individuals persistently infected with hepatitis C virus (HCV), cellular responses initiate within the first 6 months of primary infection and collapse thereafter, whereas humoral responses activate later during the chronic phase. Whether and how this deviation of immune responses specifically influences HCV evolution are unknown. To determine the pattern of HCV evolution during this critical period, we conducted extensive sequence analysis on annual clonal hemigenomic sequences for up to 3 years in six well-characterized subjects, using statistical methods that accounted for repeated measures. Significantly different evolutionary rates were observed in envelope versus nonenvelope genes, with an increasing rate of nonsynonymous change (dN) in envelope genes and a stable dN in nonenvelope genes (P = 0.006). The ratio of the envelope to nonenvelope nonsynonymous rate increased from 2 in year 1 to 5 in years 2 and 3. Centripetal changes (reversions toward matching of the worldwide subtype 1a consensus sequence) were frequently observed during the 3-year transition from acute infection to chronicity, even in the presence of neutralizing antibody (NAb) pressure. Remarkably, sequences of hypervariable region 1 (HVR1) remained stable for up to 21 months in the absence of NAb pressure in one subject, followed by rapid changes that were temporally associated with the detection of NAb responses, which strongly suggests that HVR1 evolution is shaped by NAb pressure. These data provide the first systematic estimates of HCV evolutionary rates in multiple genes during early infection in vivo and provide additional evidence for deterministic, rather than random, evolution of HCV.
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Affiliation(s)
- Lin Liu
- Division of Infectious Diseases, Department of Medicine, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21205, Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China 400038
| | - Brian E. Fisher
- Division of Infectious Diseases, Department of Medicine, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21205, Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China 400038
| | - Kimberly A. Dowd
- Division of Infectious Diseases, Department of Medicine, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21205, Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China 400038
| | - Jacquie Astemborski
- Division of Infectious Diseases, Department of Medicine, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21205, Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China 400038
| | - Andrea L. Cox
- Division of Infectious Diseases, Department of Medicine, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21205, Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China 400038
| | - Stuart C. Ray
- Division of Infectious Diseases, Department of Medicine, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21205, Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China 400038
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34
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Abstract
Hepatitis C virus (HCV) replication in infected patients produces large and diverse viral populations, which give rise to drug-resistant and immune escape variants. Here, we analyzed HCV populations during transmission and diversification in longitudinal and cross-sectional samples using 454/Roche pyrosequencing, in total analyzing 174,185 sequence reads. To sample diversity, four locations in the HCV genome were analyzed, ranging from high diversity (the envelope hypervariable region 1 [HVR1]) to almost no diversity (the 5' untranslated region [UTR]). For three longitudinal samples for which early time points were available, we found that only 1 to 4 viral variants were present, suggesting that productive infection was initiated by a very small number of HCV particles. Sequence diversity accumulated subsequently, with the 5' UTR showing almost no diversification while the envelope HVR1 showed >100 variants in some subjects. Calculation of the transmission probability for only a single variant, taking into account the measured population structure within patients, confirmed initial infection by one or a few viral particles. These findings provide the most detailed sequence-based analysis of HCV transmission bottlenecks to date. The analytical methods described here are broadly applicable to studies of viral diversity using deep sequencing.
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35
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Gonzalez VD, Landay AL, Sandberg JK. Innate immunity and chronic immune activation in HCV/HIV-1 co-infection. Clin Immunol 2010; 135:12-25. [PMID: 20100670 DOI: 10.1016/j.clim.2009.12.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2009] [Revised: 12/09/2009] [Accepted: 12/16/2009] [Indexed: 02/07/2023]
Abstract
Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host.
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Affiliation(s)
- Veronica D Gonzalez
- Center for Infection Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden
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36
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Dionne-Odom J, Osborn MK, Radziewicz H, Grakoui A, Workowski K. Acute hepatitis C and HIV coinfection. THE LANCET. INFECTIOUS DISEASES 2009; 9:775-83. [DOI: 10.1016/s1473-3099(09)70264-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Gonzalez VD, Falconer K, Blom KG, Reichard O, Mørn B, Laursen AL, Weis N, Alaeus A, Sandberg JK. High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol 2009; 83:11407-11. [PMID: 19710147 PMCID: PMC2772767 DOI: 10.1128/jvi.01211-09] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Accepted: 08/18/2009] [Indexed: 02/07/2023] Open
Abstract
Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.
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Affiliation(s)
- Veronica D. Gonzalez
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Karolin Falconer
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Kim G. Blom
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Olle Reichard
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Birgitte Mørn
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Alex Lund Laursen
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Nina Weis
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Annette Alaeus
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Johan K. Sandberg
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark, Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
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38
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Kim AY, Chung RT. Coinfection with HIV-1 and HCV--a one-two punch. Gastroenterology 2009; 137:795-814. [PMID: 19549523 PMCID: PMC3146750 DOI: 10.1053/j.gastro.2009.06.040] [Citation(s) in RCA: 133] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Revised: 05/22/2009] [Accepted: 06/13/2009] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis, and death; it is estimated that 180 million persons are infected with HCV worldwide. The consequences of HCV are worse in those who are coinfected with human immunodeficiency virus 1 (HIV-1), which is unfortunately a common scenario because of shared risk factors of the viruses. More studies into effects of HCV/HIV-1 coinfection are needed, but efforts have been hampered by limitations in our understanding of the combined pathogenesis of the 2 viruses. Gaining insight into the mechanisms that underlie the immunopathogenesis of these persistent viral infections could lead to new therapeutic strategies for patients with HCV/HIV-1 coinfection.
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Affiliation(s)
- Arthur Y Kim
- Division of Infectious Diseases and the Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
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Coinfection with hepatitis C virus and human immunodeficiency virus: virological, immunological, and clinical outcomes. J Virol 2009; 83:7366-74. [PMID: 19420073 DOI: 10.1128/jvi.00191-09] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Ciuffreda D, Comte D, Cavassini M, Giostra E, Bühler L, Perruchoud M, Heim MH, Battegay M, Genné D, Mulhaupt B, Malinverni R, Oneta C, Bernasconi E, Monnat M, Cerny A, Chuard C, Borovicka J, Mentha G, Pascual M, Gonvers JJ, Pantaleo G, Dutoit V. Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication. Eur J Immunol 2008; 38:2665-77. [PMID: 18958874 DOI: 10.1002/eji.200838336] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
HCV infection has a severe course of disease in HIV/HCV co-infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV-specific T-cell responses in 86 HCV mono-infected patients, 48 HIV/HCV co-infected patients and 42 liver transplant recipients. IFN-gamma and IL-2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV-derived peptides. We observed that HCV-specific T-cell responses were polyfunctional in HCV mono-infected patients, with presence of proliferating single IL-2-, dual IL-2/IFN-gamma and single IFN-gamma-producing CD4+ and dual IL-2/IFN-gamma and single IFN-gamma-producing CD8+ cells. In contrast, HCV-specific T-cell responses had an effector profile in HIV/HCV co-infected individuals and liver transplant recipients with absence of single IL-2-producing HCV-specific CD4+ and dual IL-2/IFN-gamma-producing CD8+ T cells. In addition, HCV-specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co-infected patients and liver transplant recipients. Importantly, "only effector" T-cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune-based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV-1 co-infection and liver transplantation.
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Affiliation(s)
- Donatella Ciuffreda
- Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, CHUV, Lausanne, Switzerland
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Netski DM, Mao Q, Ray SC, Klein RS. Genetic divergence of hepatitis C virus: the role of HIV-related immunosuppression. J Acquir Immune Defic Syndr 2008; 49:136-41. [PMID: 18769357 PMCID: PMC3071283 DOI: 10.1097/qai.0b013e3181869a6f] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND We tested the hypothesis that HIV-related immunosuppression alters the host-hepatitis C virus (HCV) interaction, resulting in fewer amino acid-changing substitutions in HCV viral variants. Higher HCV RNA levels in persons coinfected with HIV compared with HCV infection alone suggest increased viral replication. If this increase is dependent on decreased immune selective pressure, then a reduced rate of nucleotide changes resulting in amino acid replacements (nonsynonymous changes, dN) would be expected. METHODS We investigated HCV envelope sequences over time in 79 persons with chronic HCV infection who were HIV negative (group 1) or HIV positive with (group 3) or without (group 2) severe immunodeficiency. We amplified a 1026-nt region of the HCV genome, which encodes a portion of the envelope glycoproteins E1 and E2, including hypervariable region-1 for direct sequence analysis. RESULTS The overall divergence between paired sequences, dS, dN, and dN/dS, all showed no significant differences among the 3 groups. CONCLUSIONS By measuring nucleotide substitutions in HCV sequences over time, we found no significant differences in the genetic divergence between HCV-monoinfected control subjects and HIV/HCV-coinfected subjects with various levels of immunodeficiency as measured by CD4+ T-cell counts.
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Affiliation(s)
- Dale M. Netski
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Qing Mao
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Stuart C. Ray
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Robert S. Klein
- Departments of Medicine and Epidemiology & Population Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
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Tseng FC, Edlin BR, Zhang M, Kral A, Busch MP, Ortiz-Conde BA, Welzel TM, O’Brien TR. The inverse relationship between chronic HBV and HCV infections among injection drug users is associated with decades of age and drug use. J Viral Hepat 2008; 15:690-8. [PMID: 18507757 PMCID: PMC4751881 DOI: 10.1111/j.1365-2893.2008.01005.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Infection with hepatitis C virus (HCV) may suppress co-infection with hepatitis B virus (HBV) during acute or chronic HBV infection. We examined relationships between HBV infection, HCV infection and other factors among injection drug users (IDUs) with antibodies to both viruses. Participants enrolled in a cross-sectional study during 1998-2000 were considered to have been infected with HBV if they had core antibody, to be chronically infected if they had hepatitis B surface antigen (HBsAg), to have been infected with HCV if they had HCV antibody and to be chronically infected if they had HCV RNA. Among 1694 participants with antibody to both viruses, HBsAg prevalence decreased with increasing age among those positive for HCV RNA [from 4.55% in those 18-29 years to 1.03% in those >or=50 years old (P(trend) = 0.02)], but not among those who were negative for HCV RNA. Chronic HBV infection was less common overall among those with chronic HCV infection (odds ratio [OR], 0.25; P < 0.0001), but this inverse relationship was much stronger in the oldest (>50 years; OR = 0.15) than the youngest (18-29 years; OR = 0.81) participants (P(trend) = 0.03). Similar results were obtained when duration of injection drug use was substituted for age (P(trend) = 0.05). Among IDUs who have acquired both HBV and HCV, chronic HBV infection is much less common among those with chronic HCV infection, but this inverse relationship increases markedly with increasing years of age and injection drug use. Co-infection with HCV may enhance the resolution of HBsAg during the chronic phases of these infections.
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Affiliation(s)
- Fan-Chen Tseng
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | - Brian R. Edlin
- University of California, San Francisco, CA
- Weill Medical College of Cornell University, New York, NY
| | - Mingdong Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | - Alex Kral
- University of California, San Francisco, CA
- RTI International, San Francisco Regional Office
| | - Michael P. Busch
- University of California, San Francisco, CA
- Blood Systems Research Institute, San Francisco, CA
| | | | - Tania M. Welzel
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
| | - Thomas R. O’Brien
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
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Xia X, Luo J, Bai J, Yu R. Epidemiology of hepatitis C virus infection among injection drug users in China: systematic review and meta-analysis. Public Health 2008; 122:990-1003. [PMID: 18486955 DOI: 10.1016/j.puhe.2008.01.014] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 12/06/2007] [Accepted: 01/29/2008] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Injection drug use (IDU) is the predominant mode of hepatitis C virus (HCV) transmission in China. This paper aims to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for HCV infection in injection drug users (IDUs) in China to help inform prevention programmes and guide future research. STUDY DESIGN Data from articles and reports according to pre-defined criteria on HCV infection rates among IDUs of different regions, genders, ethnic backgrounds and risk factors (injecting practice, needle sharing, long duration, sex behaviour and co-infection status) were abstracted and pooled by meta-analysis. A systematic review was constructed based on both pooled data and representative viewpoints. METHODS Ninety-five percent confidence intervals (CI) of infection rates were calculated using the approximate normal distribution model. Odds ratios and 95% CI were calculated by fixed or random effects models. Publication bias was examined using Begg's test and Egger's test. Data manipulation and statistical analyses were undertaken using STATA 7.0 and RevMan 4.2. Epi Info 3.4.3 was used for map construction. RESULTS The pooled prevalence of HCV infection among IDUs in China was 61.4% (95% CI 55.7-67.2%), and the epidemic was most severe in Hubei, Yunnan, Guangxi, Hunan and Xinjiang. No significant difference was found in HCV infection rates between male and female IDUs. A significant association was found between HCV infection and ethnic-minority status. IDUs were 9.24 times more likely to be infected with HCV than non-IDUs, while non-IDUs were more likely to be infected with HCV than members of the general population and other risk populations. There was no significant difference in the risk of HCV infection for needle-sharing IDUs and non-needle-sharing IDUs. A longer duration of IDU was associated with increased HCV prevalence. High-risk sexual practices were strongly associated with drug injection behaviours. Co-infection with human immunodeficiency virus (HIV) greatly increased the probability of HCV infection among IDUs, while the probability of hepatitis B virus infection remained similar for HCV-positive and HCV-negative IDUs in China. CONCLUSIONS IDU continues to fuel the HCV/HIV epidemics spreading throughout China. Many pragmatic strategies are being implemented but need further evaluation.
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Affiliation(s)
- Xian Xia
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, Jiangsu 210029, PR China
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Wu X, Ishaq M, Hu J, Guo D. HCV NS3/4A protein activates HIV-1 transcription from its long terminal repeat. Virus Res 2008; 135:155-60. [PMID: 18433908 DOI: 10.1016/j.virusres.2008.03.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2007] [Revised: 03/02/2008] [Accepted: 03/07/2008] [Indexed: 12/23/2022]
Abstract
Approximately 30-40% of patients infected with the human immunodeficiency virus (HIV) in the U.S. are also infected with the hepatitis C virus (HCV). Studies have shown that HIV can worsen hepatitis C, while the impact of hepatitis C on HIV disease is less clear. In this study, we described that HCV NS3/4A protein can activate HIV-1 transcription from its long terminal repeat (LTR) region, while the serine protease-inactive mutant of NS3/4A fails to do so. The activation effect of NS3/4A to HIV-1 transcription can be explained by its ability to enhance DNA binding activities of the transcription factor AP-1. These results have provided insights into the mechanism involved in the co-infection of HCV and HIV.
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Affiliation(s)
- Xiaoyun Wu
- State Key Laboratory of Virology and the Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, PR China
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the Swiss HIV Cohort Study, Rauch A, Gaudieri S, Evison J, Nolan D, Cavassini M, Weber R, James I, Furrer H, For The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Investigators. Low Current and Nadir CD4 + T-Cell Counts are Associated with Higher Hepatitis C virus RNA Levels in the Swiss HIV Cohort Study. Antivir Ther 2008. [DOI: 10.1177/135965350801300301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background The aim of this study was to evaluate the effect of CD4+ T-cell counts and other characteristics of HIV-infected individuals on hepatitis C virus (HCV) RNA levels. Methods All HIV–HCV-coinfected Swiss HIV Cohort Study participants with available HCV RNA levels and concurrent CD4+ T-cell counts before starting HCV therapy were included. Potential predictors of HCV RNA levels were assessed by multivariate censored linear regression models that adjust for censored values. Results The study included 1,031 individuals. Low current and nadir CD4+ T-cell counts were significantly associated with higher HCV RNA levels ( P=0.004 and 0.001, respectively). In individuals with current CD4+ T-cell counts <200/μl, median HCV RNA levels (6.22 log10 IU/ml) were +0.14 and +0.24 log10 IU/ml higher than those with CD4+ T-cell counts of 200-500/μ l and >500/μl. Based on nadir CD4+ T-cell counts, median HCV RNA levels (6.12 log10 IU/ml) in individuals with <200/μl CD4+ T-cells were +0.06 and +0.44 log10 IU/ml higher than those with nadir T-cell counts of 200-500/μ l and >500/μ l. Median HCV RNA levels were also significantly associated with HCV genotype: lower values were associated with genotype 4 and higher values with genotype 2, as compared with genotype 1. Additional significant predictors of lower HCV RNA levels were female gender and HIV transmission through male homosexual contacts. In multivariate analyses, only CD4+ T-cell counts and HCV genotype remained significant predictors of HCV RNA levels. Conclusions Higher HCV RNA levels were associated with CD4+ T-cell depletion. This finding is in line with the crucial role of CD4+ T-cells in the control of HCV infection.
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Affiliation(s)
| | - Andri Rauch
- Division of Infectious Diseases, University Hospital Bern and University of Bern, Switzerland
- Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia
| | - Silvana Gaudieri
- Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia
- Centre for Forensic Science and School of Anatomy and Human Biology, University of Western Australia, Perth, Australia
| | - John Evison
- Division of Infectious Diseases, University Hospital Bern and University of Bern, Switzerland
| | - David Nolan
- Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia
| | | | - Rainer Weber
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland
| | - Ian James
- Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia
| | - Hansjakob Furrer
- Division of Infectious Diseases, University Hospital Bern and University of Bern, Switzerland
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Operskalski EA, Mack WJ, Strickler HD, French AL, Augenbraun M, Tien PC, Villacres MC, Spencer LY, Degiacomo M, Kovacs A. Factors associated with hepatitis C viremia in a large cohort of HIV-infected and -uninfected women. J Clin Virol 2008; 41:255-63. [PMID: 18243785 PMCID: PMC3493623 DOI: 10.1016/j.jcv.2007.08.021] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2007] [Accepted: 08/28/2007] [Indexed: 12/17/2022]
Abstract
BACKGROUND Co-infection with hepatitis C virus (HCV) is common among HIV-infected women. OBJECTIVE To further our understanding of the risk factors for HCV viremia and the predictors of HCV viral load among women. STUDY DESIGN We investigated sociodemographic, immunologic, and virologic factors associated with presence and level of HCV viremia among 1049 HCV-seropositive women, 882 of whom were HIV-infected and 167 HIV-uninfected at their entry into the Women's Interagency HIV Study. RESULTS Plasma HCV RNA was detected in 852 (81%) of these 1049 women (range: 1.2-7.8 log(10)copies/ml). HCV-viremic women were more likely to have an HIV RNA level >100,000 copies/ml (P=0.0004), to have reported smoking (P=0.01), or to be Black (P=0.005). They were less likely to have current or resolved hepatitis B infection. HCV RNA levels were higher in women who were >35 years old, or HIV-infected. Current smoking and history of drug use (crack/freebase cocaine, marijuana, amphetamines, or heroin) were each associated with both presence and level of viremia. CONCLUSIONS Substance abuse counseling aimed at eliminating ongoing use of illicit drugs and tobacco may reduce clinical progression, improve response to treatment, and decrease HCV transmission by lowering levels of HCV viremia in women.
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Affiliation(s)
- Eva A Operskalski
- Maternal Child and Adolescent Center for Infectious Diseases and Virology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Seal KH, Monto A, Dove L, Shen H, Vittinghoff E, Tracy D, Miller E, Lau E, Wright TL. The association of human immunodeficiency virus infection with spontaneously resolved hepatitis C virus infection and level of viremia among injection drug users. Dig Dis Sci 2007; 52:3423-30. [PMID: 17443407 DOI: 10.1007/s10620-006-9277-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2005] [Accepted: 03/01/2006] [Indexed: 12/09/2022]
Abstract
This study aimed to investigate whether HIV and HIV-related factors are associated with spontaneously resolved hepatitis C virus (HCV) infection and levels of hepatitis C viremia. Among 351 anti-HCV(+) injection drug users, with and without HIV infection, multivariate methods were used to evaluate whether HIV status and HIV viral load, CD4 T-cell count, and concurrent HIV antiretroviral therapy were associated with (1) spontaneously resolved HCV infection and (2) HCV RNA levels. In 186 HIV patients, decreased HCV resolution was independently associated with Black race and modestly associated with CD4 T-cell count <200 cells/ml. Among 310 patients with persistent HCV infection, higher HCV RNA levels were independently associated with HIV status but not with other HIV-related factors. HIV may be associated with persistent HCV infection in patients with low CD4 T-cell counts. Moreover, HIV is associated with increased HCV viral load, which may attenuate response to HCV antiviral treatment in coinfected patients.
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Affiliation(s)
- Karen H Seal
- San Francisco Veteran's Administration Medical Center, San Francisco, California 94121, USA.
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Abstract
The authors discuss our current understanding of the immunopathogenesis of HCV-HIV coinfection.
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Affiliation(s)
- Paul Klenerman
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Walsh N, Higgs P, Crofts N. Recognition of Hepatitis C Virus Coinfection in HIV-Positive Injecting Drug Users in Asia. J Acquir Immune Defic Syndr 2007; 45:363-5. [PMID: 17592339 DOI: 10.1097/qai.0b013e318050d8d8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Ticehurst JR, Hamzeh FM, Thomas DL. Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis. J Clin Microbiol 2007; 45:2426-33. [PMID: 17537941 PMCID: PMC1951216 DOI: 10.1128/jcm.02448-06] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The serum concentration of hepatitis C virus (HCV) RNA is usually stable (4 to 8 log(10) IU/ml) in untreated patients with chronic hepatitis C. While this baseline HCV RNA concentration ([HCV RNA](BL)) is predictive of a sustained virologic response to treatment, its determinants are only partially identified. We therefore analyzed the baseline characteristics of 2,472 HCV genotype 1-infected patients to identify correlations with gender, age, race, weight, body mass index (BMI), HCV acquisition mode, HCV subtype, alanine aminotransferase concentration, or histopathologic changes in the liver. After separation of the data according to four [HCV RNA](BL) groups (< or =5.0, >5.0 to 5.6, >5.6 to 5.9, and >5.9 log(10) IU/ml), we determined that increasing [HCV RNA](BL) correlated (P < 0.05) with increasing proportions of patients who were male, >40 years of age, or heavier (a weight of >85 kg or a BMI of >27 kg/m(2)). Histologic activity index (HAI) data were available for 1,304 of these patients: increasing [HCV RNA](BL) correlated with higher fibrosis and necrosis-inflammation scores. As a continuous variable, [HCV RNA](BL) correlated with age, gender, weight (continuous or < or =85 versus >85 kg), BMI (continuous or < or =27 versus >27 kg/m(2)), subtype, fibrosis score, and necrosis-inflammation score; however, multiple-regression analysis yielded P values of <0.1 only for age, gender, BMI (< or =27 versus >27 kg/m(2)), and fibrosis score. While our findings are suggestive of a role for these factors in maintenance of the pretreatment state of HCV infection, the multiple-regression model accounted for only < or =4.6% of the [HCV RNA](BL) differences between individuals (R(2) = 0.046 for 1,304 patients with HAI scores; 0.043 for all 2,472 patients).
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Affiliation(s)
- John R Ticehurst
- Johns Hopkins Bayview Medical Center Clinical Laboratories and Johns Hopkins Hospital Division of Medical Microbiology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21224, USA.
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