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Wu Y, Ren L, Mao C, Shen Z, Zhu W, Su Z, Lin X, Lin X. Small hepatitis B virus surface antigen (SHBs) induces dyslipidemia by suppressing apolipoprotein-AII expression through ER stress-mediated modulation of HNF4α and C/EBPγ. J Virol 2024; 98:e0123924. [PMID: 39470210 PMCID: PMC11575332 DOI: 10.1128/jvi.01239-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/26/2024] [Indexed: 10/30/2024] Open
Abstract
Persistent infection with hepatitis B virus (HBV) often leads to disruptions in lipid metabolism. Apolipoprotein AII (apoAII) plays a crucial role in lipid metabolism and is implicated in various metabolic disorders. However, whether HBV could regulate apoAII and contribute to HBV-related dyslipidemia and the underlying mechanism remain unclear. This study revealed significant reductions in apoAII expression in HBV-expressing cell lines, the serum, and liver tissues of HBV-transgenic mice. The impact of HBV on apoAII is related to small hepatitis B virus surface antigen (SHBs). Overexpression of SHBs decreased apoAII levels in SHBs-expressing hepatoma cells, transgenic mice, and the serum of HBV-infected patients, whereas suppression of SHBs increased apoAII expression. Mechanistic investigations demonstrated that SHBs repressed the apoAII promoter activity through a HNF4α- and C/EBPγ-dependent manner; SHBs simultaneously upregulated C/EBPγ and downregulated HNF4α by inhibiting the PI3K/AKT signaling pathway through activating endoplasmic reticulum (ER) stress. Serum lipid profile assessments revealed notable decreases in high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) in SHBs-transgenic mice compared to control mice. However, concurrent overexpression of apoAII in these mice effectively counteracted these reductions in lipid levels. In HBV patients, SHBs levels were negatively correlated with serum levels of HDL-C, LDL-C, TC, and TG, whereas apoAII levels positively correlated with lipid content. This study underscores that SHBs contributes to dyslipidemia by suppressing the PI3K/AKT pathway via inducing ER stress, leading to altered expression of HNF4α and C/EBPγ, and subsequently reducing apoAII expression.IMPORTANCEThe significance of this study lies in its comprehensive examination of how the hepatitis B virus (HBV), specifically through its small hepatitis B virus surface antigen (SHBs), impacts lipid metabolism-a key aspect often disrupted by chronic HBV infection. By elucidating the role of SHBs in regulating apolipoprotein AII (apoAII), a critical player in lipid processes and associated metabolic disorders, this research provides insights into the molecular pathways contributing to HBV-related dyslipidemia. Discovering that SHBs downregulates apoAII through mechanisms involving the repression of the apoAII promoter via HNF4α and C/EBPγ, and the modulation of the PI3K/AKT signaling pathway via endoplasmic reticulum (ER) stress, adds critical knowledge to HBV pathogenesis. The research also shows an inverse correlation between SHBs expression and key lipid markers in HBV-infected individuals, suggesting that apoAII overexpression could counteract the lipid-altering effects of SHBs, offering new avenues for understanding and managing the metabolic implications of HBV infection.
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Affiliation(s)
- Yunli Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Lan Ren
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Chenglei Mao
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Zhiqing Shen
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Wenyu Zhu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Zhijun Su
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Xinjian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Xu Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
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Cao X, Hu Q, Xu W, Li Q, Zhang J, Chen L, Huang Y, Qi X. Kinetics changes in total cholesterol predict HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon-alfa. J Viral Hepat 2023; 30:310-318. [PMID: 36529685 DOI: 10.1111/jvh.13787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/24/2022] [Accepted: 12/10/2022] [Indexed: 01/07/2023]
Abstract
There is no satisfactory standard for predicting HBeAg seroconversion during Pegylated interferon alpha (PegIFNα) treatment. Studies have shown that IFNα therapy in chronic hepatitis C patients could alter serum lipid profiles. However, there have been no studies on lipid changes that predict the outcome of PegIFNα monotherapy in treated-naive chronic hepatitis B (CHB) patients. This retrospective study included 130 treated-naive HBeAg-positive CHB patients receiving PegIFNα monotherapy. The relationship between serum lipid changes and HBeAg seroconversion was analysed. The TC-ALT-HBsAg-HBeAg-Genotype-Age (CASEGA) model was established to predict HBeAg seroconversion after PegIFN-α monotherapy. Among 130 patients, 33 achieved HBeAg seroconversion (SR) and 97 did not achieve HBeAg seroconversion (NR). The decrease in serum total cholesterol (TC) in the NR group was significantly higher than in the SR group at Week 24 (-9.59% vs. -0.31%, p < 0.001). Multivariate logistic regression analysis showed that the change in TC at Week 24 (odds ratio = 1.065, p = 0.009) was an independent predictor of HBeAg seroconversion. The area under the receiver operating characteristic curve for the CASEGA model was 0.883. The model score at the maximum Youden index was 90, and the specificity, sensitivity, positive predictive value and negative predictive value were 0.727, 0.794, 0.546 and 0.895, respectively. The HBeAg seroconversion rate at Week 72 in patients with scores >90 was significantly higher than that in patients with scores <90 (54.55% vs. 10.47%, p < 0.001). This study indicated that the change in the TC level at 24 weeks in CHB patients treated with PegIFNα was associated with HBeAg seroconversion. The CASEGA prediction model based on the TC change rate of 24 weeks has good predictive efficiency for HBeAg seroconversion.
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Affiliation(s)
- Xiongyue Cao
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qiankun Hu
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wei Xu
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qiang Li
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Liang Chen
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.,Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xun Qi
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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Trifan A, Cuciureanu T, Nastasa R, Stratina E, Zenovia S, Muzica CM, Huiban L, Singeap AM, Chiriac S, Sfarti C, Cojocariu C, Girleanu I, Minea H, Stafie R, Rotaru A, Stanciu C. Changes in Components of Metabolic Syndrome after Antiviral Eradication in Hepatitis C Virus Infection. Life (Basel) 2023; 13:534. [PMID: 36836890 PMCID: PMC9959799 DOI: 10.3390/life13020534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/10/2023] [Accepted: 02/12/2023] [Indexed: 02/17/2023] Open
Abstract
Chronic hepatitis C infection is a systemic disease that affects over 71 million patients all over the world and it is to be considered nowadays as a new cardiometabolic risk factor. This study aimed to evaluate the weight and metabolic changes after viral eradication in patients with hepatitis C virus (HCV) infection. We conducted a prospective study between October 2017 to December 2021, in a tertiary care center, in which we included 132 patients with HCV or cirrhosis. All patients received treatment with direct antivirals (DAAs) and achieved sustained viral response at 12 weeks (SVR12). During the study, clinical laboratory data and Fibroscan examinations were recorded in all patients. The study group was evaluated at the initiation of antiviral treatment, at SVR12, and within an average follow-up period of 6 months to 12 months after the previous evaluation. Evaluation at SVR12 and the data recorded in the post-SVR surveillance period show a further increase in BMI compared with baseline measurements with a statistically significant difference (27.11 ± 3.22 vs. 27.415 ± 3.03 vs. 28.04 ± 1.11 kg/m2, p = 0.012). The same observation was noticed for waist circumference (WC) at post-SVR evaluation (87.6 ± 13.1 vs. 88.4 ± 13.6 cm, p = 0.031). Moreover, the study population registered an increase in the average total cholesterol (TC) values at post-SVR evaluation (177.01 ± 42.2 mg/dL, p = 0.014) compared to baseline. In addition, the serum level of triglycerides had been modified after viral clearance, with a minimal decrease in the mean values of triglycerides (TGD) at SVR-12 assessment (133.48 ± 41.8 mg/dL, p = 0.78), followed by a significant increase to the mean value of 145.4 ± 47.2 mg/dL (p = 0.026) in the third evaluation. Our study highlights that HCV eradication does not improve the lipid profile in the short term, and these patients still have an additional cardiovascular risk factor due to high levels of TC, TGD, and weight gain.
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Affiliation(s)
- Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Tudor Cuciureanu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Robert Nastasa
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ermina Stratina
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Sebastian Zenovia
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Cristina Maria Muzica
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Laura Huiban
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Stefan Chiriac
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Catalin Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Camelia Cojocariu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Horia Minea
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Remus Stafie
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Adrian Rotaru
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
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Röhrig AM, Jakobi K, Dietz J, Thomas D, Herrmann E, Welsch C, Sarrazin C, Pfeilschifter J, Zeuzem S, Grammatikos G. The role of serum sphingolipids as potential biomarkers of non-response to direct acting antiviral therapy in chronic hepatitis C virus infection. J Viral Hepat 2023; 30:138-147. [PMID: 36463431 DOI: 10.1111/jvh.13776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/07/2022] [Accepted: 11/14/2022] [Indexed: 12/09/2022]
Abstract
Elimination strategies of chronic hepatitis C virus (HCV) infection aim to optimize the high antiviral potency of direct-acting antivirals (DAAs). Sphingolipids (SLs) constitute bioactive lipid compounds with a remarkable second messenger potential. SL levels associate with responsiveness to interferon treatment in HCV-patients, thus prompting the question whether failure to DAAs can be predicted by the serologic sphingolipidomic profile. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to retrospectively quantify various sphingolipid metabolites in baseline serum samples of 97 chronic HCV patients with DAA failure compared with an age-matched cohort of 95 HCV-patients with sustained virological response (SVR). Sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) serum concentrations were significantly upregulated at baseline in patients with DAA failure compared to patients with SVR. Similarly, GluC24:1Cer baseline levels were significantly upregulated in patients with DAA failure compared to the patients with SVR. However, GluC18Cer serum levels showed decreased baseline levels for patients with DAA failure compared to patients with SVR. In multivariate analysis sphinganine (OR 0.08494, CI 0.07393-0.9759, p = .021223), SA1P (OR 0.9818, CI 0.9653-0.9987, p = .034801), GluCerC18 (OR 1.0683, CI 1.0297-1.1104, p = .000786) and GluCer24:1 (OR 0.9961, CI 0.994-0.998, p = .000294) constituted independent predictors of treatment response. In conclusion, serum sphingolipid concentrations, in particular sphingosine, sphinganine and their derivatives S1P and SA1P as well as glucosylceramides may identify at baseline the minority of HCV patients with DAA failure. Serum sphingolipids could constitute additional biomarkers for national treatment strategies aiming to eliminate HCV infection.
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Affiliation(s)
- Aissa Miriam Röhrig
- Department of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, Germany
| | - Katja Jakobi
- Goethe University Hospital, Pharmazentrum Frankfurt/ZAFES, Frankfurt am Main, Germany
| | - Julia Dietz
- Department of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, Germany
| | - Dominique Thomas
- Goethe University, Institute of Clinical Pharmacology, Frankfurt am Main, Germany
| | - Eva Herrmann
- Department of Medicine, Goethe University, Institute of Biostatistics and Mathematical Modelling, Frankfurt am Main, Germany
| | - Christoph Welsch
- Department of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, Germany
| | - Christoph Sarrazin
- Department of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, Germany.,St. Josefs-Hospital, Wiesbaden, Germany
| | - Josef Pfeilschifter
- Goethe University Hospital, Pharmazentrum Frankfurt/ZAFES, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, Germany
| | - Georgios Grammatikos
- Department of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, Germany.,St' Lukes Hospital, Thessaloniki, Greece
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Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact. Biomedicines 2023; 11:biomedicines11020271. [PMID: 36830808 PMCID: PMC9953247 DOI: 10.3390/biomedicines11020271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.
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The interplay between non-alcoholic fatty liver disease and innate immunity in hepatitis B virus patients. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00084-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most epidemic liver disorder worldwide as a result of rapid lifestyle transformation over the past few decades and is expected to elevate in the next few years as well as it is ranging from plain hepatic steatosis via non-alcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC).
Main text
NAFLD can also stimulate the diseases progression as diabetes and cardiovascular. Therefore, understanding the NAFLD pathogenesis is of vital clinical interest additionally is a crucial for disease treatment and prevention. After analyzing NAFLD and liver diseases prevalence, it has been a belief regarding the interaction between NAFLD and chronic hepatitis B (CHB).
Conclusion
The liver is an essential innate immune organ with large numbers of innate immune cells that contribute in NAFLD pathogenesis, additionally play the influential role that control NAFLD progression in the hepatitis B patients. Here, we summarized the recent advances in understanding and managing the NAFLD patients with chronic hepatitis B infection and interplay with innate immunity.
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Xia Z, Zheng J, Zheng L, Zheng E, Zou Z, Sheng X, Wu J. Effects of dyslipidemia on E antigen seroconversion of patients with chronic hepatitis B treated by nucleoside (acid) analogs. Lipids Health Dis 2021; 20:148. [PMID: 34717643 PMCID: PMC8557562 DOI: 10.1186/s12944-021-01582-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 10/18/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The prevalence of dyslipidemia in China is increasing annually. Current studies suggest that dyslipidemia affects the antiviral efficacy of hepatitis C virus (HCV) therapies, while recent studies suggest that serum lipids influence the response rates of chronic hepatitis B (CHB) patients receiving PEGylated interferon-alpha (Peg IFN-α) treatment. However, the role of dyslipidemia in the efficacy of nucleoside (acid) analogues (NAs) in CHB patients remains unclear. METHODS From January 2010 to December 2013, data from 179 treatment-naive patients with CHB who were hepatitis B e antigen (HBeAg)-positive and had visited the first affiliated hospital of Wenzhou Medical University were assessed. Of these patients, 68 were assigned to the dyslipidemia group (diagnosed with CHB complicated with dyslipidemia) and 111 to the normolipidemic group. The following 3 treatment strategies were performed for all CHB patients over a 5-year period: lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy, telbivudine (LdT) monotherapy, and entecavir (ETV) monotherapy. Serum assessments, blood biochemistry, HBV serological markers, HBV DNA before treatment and HBeAg serological conversion and virological responses at different timepoints after treatment were compared between the two groups. Measurement data were compared by τ tests and enumeration data by χ2 tests. Correlation analysis was performed using binary logistic regression analysis. RESULTS The rates of HBeAg seroconversion in the dyslipidemia group at years 1, 2, 3, and 4 were 10.3, 13.2, 17.6, and 22.1%, respectively, which were not significantly lower than those of the normolipidemic group (11.7, 16.2, 18.0 and 33.3%; χ2 = 0.085, 0.293, 0.004, and 2.601, respectively; Ρ > 0.05). However, the rates of HBeAg seroconversion in the dyslipidemia group were significantly lower than those in the normolipidemic group at year 5 (27.9% vs. 43.2%, χ2 = 4.216, Ρ < 0.05). Univariate logistic regression analysis revealed significant differences in group, gender, PTA, ALT, AST, CR, and LDL-C between groups with and without seroconversion. Multivariate regression analysis demonstrated that dyslipidemia (OR = 1.993, Ρ = 0.038) and male gender (OR = 2.317, Ρ = 0.029) were risk factors associated with HBeAg seroconversion. CONCLUSIONS During antiviral therapy, dyslipidemia affects HBeAg seroconversion in CHB patients treated with NAs, but does not affect the virological response.
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Affiliation(s)
- Ziqiang Xia
- Department of Gastroenterology, Wenzhou People's Hospital, Wenzhou, 325000, China
| | - Juzeng Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Liang Zheng
- Department of Gastroenterology, Wenzhou People's Hospital, Wenzhou, 325000, China
| | - Endian Zheng
- Department of Gastroenterology, Wenzhou People's Hospital, Wenzhou, 325000, China
| | - Zhuolin Zou
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing College, Jiaxing, 314000, China
- Department of Infectious Diseases, The First Hospital of Jiaxing, Jiaxing, 314000, China
| | - Xiong Sheng
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing College, Jiaxing, 314000, China.
- Department of Infectious Diseases, The First Hospital of Jiaxing, Jiaxing, 314000, China.
| | - Jinming Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Shengir M, Elgara M, Sebastiani G. Metabolic and cardiovascular complications after virological cure in hepatitis C: What awaits beyond. World J Gastroenterol 2021; 27:1959-1972. [PMID: 34007133 PMCID: PMC8108037 DOI: 10.3748/wjg.v27.i17.1959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/06/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
The association between chronic hepatitis C (CHC) infection and extrahepatic manifestations (EHMs), particularly cardiometabolic diseases, has been extensively examined. However, there has still been insufficient evaluation for these EHMs after virological cure. Several multidirectional mechanisms have been proposed explaining the ability of hepatitis C virus (HCV) developing EHMs, cardiometabolic ones, as well as the effect of antiviral therapy to resolve these EHMs. Data on these manifestations after achieving sustained virologic response (SVR) are still conflicting. However, current evidence suggests that reversal of hepatic steatosis and its coexistent hypocholesterolemia after successful viral eradication led to unfavorable lipid profile, which increases cardiovascular disease (CVD) risk. Additionally, most observations showed that metabolic alterations, such as insulin resistance and diabetes mellitus (DM), undergo some degree of reduction after viral clearance. These changes seem HCV-genotype dependent. Interferon-based antiviral therapy and direct acting antiviral drugs were shown to minimize incidence of DM. Large epidemiological studies that investigated the effect of SVR on CVD showed great discrepancies in terms of results, with predominant findings indicating that CVD events decreased in patients with SVR compared to non-responders or untreated ones. In this review, we present a summary of the current knowledge regarding extrahepatic sequelae of CHC following SVR, which may have an impact on healthcare providers’ clinical practice.
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Affiliation(s)
- Mohamed Shengir
- Department of Medicine, McGill University, Montreal, Quebec H3A0G4, Canada
| | - Mohamed Elgara
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Giada Sebastiani
- Department of Medicine, McGill University Health Center, Montreal, Quebec H4A3J1, Canada
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Sidorkiewicz M, Grek-Kowalinska M, Piekarska A. Changes in miR-122 and Cholesterol Expression in Chronic Hepatitis C Patients after PegIFN-Alpha/Ribavirin Treatment. Pathogens 2020; 9:pathogens9060514. [PMID: 32630479 PMCID: PMC7350302 DOI: 10.3390/pathogens9060514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/08/2020] [Accepted: 06/22/2020] [Indexed: 12/15/2022] Open
Abstract
The hepatitis C virus (HCV) is known as a main etiological cause of chronic hepatitis. HCV infection disturbs cholesterol metabolism of the host, which is frequently observed in patients suffering from chronic hepatitis C (CHC). The course of viral infections remains under strict control of microRNA (miRNA). In the case of HCV, miR-122 exerts a positive effect on HCV replication in vitro. The purpose of this study was to investigate the impact of peginterferon alpha (pegIFN-α) and ribavirin treatments on the expression of miR-122 and the cholesterol level in the peripheral blood mononuclear cells (PBMCs) of CHC patients. We report here that the level of miR-122 expression in the PBMCs decreased after the antiviral treatment in comparison to the pretreated state. Simultaneously, the level of cholesterol in the PBMCs of CHC patients was higher six months following the treatment than it was pretreatment. Consequently, it seems that the decrease of miR-122 expression in the PBMCs of CHC patients is one of the antiviral effects connected with the pegIFN-alpha/ribavirin treatments.
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Affiliation(s)
- Malgorzata Sidorkiewicz
- Department of Medical Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland;
- Correspondence: ; Tel.: +48-42-2725685
| | | | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Lodz, 90-419 Lodz, Poland;
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Özdoğan O, Yaraş S, Ateş F, Üçbilek E, Sezgin O, Altıntaş E. The impact of direct-acting antiviral treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients: temporary? permanent? TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:384-392. [PMID: 32519958 DOI: 10.5152/tjg.2020.19273] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS In previous studies that investigated the impact of direct-acting antiviral (DAA) treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients have been compared to baseline values with either end of treatment or post-treatment values. The results are inconsistent. We evaluated patients throughout the treatment and after treatment. MATERIALS AND METHODS 121 patients were included in the study. 93 patients were treated with sofosbuvir/ledipasvir±Ribavirin (RBV), and 28 patients were treated with ombitasvir/paritaprevir/ritonavir+dasabuvir±RBV. Total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) and homeostatic model assessment-insulin resistance (HOMA-IR) levels were measured at the onset of treatment, after the1st month of treatment, at the end of treatment, and 6 and 12 months after the end of treatment. RESULTS 117 patients were genotype 1. Sustained virological response was 98.4%. HOMA-IR values during treatment were significantly higher than at the beginning of treatment (p=0.0001). At 12 months there was a decrease in HOMA-IR, but this was not statistically significant (p=0.2048). TC and LDL levels were significantly increased in the first month of treatment (TC; 159±30, 180±34 mg/dl; LDL; 84±28, 100±30 mg/dl, respectively) (p<0.0001) and this increase was present during and after treatment. There was no statistically significant increase in TG (p=0120). Both treatment regimens showed similar effects on HOMA-IR, TC, and LDL. CONCLUSION Patients with HCV treated with DAAs drugs showed increased IR, TC, and LDL cholesterol levels during treatment. After the end of treatment, IR goes back to normal, while the elevated TC and LDL levels persist indefinitely.
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Affiliation(s)
- Osman Özdoğan
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Fehmi Ateş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Enver Üçbilek
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
| | - Engin Altıntaş
- Department of Gastroenterology, Mersin University School of Medicine, Mersin, Turkey
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11
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Xun Z, Lin JP, Liu C, Huang JL, Shen Y, Xu SY, Wu WN, Ou QS. Association of serum total cholesterol with pegylated interferon-α treatment in HBeAg-positive chronic hepatitis B patients. Antivir Ther 2020; 24:85-93. [PMID: 30520414 DOI: 10.3851/imp3282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recent studies suggest that serum lipids are associated with pegylated interferon-alpha (PEG-IFN-α) treatment response in chronic hepatitis C patients. However, the role of serum lipids in influencing the outcome of HBV treatment is not well understood. This study aims to investigate the association of serum lipids with the response to interferon-alpha treatment for chronic hepatitis B (CHB) patients. METHODS We dynamically measured 11 clinical serum lipid parameters of 119 hepatitis B e antigen (HBeAg)-positive CHB patients, including 53 patients who achieved sustained response (SR) and 66 patients who achieved non-response (NR) induced by PEG-IFN-α treatment for 48 weeks. RESULTS The dynamic analysis showed that the baseline serum total cholesterol (TCHO) level was higher in the NR group than that in the SR group (P=0.004). Moreover, the correlation analysis demonstrated a significant positive correlation between TCHO and hepatitis B surface antigen (HBsAg) at baseline (P=0.009). In addition, CHB patients with high baseline TCHO levels exhibited higher HBV DNA, HBsAg, HBeAg and hepatitis B e antibody (HBeAb) levels during early treatment periods (weeks 0, 4, 12 and 24) than those with the low TCHO levels. Furthermore, the logistic regression analysis identified that baseline serum TCHO was a risk factor for NR achievement (OR=4.94; P=0.047). CONCLUSIONS Our results indicated that serum TCHO was associated with PEG-IFN-α therapeutic response in HBeAg-positive CHB patients which suggested that serum TCHO could be useful as an auxiliary clinical factor to predict poor efficacy of PEG-IFN-α therapy.
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Affiliation(s)
- Zhen Xun
- First Clinical College, Fujian Medical University, Fuzhou, China.,Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jin-Piao Lin
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Can Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jin-Lan Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ye Shen
- First Clinical College, Fujian Medical University, Fuzhou, China.,Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Si-Yi Xu
- First Clinical College, Fujian Medical University, Fuzhou, China.,Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Wen-Nan Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qi-Shui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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12
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Nevola R, Rinaldi L, Zeni L, Sasso FC, Pafundi PC, Guerrera B, Marrone A, Giordano M, Adinolfi LE. Metabolic and renal changes in patients with chronic hepatitis C infection after hepatitis C virus clearance by direct-acting antivirals. JGH OPEN 2020; 4:713-721. [PMID: 32782961 PMCID: PMC7411572 DOI: 10.1002/jgh3.12324] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/27/2020] [Accepted: 02/27/2020] [Indexed: 12/12/2022]
Abstract
Background and Aim The impact of hepatitis C virus (HCV) clearance by direct-acting antiviral agents (DAAs) on HCV-related extrahepatic manifestations is not well known. We evaluated the effect of viral clearance on metabolic and renal parameters. Methods In this prospective study, HCV patients who achieved a sustained virologic response (SVR) by DAAs were evaluated before, at the end, and 24 weeks after treatment for glycemic (serum glucose and insulin, HOMA-IR, HOMA-β, and HOMA-S) and lipid (serum cholesterol, triglycerides, low-density lipoprotein [LDL], high-density lipoprotein) metabolism and renal function (serum creatinine, estimated glomerular filtration rate [eGFR]). Results A total of 343 consecutive HCV patients were evaluated. At 24 weeks of post-follow-up, an increase in body mass index (BMI) was observed (P < 0.05). Regardless of hepatic fibrosis levels and BMI, a reduction in serum glucose (P = 0.001), HOMA-IR (P < 0.001) and HOMA-β (P < 0.001) and an increase in HOMA-S (P < 0.001) values were observed at 24 weeks after HCV clearance as compared to pretreatment values; 32.4% of patients with impaired fasting glucose normalized serum glucose values and 44.6% of diabetics showed an improvement in glycemic control. In contrast, serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.001) values were increased. Renal function was improved with about 10% reduction of serum creatinine values (P < 0.02) and an increase of eGFR (P < 0.001). A baseline eGFR of ≤60 mL/min/1.73 m2 was a negative predictor of renal function improvement. HCV clearance was an independent factor improving glucose metabolism and renal function. Conclusions Our study shows an occurrence of changes in metabolic and renal parameters in HCV patients with SVR, anticipating possible future clinical scenarios that the clinician must know for proper management.
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Affiliation(s)
- Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | - Letizia Zeni
- Department of Translational Medical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | - Ferdinando C Sasso
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | - Pia C Pafundi
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | | | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
| | - Luigi E Adinolfi
- Department of Advanced Medical and Surgical Sciences University of Campania "Luigi Vanvitelli" Naples Italy
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13
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Todorovska B, Joksimovic N, Caloska-Ivanova V, Dimitrova-Genadieva M, Trajkovska M, Curakova E, Kiprijanovska S, Zafirova-Ivanovska B, Serafimoski V. Factors That Influence the Virological Response in Patients with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin. ACTA ACUST UNITED AC 2019; 38:25-33. [PMID: 28593897 DOI: 10.1515/prilozi-2017-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The success of the antiviral treatment in patients with chronic hepatitis C depends on the factors related to the virus and the host. The aim of the study is the analysis of the antiviral therapy which is a combination of pegylated interferon and ribavirin, considering various factors that will identify the predictors of the sustained virological response. MATERIAL AND METHODS This retrospective study included 226 patients, divided in two groups. Patients with sustained virological response and patients without sustained virological response were compared in terms of the following factors: genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, metabolic abnormalities, obesity and fatty liver. RESULTS The rate of the sustained virological response is 83.6%, more frequently in patients with genotype 3, with evidenced statistical significance (90.54%). The factors that significantly contribute to sustained virological response are related to the age (p = 0.0001), genotype (p = 0.002), mode of transmission (p = 0.005), inflammatory changes in the liver (p = 0.028), body mass index (p = 0.022) and insulin resistance (p = 0.039). The high rate of sustained virological response is related to the younger age of the patients which indirectly means short Hepatitis C Virus infection duration, absence of advanced liver disease and lack of significant co-morbid conditions. Single confirmed independent predictors of sustained virological response are the age (OR 0.928, p = 0.0001) and genotype (OR 3.134, p = 0.005). CONCLUSIONS Factors that are related to the virological response are the age, genotype, mode of transmission, inflammatory changes in the liver, body mass index and insulin resistance, but still, independent predictors of sustained virologic response are the age and the genotype.
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Affiliation(s)
- Beti Todorovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Nenad Joksimovic
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Viktorija Caloska-Ivanova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | | | - Meri Trajkovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Elena Curakova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Sanja Kiprijanovska
- Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Skopje
| | - Beti Zafirova-Ivanovska
- Institute of Epidemiology and Biostatistics, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
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14
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Ichikawa T, Miyaaki H, Miuma S, Motoyoshi Y, Narita S, Toda S, Takahashi Y, Honda T, Yajima H, Uehara R, Hino N, Hori T, Hirata R, Taura N, Nakao K. Carotid Intima-media Thickness and Small Dense Low-density Lipoprotein Cholesterol Increase after One Year of Treatment with Direct-acting Antivirals in Patients with Hepatitis C Virus Infection. Intern Med 2019; 58:1209-1215. [PMID: 30626818 PMCID: PMC6543209 DOI: 10.2169/internalmedicine.1514-18] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective Direct-acting antivirals (DAAs) for treating hepatitis C virus (HCV) infection exert a significantly high sustained viral response (SVR), and patients experience a rebound increase in low-density lipoprotein cholesterol (LDL) and total cholesterol levels. Carotid intima-media thickness (IMT) is a highly reproducible and non-invasive parameter for assessing the atherosclerotic process, and the small dense (sd) LDL level is useful for clinically evaluating the atherogenic risk. Methods A total of 48 patients with chronic HCV infection were treated with DAAs. All patients exhibited an SVR 24 weeks later. We compared the metabolic profiles of the patients, including the sdLDL and IMT values, at the start of DAA treatment with those after one year of treatment. We verified whether the HCV clearance after the administration of DAAs is associated with the development of atherosclerosis. Results The sdLDL, %sdLDL (sdLDL/LDL), and LDL values were exacerbated after a year of treatment; however, the triglyceride level, glycated hemoglobin level, insulin resistance, and body weight remained unaltered. The max-IMT was increased after a year compared to that at the start of treatment. Differences in the max-IMT (dmax-IMT) were greater in men than in women; however, no correlation was observed between the dmax-IMT and genotype, fibrosis, hypertension, hyperlipidemia, diabetes, obesity, and dialysis status. The %sdLDL at the start and a year later was positively correlated with the dmax-IMT. No correlation was observed among various factors including the LDL, triglyceride, body mass index, insulin resistance and dmax-IMT. In uni- and multivariate analyses, a significant correlation was observed between %sdLDL≥16% at the start of treatment and the sex and dmax-IMT. Conclusion Because the sdLDL and IMT values were exacerbated after a year of DAA treatment, atherosclerosis must be evaluated in patients achieving an SVR.
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Affiliation(s)
- Tatsuki Ichikawa
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
- Innovation and Translational Research Center, Nagasaki Harbor Medical Center, Japan
- Department of Comprehensive Community Care Systems, Graduate School of Biomedical Sciences, Nagasaki University, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Japan
| | | | - Syouhei Narita
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
| | - Satomi Toda
- Innovation and Translational Research Center, Nagasaki Harbor Medical Center, Japan
| | - Youichi Takahashi
- Innovation and Translational Research Center, Nagasaki Harbor Medical Center, Japan
| | - Tetsurou Honda
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
| | - Hiroyuki Yajima
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
| | - Ryouhei Uehara
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
| | - Naoyuki Hino
- Department of Comprehensive Community Care Systems, Graduate School of Biomedical Sciences, Nagasaki University, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Japan
| | - Tomoko Hori
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
| | - Ryousuke Hirata
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Japan
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15
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González-Aldaco K, Torres-Reyes LA, Ojeda-Granados C, José-Ábrego A, Fierro NA, Román S. Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy. Ann Hepatol 2018; 17:908-919. [PMID: 30600305 DOI: 10.5604/01.3001.0012.7191] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a lipid-enveloped virion particle that causes infection to the liver, and as part of its life cycle, it disrupts the host lipid metabolic machinery, particularly the cholesterol synthesis pathway. The innate immune response generated by liver resident immune cells is responsible for successful viral eradication. Unfortunately, most patients fail to eliminate HCV and progress to chronic infection. Chronic infection is associated with hepatic fat accumulation and inflammation that triggers fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Despite that the current direct-acting antiviral agents have increased the cure rate of HCV infection, viral genotype and the host genetic background influence both the immune response and lipid metabolism. In this context, recent evidence has shown that cholesterol and its derivatives such as oxysterols might modulate and potentialize the hepatic innate immune response generated against HCV. The impairment of the HCV life cycle modulated by serum cholesterol could be relevant for the clinical management of HCV-infected patients before and after treatment. Alongside, cholesterol levels are modulated either by genetic variations in IL28B, ApoE, and LDLR or by dietary components. Indeed, some nutrients such as unsaturated fatty acids have demonstrated to be effective against HCV replication. Thus, cholesterol modifications may be considered as a new adjuvant strategy for HCV infection therapy by providing a biochemical tool that guides treatment decisions, an improved treatment response and favoring viral clearance. Herein, the mechanisms by which cholesterol contributes to the immune response against HCV infection and how genetic and environmental factors may affect this role are reviewed.
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Affiliation(s)
- Karina González-Aldaco
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Luis A Torres-Reyes
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Claudia Ojeda-Granados
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Alexis José-Ábrego
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Nora A Fierro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sonia Román
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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Andrade VGD, Yamashiro FDS, Oliveira CV, Kurozawa LL, Moreira A, Silva GF. INCREASE OF LIPIDS DURING HCV TREATMENT: VIRUS ACTION OR MEDICATION? ARQUIVOS DE GASTROENTEROLOGIA 2018; 55:184-187. [PMID: 30043871 DOI: 10.1590/s0004-2803.201800000-33] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 01/09/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND The interaction between serum lipids and C virus infection is well known, as are serum lipid levels in the Peg-IFN / RBV-based treatment. However, with direct action antivirals (DAAs) this behavior is still unclear. OBJECTIVE To compare serum lipids levels between patients treated with Peg-IFN/RBV and DAAs and to evaluate lipids in sustained virological response (SVR) with DAAs. METHODS Retro prospective study comparing the behavior of total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG) serum levels during treatment with DAAs (G-DAAs) and a control historic group Peg-IFN/RBV (G-PR). Coorte, prospective study, to study the behavior of lipids in the SVR with DAAs. Data were collected at the beginning of treatment (baseline: t-base) and at week 12 of treatment (t-12) for G-DAAs and at week 24 (t-24) for G-PR, groups. In the cohort evaluation, the samples at t-base and at week 12 after the end of treatment (t-SVR). Delta lipids: difference between lipids in t-12 / t-24 minus t-base for comparison between G-PR and G-AADs groups and t-SVR minus t-base for lipid analysis in SVR. Analysis with Kruskal Wallis and Wilcoxon tests to compare the delta lipids of the groups. The P value was 0.05. RESULTS In the assessment between G-PR and G-DAAs groups, we included 63 and 121 patients, respectively. The groups did not differ one from the other (BMI, sex, genotype, fibrosis, total cholesterol, LDL, and TG) except by age (50.38±10.44 vs 56±9.69, P=0.0006). We observed a decrease in levels of TC and LDL and an increase in TG, in G-PR, and in G-DAAs the opposite (Δ TC -13.9±34.5 vs 4.12±34.3 P=0.0005, Δ LDL -7.16±32 vs 10.13±29.92, P=0.003, Δ TG 4.51±53.7 vs -8.24±49.93, P=0.0025). In the coorte analysis, we included 102 patients, 70% men and 56% F4, 95 of them reached SVR. We observed an increase of TC and LDL and a decrease of TG in both groups (SVR and non SVR), with no statistical difference (Δ TC P=0.68; Δ LDL P=0.69; Δ TG P=0.43). We did not find significant difference in delta evaluation by genotype 1 and 3 (Δ TC +29.7±40.2 vs +13.4±30.3, P=0.06; Δ LDL +21.4±28.6 vs +16.6±31.3, P=0.41; Δ TG -3.6±60.6 vs -0.7±40, P=0.91). CONCLUSION Serum lipids level differed during treatment with Peg-IFN and DAAs. Treatment with DAAs was associated with an increase of TC and LDL and a decrease of TG, independently of SVR.
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Affiliation(s)
- Vanessa Gutierrez de Andrade
- Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Campus Botucatu, Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Fabio da Silva Yamashiro
- Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Campus Botucatu, Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Cassio Vieira Oliveira
- Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Campus Botucatu, Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Leticia Lastória Kurozawa
- Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Campus Botucatu, Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Alecsandro Moreira
- Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Campus Botucatu, Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
| | - Giovanni Faria Silva
- Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Campus Botucatu, Faculdade de Medicina, Departamento de Clínica Médica, Botucatu, SP, Brasil
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17
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Hirayama T, Ikegami T, Honda A, Miyazaki T, Yara SI, Kohjima M, Nakamuta M, Matsuzaki Y. Differences in the Serum 4β-hydroxycholesterol Levels of Patients with Chronic Hepatitis C Virus (HCV) Infection: A Possible Impact on the Efficacy and Safety of Interferon (IFN)-free Treatment. Intern Med 2018; 57:1219-1227. [PMID: 29279486 PMCID: PMC5980801 DOI: 10.2169/internalmedicine.9479-17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4βHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4βHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4βHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4βHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.
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Affiliation(s)
- Takeshi Hirayama
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Sho-Ichiro Yara
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Japan
| | - Yasushi Matsuzaki
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
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Villar LM, Caldas GC, Scalioni LDP, Miguel JC, da Silva EF, Marques VA, Villela-Nogueira CA, Lewis-Ximenez LL, Lampe E. High prevalence of insulin resistance among Brazilian chronic hepatitis C patients. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2017; 61:628-632. [PMID: 29412389 PMCID: PMC10522051 DOI: 10.1590/2359-3997000000315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 07/31/2017] [Indexed: 11/22/2022]
Abstract
OBJECTIVE This study aims to estimate the prevalence of insulin resistance (IR) among chronic hepatitis C (CHC) patients and their related laboratory and demographic data. SUBJECTS AND METHODS In this study, non-diabetic CHC patients referred to Viral Hepatitis Ambulatories from Rio de Janeiro (Brazil) donated blood samples. Insulin was measured using a chemiluminescence immunoassay. IR was determined by HOMA-IR, where HOMA-IR > 2 was defined as IR. RESULTS A total of 214 CHC patients were recruited (123 females aged 53.6 years ± 10.9 years). IR was present in 133 patients (62.1%) and was associated in bivariate analysis to higher mean values of age (p = 0.040), triglycerides (p = 0.032), glucose (p = 0.000), insulin (p = 0.000), waist circumference (p = 0.001), and body mass index (p = 0.007); however, none of these variables were significant in the multivariate analysis. CONCLUSIONS The high prevalence of IR was observed among CHC patients, and there was no difference in clinical or laboratory parameters when both groups were compared in the multivariate analysis. This high IR prevalence could lead to a high risk for development of cardiovascular disease and metabolic disorders.
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Affiliation(s)
- Livia Melo Villar
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Gabriela Cardoso Caldas
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Leticia de Paula Scalioni
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Juliana Custódio Miguel
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Elisangela Ferreira da Silva
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Vanessa Alves Marques
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Cristiane Alves Villela-Nogueira
- Universidade Federal do Rio de JaneiroHospital Universitário Clementino Fraga Filho (HUCFF)Departamento de Clínica MédicaRio de JaneiroRJBrasilUnidade de Hepatologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho (HUCFF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
| | - Lia Laura Lewis-Ximenez
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Elisabeth Lampe
- Instituto Oswaldo CruzLaboratório de Hepatite ViralRio de JaneiroRJBrasilLaboratório de Hepatite Viral, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
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Xiong J, Zhang H, Wang Y, Wang A, Bian J, Huang H, Zheng Y, Sang X, Xu Y, Lu X, Zhao H. Hepatitis B virus infection and the risk of nonalcoholic fatty liver disease: a meta-analysis. Oncotarget 2017; 8:107295-107302. [PMID: 29291029 PMCID: PMC5739814 DOI: 10.18632/oncotarget.22364] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 09/04/2017] [Indexed: 12/20/2022] Open
Abstract
Some studies have reported that hepatitis B virus (HBV) infection affects the risk of nonalcoholic fatty liver disease (NAFLD). However, this association is controversial. We conducted a systematic review and meta-analysis to investigate the relationship between HBV infection and NAFLD. Relevant studies published before May 2017 were identified by searching PubMed, EMBASE, and ISI Web of Science. We used the random-effects model proposed by DerSimonian and Laird to quantify the relationship between HBV infection and risk of NAFLD. We also conducted subgroup and sensitivity analyses to validate the stability of the results. Five articles, comprising 8,272 HBV-infected patients and 111,631 uninfected controls, were included in our research. Our meta-analysis suggested that the risk of NAFLD was significantly lower in HBV-infected patients than in uninfected controls, with heterogeneity between studies (summary odds ratio [OR] = 0.71; confidence interval [CI] = 0.53–0.90; I2 = 75.2%). However, the inverse relationship was observed in only cohort (OR = 0.83; 95% CI = 0.73–0.94) and cross-sectional studies (OR = 0.63; 95% CI = 0.47–0.79), not case-control studies (OR = 3.96; 95% CI = 2.10–7.48). In conclusion, HBV infection was inversely associated with the risk of NAFLD.
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Affiliation(s)
- Jianping Xiong
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haoaohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yaqin Wang
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin Bian
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hanchun Huang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Macau SAR, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiyao Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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20
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Nakamoto S, Imazeki F, Kanda T, Wu S, Nakamura M, Yasui S, Tawada A, Mikata R, Chiba T, Arai M, Yokosuka O, Shirasawa H. Association of IFNL3 Genotype with Hepatic Steatosis in Chronic Hepatitis C Patients Treated with Peginterferon and Ribavirin Combination Therapy. Int J Med Sci 2017; 14:1088-1093. [PMID: 29104462 PMCID: PMC5666539 DOI: 10.7150/ijms.20171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 07/05/2017] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Genetic variation near the interferon lambda 3 (IFNL3) is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis. AIMS We examined whether this genetic variation is associated with host lipids and treatment response. METHODS A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between IFNL3 genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis. RESULTS Forty patients (40%) had liver steatosis before therapy. Patients with IFNL3 minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and IFNL3 major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, IFNL3 genotype was the most significant predictor, as per multivariate analysis. CONCLUSIONS Our results confirmed that IFNL3 genotype is associated with hepatic steatosis as well as IFN response.
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Affiliation(s)
- Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Japan
| | - Fumio Imazeki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Shuang Wu
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | | | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Rintaro Mikata
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Hiroshi Shirasawa
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Japan
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Yair-Sabag S, Nussinson E, Ben-Assuli O, Shibli F, Shahbari A, Zelber-Sagi S. Retrospective study of the associations between hepatitis C virus infection and metabolic factors. World J Hepatol 2016; 8:1269-1278. [PMID: 27843537 PMCID: PMC5084056 DOI: 10.4254/wjh.v8.i30.1269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 07/18/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the bidirectional association between metabolic syndrome (MS) components and antiviral treatment response for chronic hepatitis C virus (HCV) infection.
METHODS This retrospective cohort study included 119 HCV + patients treated with pegylated-interferon-α and ribavirin. Metabolic characteristics and laboratory data were collected from medical records. Differences in baseline clinical and demographic risk factors between responders and non-responders were assessed using independent samples t-tests or χ2 tests. The effects of sustained viral response (SVR) to antiviral treatment on de novo impairments in MS components, including impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), were assessed using univariable and multivariable logistic regression analysis, while the effect of MS components on SVR was assessed using univariable logistic regression analysis.
RESULTS Of the 119 patients, 80 (67%) developed SVR over the average 54 ± 13 mo follow-up. The cumulative risks for de novo T2DM and IFG were 5.07- (95%CI: 1.261-20.4, P = 0.022) and 3.87-fold higher (95%CI: 1.484-10.15, P = 0.006), respectively for non-responders than responders, when adjusted for the baseline risk factors age, sex, HCV genotype, high viral load, and steatosis. Post-treatment triglyceride levels were significantly lower in non-responders than in responders (OR = 0.27; 95%CI: 0.069-0.962, P = 0.044). Age and HCV genotype 3 were significantly different between responders and non-responders, and MS components were not significantly associated with SVR. Steatosis tended to attenuate SVR (OR = 0.596; 95%CI: 0.331-1.073, P = 0.08).
CONCLUSION SVR was associated with lower de novo T2DM and IFG incidence and higher triglyceride levels. Patients infected with HCV should undergo T2DM screening and antidiabetic treatment.
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22
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Zhu C, Gao G, Song H, Xu F, Wu K, Liu X. Hepatitis B virus inhibits apolipoprotein A5 expression through its core gene. Lipids Health Dis 2016; 15:178. [PMID: 27724895 PMCID: PMC5057420 DOI: 10.1186/s12944-016-0340-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/20/2016] [Indexed: 02/08/2023] Open
Abstract
Background Hepatitis B virus (HBV) infection causes lipid metabolism disorders. Apolipoprotein A5 (ApoA5) is a new apolipoprotein family member that plays an important role in the regulation of lipid metabolism. The present study was to investigate the impact of HBV on ApoA5 expression and its regulatory mechanism. Methods Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to measure ApoA5 mRNA and protein expression in HepG2 and HepG2.2.15 cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum ApoA5 levels in healthy individuals and HBV patients. HBV infectious clone pHBV1.3 or individual plasmids expressing the HBV genome was cotransfected with the ApoA5 promoter pGL3-Apo5-LUC plasmid into HepG2 cells to assess the luciferase activity. RT-PCR and western blotting methods were used to detect Apo5 mRNA and protein expression, respectively. Results The ApoA5 mRNA and protein expression levels were decreased in HepG2.2.15 cells compared with the control HepG2 cells. The serum ApoA5 levels were 196.4 ± 28.7 μg/L in the healthy individuals and 104.5 ± 18.3 μg/L in the HBV patients, statistical analysis showed that the ApoA5 levels were significantly lower in HBV patients than in the healthy individuals (P < 0.05). pHBV1.3 and its core gene inhibited ApoA5 promoter activity and mRNA and protein expression in HepG2 cells. Conclusion HBV inhibits ApoA5 expression at both the transcriptional and translational levels through its core gene.
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Affiliation(s)
- Chengliang Zhu
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China
| | - Guosheng Gao
- Department of Clinical Laboratory, Ningbo NO. 2 Hospital, Ningbo, 315010, People's Republic of China
| | - Hui Song
- Department of Clinical Laboratory, Gongli Hospital, Second Military Medicine University, Pudong New Area, Shanghai, 200135, People's Republic of China
| | - Fengxia Xu
- Department of Clinical Laboratory, Gongli Hospital, Second Military Medicine University, Pudong New Area, Shanghai, 200135, People's Republic of China
| | - Kailang Wu
- The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China
| | - Xinghui Liu
- Department of Clinical Laboratory, Gongli Hospital, Second Military Medicine University, Pudong New Area, Shanghai, 200135, People's Republic of China.
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23
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Grammatikos G, Dietz J, Ferreiros N, Koch A, Dultz G, Bon D, Karakasiliotis I, Lutz T, Knecht G, Gute P, Herrmann E, Zeuzem S, Mavromara P, Sarrazin C, Pfeilschifter J. Persistence of HCV in Acutely-Infected Patients Depletes C24-Ceramide and Upregulates Sphingosine and Sphinganine Serum Levels. Int J Mol Sci 2016; 17:E922. [PMID: 27304952 PMCID: PMC4926455 DOI: 10.3390/ijms17060922] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 05/27/2016] [Accepted: 05/31/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.
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Affiliation(s)
- Georgios Grammatikos
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
- Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Julia Dietz
- Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Nerea Ferreiros
- Pharmazentrum Frankfurt, Institut für klinische Pharmakologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany.
| | - Alexander Koch
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Georg Dultz
- Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Dimitra Bon
- Institute of Biostatistics and Mathematical Modelling, Department of Medicine, Goethe University, 60590 Frankfurt am Main, Germany.
| | | | - Thomas Lutz
- Infektiologikum, 60590 Frankfurt am Main, Germany.
| | - Gaby Knecht
- Infektiologikum, 60590 Frankfurt am Main, Germany.
| | - Peter Gute
- Infektiologikum, 60590 Frankfurt am Main, Germany.
| | - Eva Herrmann
- Pharmazentrum Frankfurt, Institut für klinische Pharmakologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany.
| | - Stefan Zeuzem
- Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Penelope Mavromara
- Molecular Virology, Hellenic Pasteur Institute, 11521 Athens, Greece.
- Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Christoph Sarrazin
- Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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24
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Chang ML. Metabolic alterations and hepatitis C: From bench to bedside. World J Gastroenterol 2016; 22:1461-1476. [PMID: 26819514 PMCID: PMC4721980 DOI: 10.3748/wjg.v22.i4.1461] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 08/14/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight.
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25
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Tabll AA, Kodous MA, Abbas AT, Omran MM, Elsayed EH. Association between serum aminotransferase enzymes–lipid profile ratio and spontaneous HCV clearance in blood donors. Future Virol 2016. [DOI: 10.2217/fvl.15.103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Aim: Study the role of the aminotransferase lipid profile ratio in the spontaneous clearance of HCV. Materials & methods: Blood samples from 68 blood donors were classified into three groups: negative for HCV antibodies (control group I), positive anti-HCV with negative HCV-RNA, (group II) and positive anti-HCV with positive HCV-RNA (group III). Results: A significant linear correlation was observed between the HCV-RNA levels and aminotransferase enzymes–lipid profile ratio as indicated by the values of (AST)/triglycerides (r = 0.577; p = 0.003) and ALT/triglycerides (r = 0.508; p < 0.009). AST/high-density lipoprotein had an area under the receiver operating characteristic curve of 0.72 for discriminating between nonspontaneous HCV-clearance from spontaneous HCV-clearance patients. Conclusion: AST/high-density lipoprotein can be used for the prediction of HCV clearance without treatment.
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Affiliation(s)
- Ashraf A Tabll
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
| | - Marwa A Kodous
- Chemistry Department, Faculty of Science, Port-Said University, Port-Said, Egypt
| | - Ayman T Abbas
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdul-Aziz University, Jeddah, Saudi Arabia
- Biotechnology Research Laboratories, Gastroenterology Surgery Center, Mansoura University, Mansoura, Egypt
| | - Mohamed M Omran
- Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Elsherbeny H Elsayed
- Chemistry Department, Faculty of Science, Port-Said University, Port-Said, Egypt
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26
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Del Campo JA, Romero-Gómez M. Modulation of host lipid metabolism by hepatitis C virus: Role of new therapies. World J Gastroenterol 2015; 21:10776-10782. [PMID: 26478669 PMCID: PMC4600579 DOI: 10.3748/wjg.v21.i38.10776] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/07/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
It is well established that hepatitis C virus (HCV) infection and replication relies on host lipid metabolism. HCV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides, circulating infective particles are associated with very low-density lipoprotein. On the other hand, higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HCV infection, suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy (> 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HCV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review, host genetic factors, viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism.
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27
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Sultanik P, Mallet V, Lagaye S, Casrouge A, Dorival C, Barthe Y, Fontaine H, Hézode C, Mottez E, Bronowicki JP, Carrat F, Theodorou I, Abel L, Gayat E, Fontanet A, Pol S, Albert ML. Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy. Liver Int 2015; 35:1833-44. [PMID: 25556540 DOI: 10.1111/liv.12759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 11/20/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort. METHODS We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results. RESULTS We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication. CONCLUSION These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection.
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Affiliation(s)
- Philippe Sultanik
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Vincent Mallet
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Sylvie Lagaye
- INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Armanda Casrouge
- The laboratory of Dendritic Cell Biology, Departement of Immunology, Institut Pasteur, INSERM U818, Paris, France
| | - Céline Dorival
- UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France
| | - Yoann Barthe
- UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France
| | - Hélène Fontaine
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France
| | - Estelle Mottez
- Centre for Human Immunology, Departement of Immunology, Institut Pasteur, INSERM S20, Paris, France
| | - Jean-Pierre Bronowicki
- Centre Hospitalier Universitaire de Nancy, Université de Lorraine, INSERM U954, Vandoeuvre-les-Nancy, France
| | - Fabrice Carrat
- UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France.,Department of Public Health, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Ioannis Theodorou
- Laboratory of Immunity and Infection, Groupe Hospitalier Pitié-Salpêtrière AP-HP, INSERM UMR-S 945, UPMC Université Paris 6, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker branch, INSERM U1163, Paris, France.,University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.,Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New-York, USA
| | - Etienne Gayat
- Department of Anesthesiology and Critical Care Medicine - Mobile Care Unit, Hôpital Lariboisière, AP-HP, Paris, France.,Biomarkers and cardiac diseases, Hôpital Lariboisière, INSERM U942, Paris, France
| | - Arnaud Fontanet
- Departement of Epidemiology of Infectious Disease, Institut Pasteur, Paris, France
| | - Stanislas Pol
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Matthew L Albert
- The laboratory of Dendritic Cell Biology, Departement of Immunology, Institut Pasteur, INSERM U818, Paris, France.,Centre for Human Immunology, Departement of Immunology, Institut Pasteur, INSERM S20, Paris, France
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Mechie NC, Goralzcyk AD, Reinhardt L, Mihm S, Amanzada A. Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study. BMC Res Notes 2015; 8:260. [PMID: 26109044 PMCID: PMC4479221 DOI: 10.1186/s13104-015-1248-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 06/17/2015] [Indexed: 12/18/2022] Open
Abstract
Background Chronic hepatitis C (CHC) is a global health challenge. New therapeutic agents with excellent sustained virological response (SVR) rates are available mainly in developed countries, while the majority of CHC patients live in countries with low health budget. Predictors of therapeutic response are therefore necessary. Vitamin B12 appears to be involved in hepatitis C virus replication. Methods We therefore studied retrospectively the relationship between baseline serum vitamin B12 levels and clinical features in 116 CHC genotype 1 infected patients. Logistic regression models with univariate and multivariate analysis were used in the statistical analysis. Results Baseline serum vitamin B12 levels were found to be positively associated with serum transaminase activities (AST, p = 0.002, ALT, p = 0.04), baseline viral load (p < 0.0001), stage of fibrosis (p = 0.0001) and favorable interferon-λ3/4 (IFNL3/IFNL4) rs12979860 genotypes (p = 0.04), and inversely with SVR (p < 0.001) as well as with rapid virological response (p = 0.001). Patients with baseline serum vitamin B12 levels below a cut-off value of 570 ng/L achieved a SVR rate of 59% with an odds ratio (OR) of 13.4 [confidence interval (CI) 4.3–41.9, p < 0.0001] compared to patients above the cut-off value. By combining serum vitamin B12 levels and IFNL3/IFNL4 rs12979860 genotypes, patients with baseline serum vitamin B12 levels below the cut-off value of 570 ng/L and IFNL3/IFNL4 rs12979860 CC genotype achieved a SVR rate of even 80% with an OR of 54 (CI 9.9–293, p < 0.0001) compared to patients above the cut-off value and non-CC-genotypes. Conclusion Our data suggest baseline serum vitamin B12 levels as useful noninvasive marker for characterizing CHC patients. They might further help to identify responders to a standard treatment.
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Affiliation(s)
- Nicolae-Catalin Mechie
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
| | - Armin D Goralzcyk
- Division of Internal Medicine, Clinic of Herzberg and Osterode, Dr Froessel Allee, 37412, Herzberg am Harz, Germany.
| | - Lars Reinhardt
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
| | - Sabine Mihm
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
| | - Ahmad Amanzada
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
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29
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Jiménez Macías FM, Barrero Alor F, Casado Monge PG, Ramos Lora M, Pujol de la Llave E, Ruíz-Frutos C. [Lipid kinetics during dual antiviral therapy in patients with chronic hepatitis C]. Med Clin (Barc) 2015; 144:536-43. [PMID: 24726260 DOI: 10.1016/j.medcli.2013.12.016] [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: 03/24/2013] [Revised: 12/17/2013] [Accepted: 12/18/2013] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND OBJECTIVE We analyzed baseline and kinetic characteristics of lipid metabolism during the first month of bitherapy in patients with chronic hepatitis C genotype 1 (CHC-1). PATIENTS AND METHODS A longitudinal, prospective study including 99 naïve CHC-1 patients with liver biopsy who were treated with bitherapy. Our patients were assigned to one of 5 different "degrees of lipid requirement" that we established depending on the degree of liver fibrosis, baseline viral load and infectivity ratio (ratio between the median level of triglycerides and high densitity lipoproteins-cholesterol during the first month). The goal was to achieve "a favorable lipid metabolism" (FLM) by establishing a necessary minimum level of low density lipoproteins (LDL)-cholesterol during this period for each one of them. We also analyzed the relationship with the rate of sustained virological response. RESULTS Patients with liver fibrosis F3-F4 who had higher baseline levels of LDL-cholesterol achieved higher rates of sustained virological response. Those patients who had a lower value of infectivity ratio and median levels of LDL-cholesterol during the first month of bitherapy also achieved higher rates of sustained virological response: SVR group 100 (23) mg/dl against non-SVR group: 89 (28) mg/dl; odds ratio 1.1; 95% confidence interval (1.0-1.2); P<.05, these differences being more significant for genotype IL-28B-CC (P=.013). Patients with sustained virological response had higher rates of FLM. CONCLUSIONS Not every patient with CHC-1 has the same lipid kinetics during the first month of bitherapy, and it is necessary to achieve a sustained virological response and/or a FLM to keep higher plasma levels of LDL-cholesterol during this period. Those subjects without FLM could benefit from statins.
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Affiliation(s)
| | - Fátima Barrero Alor
- Departamento de Biología Molecular y Bioquímica, Hospital Juan Ramón Jiménez, Huelva, España
| | | | | | | | - Carlos Ruíz-Frutos
- Departamento de Biología Ambiental y Salud Pública, Universidad de Huelva, Huelva, España
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Abe H, Tsubota A, Shimada N, Atsukawa M, Kato K, Takaguchi K, Asano T, Chuganji Y, Sakamoto C, Toyoda H, Kumada T, Ide T, Sata M, Aizawa Y. Factors associated with sustained virological response in 24-week telaprevir-based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype. Hepatol Res 2015; 45:387-96. [PMID: 24849518 DOI: 10.1111/hepr.12360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/11/2014] [Accepted: 05/15/2014] [Indexed: 02/08/2023]
Abstract
AIM Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. METHODS Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). RESULTS Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. CONCLUSION In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.
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Affiliation(s)
- Hiroshi Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan
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31
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Solbach P, Westhaus S, Deest M, Herrmann E, Berg T, Manns MP, Ciesek S, Sarrazin C, von Hahn T. Oxidized Low-Density Lipoprotein Is a Novel Predictor of Interferon Responsiveness in Chronic Hepatitis C Infection. Cell Mol Gastroenterol Hepatol 2015; 1:285-294.e1. [PMID: 28210681 PMCID: PMC5301270 DOI: 10.1016/j.jcmgh.2015.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 03/03/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C. METHODS Baseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells. RESULTS In the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment. CONCLUSIONS Oxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.
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Key Words
- Cell-to-Cell Spread
- DAA, direct-acting antiviral drug
- DMEM, Dulbecco’s modified Eagle medium
- DTT, dithiothreitol
- HCV, hepatitis C virus
- HCVcc, cell culture–grown hepatitis C virus
- IPS1, interferon promoter stimulator-1
- ITX-5061, N-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-2-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]-2-oxoacetamide;hydrochloride
- LDL, low-density lipoprotein
- NLS, nuclear localization signal
- PBS, phosphate-buffered saline
- RBV, ribavirin
- RFP, red fluorescent protein
- ROC, receiver operating characteristic
- SR-BI
- SR-BI, scavenger receptor class B member I
- SVR
- SVR, sustained virologic response
- oxLDL
- oxLDL, oxidized low-density lipoprotein
- peg-IFN, pegylated interferon α
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Affiliation(s)
- Philipp Solbach
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Sandra Westhaus
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Maximilian Deest
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany
| | - Thomas Berg
- Hepatology Section, Department of Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Sandra Ciesek
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Christoph Sarrazin
- German Center for Infection Research (DZIF), Hannover, Germany,Medical Clinic I, Zentrum der Inneren Medizin, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany
| | - Thomas von Hahn
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany,Correspondence Address correspondence to: Thomas von Hahn, MD, Medizinische Hochschule Hannover, Institut für Molekularbiologie, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. fax: +49 511 532-4896.
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Laird ME, Mohsen A, Duffy D, Mamdouh R, LeFouler L, Casrouge A, El-Daly M, Rafik M, Abdel-Hamid M, Soulier A, Pawlotsky JM, Hézode C, Rosa I, Renard P, Mohamed MK, Bonnard P, Izopet J, Mallet V, Pol S, Albert ML, Fontanet A. Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection. J Hepatol 2014; 61:770-6. [PMID: 24905490 DOI: 10.1016/j.jhep.2014.05.040] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 05/05/2014] [Accepted: 05/25/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment. METHODS We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance. RESULTS Plasma apolipoprotein H (ApoH) levels were significantly higher in patients who achieved spontaneous clearance or responded to pegylated-interferon/ribavirin therapy. Strikingly, patients carrying the IL28B rs12979860 CC SNP correlated with the plasma concentration of ApoH in all three cohorts. Both ApoH and IL28B CC SNP were associated with HCV clearance in univariate analysis. Additional multivariate analysis revealed that the association between IL28B and HCV clearance was closely linked to that of Apo H and HCV clearance, suggesting that both belong to the same biological pathway to clearance. The association between IL28B CC SNP and ApoH was not observed in healthy individuals, suggesting that early post-infection events trigger differential ApoH expression in an IL28B allele dependent manner. CONCLUSIONS This relationship identifies ApoH as the first induced protein quantitative trait associated with IL28B, and characterises a novel host factor implicated in HCV clearance.
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Affiliation(s)
- Melissa E Laird
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France
| | - Amira Mohsen
- Community Medicine Department, National Research Center, Cairo, Egypt
| | - Darragh Duffy
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France
| | - Rasha Mamdouh
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Lenaig LeFouler
- Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France
| | - Armanda Casrouge
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France
| | - Mai El-Daly
- Liver Disease Research Unit, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | - Mona Rafik
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Abdel-Hamid
- Liver Disease Research Unit, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt; Faculty of Medicine, Minia University, Egypt
| | - Alexandre Soulier
- National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France
| | - Christophe Hézode
- INSERM U955, Créteil, France; Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Isabelle Rosa
- INSERM U955, Créteil, France; Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Philippe Renard
- Department of Gastroenterology and Hepatology, Hôpital Victor Dupouy, Argenteuil, France
| | - Mostafa K Mohamed
- Liver Disease Research Unit, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | - Philippe Bonnard
- Maladies Infectieuses et Tropicales, Hôpital Tenon (APHP), Paris, France; INSERM U-707, UPMC, Paris, France
| | - Jacques Izopet
- Department of Virology, CHU Toulouse, Toulouse, France; INSERM U1043, IFR-BMT, Toulouse, France
| | - Vincent Mallet
- Université Paris Descartes, Paris, France; Institut Cochin, INSERM (IMR-S1016), CNRS (UMR 8104), Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hepatologie, Paris, France
| | - Stanislas Pol
- Université Paris Descartes, Paris, France; Institut Cochin, INSERM (IMR-S1016), CNRS (UMR 8104), Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hepatologie, Paris, France
| | - Matthew L Albert
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hepatologie, Paris, France.
| | - Arnaud Fontanet
- Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France; Conservatoire National des Arts et Métiers, Paris, France.
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Niederau C, Mauss S, Schober A, Stoehr A, Zimmermann T, Waizmann M, Moog G, Pape S, Weber B, Isernhagen K, Sandow P, Bokemeyer B, Alshuth U, Steffens H, Hüppe D. Predictive factors for sustained virological response after treatment with pegylated interferon α-2a and ribavirin in patients infected with HCV genotypes 2 and 3. PLoS One 2014; 9:e107592. [PMID: 25238535 PMCID: PMC4169557 DOI: 10.1371/journal.pone.0107592] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 08/12/2014] [Indexed: 12/15/2022] Open
Abstract
Background Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management. Aims The present study looks for differences between the two genotypes and analyzes predictive factors for SVR. Methods Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012. Results When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis. Conclusions The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis. Trial Registration Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov NCT02106156
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Affiliation(s)
- Claus Niederau
- Clinic for Internal Medicine, St. Josef Hospital, Oberhausen, Germany
- * E-mail:
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
| | | | - Albrecht Stoehr
- ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
| | - Tim Zimmermann
- 1st Medical Clinic, Dept. Gastroenterology and Hepatology, Johannes Gutenberg University of Mainz, Mainz, Germany
| | | | - Gero Moog
- Center of Gastroenterology, Kassel, Germany
| | - Stefan Pape
- Center of Gastroenterology, Paderborn, Germany
| | - Bernd Weber
- Competence Center for Addiction, Praxiszentrum Friedrichsplatz, Kassel, Germany
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Chang ML, Tsou YK, Hu TH, Lin CH, Lin WR, Sung CM, Chen TH, Cheng ML, Chang KC, Chiu CT, Yeh CT, Pang JHS, Shiao MS. Distinct patterns of the lipid alterations between genotype 1 and 2 chronic hepatitis C patients after viral clearance. PLoS One 2014; 9:e104783. [PMID: 25122116 PMCID: PMC4133245 DOI: 10.1371/journal.pone.0104783] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The hepatitis C virus (HCV) genotype-specific impacts on the host metabolic alterations remained inconclusive. METHODS A prospective study including 229 (118 genotype 1 (G1) and 111 G2) consecutive chronic HCV patients who had completed a course of anti-HCV treatment and underwent pre- and 24 weeks post-treatment surveys of metabolic profiles was conducted. Patients were stratified according to the therapeutic response, viral genotype and baseline insulin resistance (IR: homeostasis model assessments of IR (HOMA-IR) ≥ 2.5). Paired t-tests were used to compare the pre- and post-treatment variables. RESULTS Significant post-therapeutic increases in cholesterol, triglyceride, HDL, LDL, apolipoprotein A1 and apolipoprotein B were observed in patients with sustained virological response (SVR) but not in those without. Among those with SVR, post-therapeutic increases in HDL (p<0.001) and apolipoprotein A1 (p = 0.012) were only found in G2, whereas increased triglyceride/HDL (p = 0.01) ratios were only found in G1 patients. When stratified by baseline IR among those with SVR, a significant increase in post-treatment HDL (p = 0.019) and apolipoprotein A1 (p = 0.012) but a decrease in HOMA-IR (p = 0.04), C-peptide (p = 0.019) and hemoglobin A1c (p = 0.047) were found in patients with baseline IR; a significant increase in HOMA-IR (p = 0.002) was found in patients without baseline IR. The latter change was observed only in G1 (p = 0.01) but not G2 patients. Although the pre-treatment metabolic profiles of G1 and G2 patients were indifferent, G1 had higher post-treatment triglyceride/HDL ratios (p = 0.041) and triglyceride (p = 0.044) levels than G2 patients. CONCLUSIONS G2 benefit more than G1 patients from viral clearance in metabolic alterations, particularly in those without baseline IR.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Kuan Tsou
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Hui Lin
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wey-Ran Lin
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chang-Mu Sung
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tsung-Hsing Chen
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Mei-Ling Cheng
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Tang Chiu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jong-Hwei Su Pang
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Shi Shiao
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
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Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, Zeuzem S, Herrmann E. The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepat 2014; 21:533-41. [PMID: 24943517 DOI: 10.1111/jvh.12274] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 05/25/2014] [Indexed: 12/16/2022]
Abstract
Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, whereas combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. We conducted a literature search to identify trials that included monoinfected HCV patients, treated with statins or fibrates as monotherapy with the primary end point of our meta-analysis being the quantitative change of HCV-RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CIs) were calculated according to the DerSimonian-Laird estimate. Statistical heterogeneity was assessed with the I² statistic. We identified eight observational studies that evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV-RNA in HCV-monoinfected patients (n = 281). Overall, a significant reduction of viral load with mean 0.19 [log10 IU/mL] (95%-confidence interval, (CI) 0.11-0.28) could be observed when antihyperlipidemic medications were administered. Bezafibrate featured the highest antiviral efficacy (0.45 log10 reduction, 95%-CI, 0.17-0.72) among all medications and fluvastatin (0.20 log10 reduction, 95%-CI, 0.09-0.31) among all statins tested. Based on meta-analysis, fibrates and statins induce a reduction of HCV viral load. We suggest that the addition of statins and fibrates to antiviral regimes, especially in HCV patients with concomitant dyslipidemia, could beside the established reduction of cardiovascular risk increase the potency of antiviral therapy.
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Affiliation(s)
- G Grammatikos
- University Hospital Frankfurt, Frankfurt am Main, Germany
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Van Thiel DH, George M, Attar BM, Ramadori G, Ion-Nedelcu N. Plasma triglyceride levels may modulate hepatitis C viral replication. Dig Dis Sci 2014; 59:881-5. [PMID: 24563239 DOI: 10.1007/s10620-014-3079-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 02/11/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND Plasma and hepatic lipid abnormalities are frequent in hepatitis C infected individuals. METHODS Plasma lipid and medical records profiles were prospectively obtained in 130 consecutive individuals seen by a single hepatologist in a university liver disease clinic. The relationships between viral load, genotype, plasma lipid fractions, HDL, LDL particle number and particle size were examined. RESULTS Of 130 individuals studied, 74 had hepatitis C while 15 had NAFLD/NASH and 30 had alcohol related liver disease. The LDL particle number and LDL-C levels did not differ between those with and without hepatitis C although the number of small LDL particles was greater in those with hepatitis C infection. The HDL-C and total cholesterol levels were greater in those without hepatitis C than those with hepatitis C (P = 0.009). In contrast, the serum triglyceride level was greater in the hepatitis C viral group (P = 0.013). Importantly, the hepatitis C viral load regardless of the genotype correlated directly with the triglyceride and VLDL levels with r values of 0.73 and 0.84, respectively. CONCLUSIONS There are: (1) important differences in lipid classes, number and the size of lipid particles exist between hepatitis C virus infected and noninfected liver disease groups, (2) the serum total triglyceride and the LDL levels correlate significantly with the hepatitis C viral load and, (3) Serum triglyceride level may play an important role in viral replication. These data further suggest that therapies directed at lowering plasma triglyceride levels may enhance the efficacy of current antiviral treatment regimens.
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Gatselis NK, Zachou K, Saitis A, Samara M, Dalekos GN. Individualization of chronic hepatitis C treatment according to the host characteristics. World J Gastroenterol 2014; 20:2839-53. [PMID: 24659876 PMCID: PMC3961989 DOI: 10.3748/wjg.v20.i11.2839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/19/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
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Grasso A, Malfatti F, Testa R. Are metabolic factors still important in the era of direct antiviral agents in patients with chronic hepatitis C? World J Gastroenterol 2013; 19:6947-6956. [PMID: 24222938 PMCID: PMC3819530 DOI: 10.3748/wjg.v19.i41.6947] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/27/2013] [Accepted: 08/17/2013] [Indexed: 02/06/2023] Open
Abstract
The high rate of sustained viral response (SVR) to boceprevir or telaprevir-based triple therapy in hepatitis C (HCV)-related, non-cirrhotic naïve patients or relapsers to previous antiviral treatment leads clinicians to believe that the impact of metabolic host factors on SVR is minimal when triple therapy is used, unlike what is observed with the peginterferon and ribavirin schedules. This concept is strongly expressed by some opinion leaders on the basis of the data derived from sub-analyses of registrative trials as well as from a post-hoc analysis of the phase II C208 clinical trial. The perception of unrestrainable therapeutic success with the use of newer, more powerful antivirals is now reinforced by the brilliant results obtained with sofosbuvir, an HCV NS5B polymerase inhibitor, as well as by the data from the phase II and III studies on the various combinations of second-generation NS3/4A inhibitors and NS5A and/or NS5B inhibitors. However, a great deal of concern has emerged from the real world scenario in which patients are often older and have more comorbidities than patients in the “world of trials”. Furthermore, many of them have advanced fibrosis and previous failure with peginterferon and ribavirin treatment. Some data from the recent literature suggest that the host metabolic factors may play a minor but non-negligible role in these difficult-to-treat patients, an issue that will hopefully be investigated in further studies. This editorial aims to provide a detailed analysis of the role that host metabolic factors played in the past and what role they may play in the era of direct antiviral agents.
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Eslam M, Booth DR, George J, Ahlenstiel G. Interaction of IFNL3 with insulin resistance, steatosis and lipid metabolism in chronic hepatitis C virus infection. World J Gastroenterol 2013; 19:7055-61. [PMID: 24222948 PMCID: PMC3819540 DOI: 10.3748/wjg.v19.i41.7055] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Revised: 09/14/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
Metabolic changes are inextricably linked to chronic hepatitis C (CHC). Recently polymorphisms in the IFNL3 (IL28B) region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus (HCV) infection. Further, circumstantial evidence suggests a link between IFNL3 single nucleotide polymorphisms and lipid metabolism, steatosis and insulin resistance in CHC. The emerging picture suggests that the responder genotypes of IFNL3 polymorphisms are associated with a higher serum lipid profile, and less frequent steatosis and insulin resistance. This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.
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Metabolic factors and chronic hepatitis C: a complex interplay. BIOMED RESEARCH INTERNATIONAL 2013; 2013:564645. [PMID: 23956991 PMCID: PMC3730187 DOI: 10.1155/2013/564645] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/29/2013] [Indexed: 12/15/2022]
Abstract
In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.
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Aizawa Y, Shimada N, Abe H, Seki N, Aida Y, Ishiguro H, Ika M, Kato K, Tsubota A. Serum lipoprotein profiles and response to pegylated interferon plus ribavirin combination therapy in patients with chronic HCV genotype 1b infection. HEPATITIS MONTHLY 2013; 13:e8988. [PMID: 23967025 PMCID: PMC3743300 DOI: 10.5812/hepatmon.8988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 03/07/2013] [Accepted: 04/07/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Abnormal serum lipid profiles have been noted in patients with chronic hepatitis C virus (HCV) infection. Moreover, many reports suggest that serum lipoprotein profiles are more profoundly distorted in patients with HCV G1b infection who have an unfavorable response to pegylated interferon (peg-IFN) plus ribavirin (RBV) combination therapy. However, after the discovery of single nucleotide polymorphisms near the IL28B gene (rs8099917 and rs12979860) as potent predictive factors affecting the response to peg-IFN plus RBV, lipid factors are thought to be confounding factors. OBJECTIVES To re-examine the significance of lipoprotein profiles on virological response to peg-IFN plus RBV combination therapy in patients with chronic HCV G1b infection, we examined cholesterol and triglyceride concentrations in each lipoprotein fraction separated by high performance liquid chromatography. PATIENTS AND METHODS Lipoprotein profiles were examined using fasting sera from 108 patients infected with HCV G1b who had chronic hepatitis, as determined by liver biopsy. Results of lipoprotein profiles and clinical data, including IL28B genotype and amino acid substitution at aa70 of HCV G1b, were compared between patients with a sustained virological response (SVR) and non-SVR or a non-virological response (NVR) and virological responses other than NVR (non-NVR). In addition, significant predictive factors independently associated with virological response to peg-IFNα-2b plus RBV were determined by logistic regression analysis. RESULTS An increased ratio of cholesterol/triglyceride in very low-density lipoprotein (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.01-9.44) along with a major genotype of rs8099917 (OR 9.09; 95% CI 2.94-33.33), were independent predictive factors for SVR. In contrast, lipid factors were not elucidated as independent predictive factors for NVR. CONCLUSIONS Examination of the fasting lipid profile has clinical importance in predicting the efficacy of peg-IFN-α-2b plus RBV combination therapy for patients with HCV G1b even after the discovery of the IL28 genotype as a potent predictive factor.
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Affiliation(s)
- Yoshio Aizawa
- Department of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan
- Corresponding author: Yoshio Aizawa, Department of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan, Tel.: +81-336032111, Fax: +81-338389944, E-mail:
| | - Noritomo Shimada
- Department of Gastroenterology and Hepatology, Shinmatsudo Chuo General Hospital, Chiba, Japan
| | - Hiroshi Abe
- Department of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuyoshi Seki
- Department of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan
| | - Yuta Aida
- Department of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan
| | - Haruya Ishiguro
- Department of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan
| | - Makiko Ika
- Department of Gastroenterology and Hepatology, Shinmatsudo Chuo General Hospital, Chiba, Japan
| | - Keizo Kato
- Department of Gastroenterology and Hepatology, Shinmatsudo Chuo General Hospital, Chiba, Japan
| | - Akihito Tsubota
- Institute of Clinical Medicine and Research, Jikei University Kashiwa Hospital, Chiba, Japan
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Hepatitis C virus, cholesterol and lipoproteins--impact for the viral life cycle and pathogenesis of liver disease. Viruses 2013; 5:1292-324. [PMID: 23698400 PMCID: PMC3712309 DOI: 10.3390/v5051292] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/10/2013] [Accepted: 04/27/2013] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.
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Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C. Proc Natl Acad Sci U S A 2013; 110:7844-9. [PMID: 23613588 DOI: 10.1073/pnas.1306138110] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.
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Intensified peginterferon α-2a dosing increases sustained virologic response rates in heavy, high viral load hepatitis C genotype 1 patients with high low-density lipoprotein. J Clin Gastroenterol 2013; 47:271-9. [PMID: 22951527 DOI: 10.1097/mcg.0b013e31826102eb] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND GOAL Patients infected with hepatitis C virus (HCV) with elevated low-density lipoprotein (LDL) levels achieve higher sustained virologic response (SVR) rates after peginterferon (PegIFN)/ribavirin treatment versus patients with lower LDL. Our aim was to determine whether SVR rates in patients with low/elevated LDL can be improved by dose intensification. STUDY In PROGRESS, genotype 1 patients with baseline HCV RNA ≥ 400,000 IU/mL and body weight ≥ 85 kg were randomized to 48 weeks of 180 µg/wk PegIFN α-2a (40 kDa) plus ribavirin (A: 1200 mg/d; B: 1400/1600 mg/d) or 12 weeks of 360 µg/wk PegIFN α-2a followed by 36 weeks of 180 µg/wk, plus ribavirin (C: 1200 mg/d; D: 1400/1600 mg/d). This retrospective analysis assessed SVR rates among patients with low (<100 mg/dL) or elevated (≥ 100 mg/dL) LDL. Patients with high LDL (n=256) had higher baseline HCV RNA (5.86 × 10(6) IU/mL) versus patients with low LDL (n=262; 4.02 × 10(6) IU/mL; P=0.0003). RESULTS Multiple logistic regression analysis identified a significant interaction between PegIFN α-2a dose and LDL levels on SVR (P=0.0193). The only treatment-related SVR predictor in the nested multiple logistic regression was PegIFN α-2a dose among patients with elevated LDL (P=0.0074); therefore, data from the standard (A+B) and induction (C+D) dose arms were pooled. Among patients with low LDL, SVR rates were 40% and 35% in the standard and induction-dose groups, respectively; SVR rates in patients with high LDL were 44% and 60% (P=0.014), respectively. CONCLUSIONS Intensified dosing of PegIFN α-2a increases SVR rates in patients with elevated LDL even with the difficult-to-cure characteristics of genotype 1, high baseline viral load, and high body weight.
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Sheridan DA, Neely RDG, Bassendine MF. Hepatitis C virus and lipids in the era of direct acting antivirals (DAAs). Clin Res Hepatol Gastroenterol 2013; 37:10-6. [PMID: 22959093 DOI: 10.1016/j.clinre.2012.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Revised: 07/23/2012] [Accepted: 07/25/2012] [Indexed: 02/07/2023]
Abstract
The six different HCV-genotypes have marked differences in response to therapy with pegylated interferon-α and ribavirin. The introduction of the direct acting antiviral (DAA) protease inhibitors, telaprevir and boceprevir in combination with pegylated interferon-α and ribavirin has become the new standard of care for genotype 1 infection. Several host factors associated with response to pegylated interferon-α and ribavirin are not as important in predicting response to triple therapy, and yet low-density lipoprotein cholesterol (LDLC) and statin use remain important associations of outcome with DAAs. This review focuses on the clinical associations between lipids and treatment response to interferon based antiviral treatments. We consider how understanding the interactions of HCV and host lipid metabolism remains relevant in the era of DAAs for genotype 1 infection and for treatment of non-genotype 1 chronic hepatitis C.
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Affiliation(s)
- David A Sheridan
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
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Hsu CS, Hsu SJ, Liu WL, Chen CL, Liu CJ, Chen PJ, Chen DS, Kao JH. IL-21R gene polymorphisms and serum IL-21 levels predict virological response to interferon-based therapy in Asian chronic hepatitis C patients. Antivir Ther 2013; 18:599-606. [PMID: 23296193 DOI: 10.3851/imp2502] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2012] [Indexed: 10/27/2022]
Abstract
BACKGROUND IL-21R polymorphisms have been identified as potential predictors of virological outcomes in Western chronic hepatitis C (CHC) patients receiving interferon-based treatment. We aimed to examine the associations of IL-21R genotypes and serum IL-21 levels with virological responses to interferon-based treatment in Asian CHC patients. METHODS Genomic and clinical data were collected from 178 consecutive Taiwanese HCV genotype 1 patients who received interferon-based therapy and 72 non-HCV healthy subjects. Among them, serum IL-21 levels, IL-21R and IL-28B genotypes were determined in 124 CHC patients and healthy controls. RESULTS Among patients with IL28B rs8099917 non-TT genotypes, patients with IL-21R rs3093390 CC genotype had a higher sustained virological response rate than those with non-CC genotypes (CC versus non-CC 14/24 versus 0/4; P = 0.031). Compared with non-HCV controls, CHC patients had higher serum IL-21 levels (mean ± sd HCV versus non-HCV 377.8 ± 780.9 versus 70.5 ± 33.2 pg/ml; P = 0.001). Patients with sustained virological response had higher pretreatment serum IL-21 levels than those without (adjusted OR 0.23, 95% CI 0.07, 0.80; P = 0.021). CONCLUSIONS CHC patients have higher serum IL-21 levels than healthy adults. Higher pretreatment serum IL-21 levels and IL-21R polymorphisms may serve as potential factors predictive of treatment outcomes in CHC patients with interferon-based therapy.
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Affiliation(s)
- Ching-Sheng Hsu
- Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
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Del Campo JA, Ampuero J, Rojas L, Conde M, Rojas A, Maraver M, Millán R, García-Valdecasas M, García-Lozano JR, González-Escribano MF, Romero-Gómez M. Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism. Aliment Pharmacol Ther 2013; 37:74-80. [PMID: 23121166 DOI: 10.1111/apt.12113] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 07/22/2012] [Accepted: 10/09/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Insulin resistance has been strongly associated with the attainment of sustained viral response (SVR) in hepatitis C patients. AIM To determine, in a cohort of Spanish patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R), whether insulin resistance predicts SVR independently of interleukin-28B rs12979860 polymorphism. METHODS Insulin resistance was measured as [HOMA-IR = Insulin (IU/mL)*glucose (mmol/L)/22.5]. Genotype, viral load and histological fibrosis using Scheuer score were also measured. Binary logistic regression analysis was used for statistical purposes. RESULTS In a cohort of 240 patients [78% genotype 1, 24% showing advanced fibrosis, 71% high viral load (≥800 000 IU/mL), 31% IL28b genotype CC and 50% with HOMA >2] treated with P+R, 126 (53%) reached SVR. HOMA-IR index (HOMA <2: 63% vs. HOMA >2: 42%; P = 0.001 and IL28b (genotype CC: 68% vs. genotype CT/TT: 45%; P = 0.002) were significantly associated with SVR. In multivariable logistic regression analysis in the overall cohort, variables independently associated were: viral genotype OR: 0.29 (95% CI: 0.11-0.78), P = 0.01; fibrosis OR: 1.62 (95% CI: 1.22-2.16), P = 0.001; HOMA-IR OR: 1.22 (95% CI: 1.02-1.47), P = 0.03; and IL28B genotype OR: 2.43 (95% CI: 1.45-4.07), P = 0.001. The analyses also showed that degree of steatosis, HOMA-IR >2, mild fibrosis and IL28B CC genotype were significantly related to SVR in patients infected with HCV genotypes 1&4, but not in those with genotypes 2&3. No differences were seen in glucose, insulin level or HOMA-IR index segregated according to IL28B genotypes. CONCLUSION Our results suggest that insulin resistance, fibrosis stage and IL28B polymorphisms were independent variables associated with sustained viral response.
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Affiliation(s)
- J A Del Campo
- UCM Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
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Baseline serum cholesterol is associated with a response to pegylated interferon alfa-2b and ribavirin therapy for chronic hepatitis C genotype 2. Gastroenterol Res Pract 2012. [PMID: 23193392 PMCID: PMC3501951 DOI: 10.1155/2012/317580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P = 0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.
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Li L, Luo M, Yang EN, Wang R, Wang HQ, Cao WK. Relationship between efficacy of antiviral treatment and changes in blood lipid metabolism in patients with chronic hepatitis C. Shijie Huaren Xiaohua Zazhi 2012; 20:2961-2965. [DOI: 10.11569/wcjd.v20.i30.2961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe changes in blood lipid metabolism in patients with chronic hepatitis C (CHC) who have received antiretroviral treatment, and to investigate the relationship between efficacy of antiviral treatment and changes in blood lipid metabolism.
METHODS: Seventy-four patients with CHC who have received pegylated interferon α-2α and ribavirin for 48 wk were followed. HCV-RNA quantification and serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) at 0, 12, 24, and 48 wk were detected and analyzed.
RESULTS: Sustained virological response (SVR) was found in 43 (58%) patients with CHC, and 31 (42%) patients had non-sustained virological response (Non-SVR). Although the SVR group had lower serum levels of TG, TC, HDL-C and higher serum levels of LDL-C before antiviral treatment, there were no significant differences in these parameters between the two groups. The changes in serum levels of different parameters showed different trends during the treatment. TG levels showed an increasing trend in both groups. Serum levels of HDL-C decreased more visibly in the SVR group than in the non-SVR group, but there was no significant difference between them. The decreasing trend of LDL-C levels was the same between the two groups at the early stage of treatment; however, serum levels of LDL-C gradually increased after 12 wk in the non-SVR group, although serum levels of LDL-C at 48 wk were still lower than baseline level, and HCV-RNA was still detectable. Serum LDL-C was maintained at low levels in the SVR group until the end of treatment, although HCV-RNA was undetectable at this time. After 12 weeks of treatment, serum levels of TC significantly decreased in the SVR group compared to those in the non-SVR group.
CONCLUSION: Efficacy of antiviral treatment is closely associated with changes in blood lipid metabolism in patients with CHC. Our finding that serum levels of LDL-C were low before treatment and rebounded during treatment indicates that the efficacy was not good. Lower serum levels of TC are beneficial to the efficacy of antiviral treatment.
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Abstract
In 2009, several different research groups simultaneously identified the polymorphisms close to IL28B gene as an important predictor of therapeutic response for chronic hepatitis C (CHC) patients receiving interferon-based treatment using approaches of genome-wide association studies. They also found that these genetic variations were strongly associated with the spontaneous viral clearance of hepatitis C virus (HCV) infection. Following these studies, ITPA gene variants were reported to affect ribavirin-induced anemia and therapeutic outcomes of CHC patients. All these lines of evidence usher in a new genomic era for the management of HCV infection. In this article, advances in recent genome-wide association studies regarding HCV infection, and their impacts on the management of CHC patients will be reviewed. In addition, the clinical usefulness of genomic variations on the addition of direct antiviral agents to current standard of care will be discussed.
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Affiliation(s)
- Ching-Sheng Hsu
- Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan
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