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系統識別號 U0026-1507202016055100
論文名稱(中文) 接受直接抗病毒藥物之慢性C 型肝炎患者血漿脂質分析及數據資料探勘
論文名稱(英文) Plasma lipid profiling of chronic hepatitis C patients receiving direct anti-viral agents by integrating laboratory and data mining platform
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 108
學期 2
出版年 109
研究生(中文) 陳曉梅
研究生(英文) Dyoness Charmaine Tan
學號 T36077016
學位類別 碩士
語文別 英文
論文頁數 79頁
口試委員 指導教授-楊孔嘉
召集委員-鄭如茜
口試委員-傅子芳
口試委員-林韋伶
口試委員-鄭斌男
中文關鍵字 C 型肝炎病毒  直接抗病毒藥物  血漿脂質代謝 
英文關鍵字 direct-acting anti-viral agent  hepatitis C virus  lipid metabolism 
學科別分類
中文摘要 C型肝炎病毒(HCV)感染造成世界巨大的健康負擔,並且是肝臟衰竭的主要原因之一。 先前研究證實,HCV在人體生長過程中會調節宿主細胞中的脂質合成與代謝,有脂質參與導致肝脂質累積。HCV會抑制肝臟分泌極低密度脂蛋白 (Very low density lipoprotein; VLDL) 到血液中,導致肝臟內VLDL的累積,提供病毒複製與合成的環境。另外,因為脂質在肝臟累積,無法釋放到血液中合成低密度蛋白(Low density lipoproteins; LDL),會使HCV患者脂質代謝失衡,造成慢性C型肝炎病毒(Chronic hepatitis C, CHC)的血脂代謝紊亂。目前,直接抗病毒藥物(Direct acting antiviral agents; DAA)是最新有效根除HCV。但是,DAA 是否能利於改善CHC患者血脂代謝問題仍然不清楚。先前研究發現,膽固醇和LDL脂質分佈的增加會提高心血管硬化的風險。因此,本研究想深入分析40 位CHC患者接受DAA治療後,長期(一年) 追蹤各類脂質及脂蛋白的變化,並計算患者的心血管風險並比較基因型1與2之間的差異。患者接受為期12週DAA藥物治療。我們收集了患者在治療前以及治療後12周24周,以及追蹤半年至一年的血漿。將血漿進行兩次高速密度梯度離心,分離出血漿中的VLDL,LDL 和高密度脂蛋白 (HDL) 分離出來。純化後的脂蛋白進行三酸甘油酯 (Triglycerides, TG) ,膽固醇 (Cholesterol, Chol) 和載脂蛋白B (apolipoprotein B) 的定量分析。脂蛋白三酸甘油酯和膽固醇負荷能力是通過將載脂蛋白B標準化來計算,以及評估DAA治療對CHC患者脂肪代謝的影響。在本研究中發現,患者DAA治療後,基因型1和2的患者血漿中的Chol 皆有增加的情形,代表DAA治療後患者的脂質不再累積於肝臟中,可供周邊循環系統使用,脂肪累積在肝臟的現象可能得以緩解。相較於基因型2的病人,DAA治療後基因型1病人的VLDL中的TG 相對於Chol 的比例值上升,這顯示TG的水解效率得到提升。此外,在成功消除HCV感染後,基因型2患者的膽固醇升高因而可能增加了心血管塞風險。結果表明,DAA藥物可能會使血脂情況惡化且會增加基因型2病患的心血管疾病風險。這項研究還利用數據分析設計預測DAA治療後患者分類。 J48算法將HDL確定為HCV基因型分類的重要因素。
英文摘要 Hepatitis C Virus (HCV) infection causes a significant health burden worldwide and one of the leading causes of liver failure. HCV life cycle is closely associated with cholesterol, lipoproteins attributing to hepatic lipid accumulation, dyslipidemia, and hypobetalipoproteinemia. HCV treatment had improved with the development of interferon-free therapy (Direct Acting Anti-viral agents, DAAs) which effectively eradicate HCV infections, but it causes a rapid change in host lipid profiles. There is a profound increase in lipid profiles of the patients particularly cholesterol following eradication of HCV. The increase of lipid profiles such as cholesterol and LDL levels increase the risk for cardiovascular events. In this study, the long-term dynamics of lipid profiles in chronic hepatitis C patients receiving DAA treatment were investigated. The cardiovascular risks of the patients were calculated and compared between genotypes. Retrospective analysis of forty patients with HCV genotype 1 and genotype 2 infection treated with DAAs for 12 weeks and followed-up thereafter. Fasting plasma samples and lipoprotein fractions were collected to quantify the triglycerides, cholesterol, and apolipoprotein B contents. Lipoprotein triglycerides and cholesterol loading capacities were calculated with normalization to apolipoprotein B. In this study, the plasma cholesterol level of both genotypes was increased, favoring the modulation of cholesterol to the periphery for use, following eradication of HCV infection. DAA treatment tends to recover the changes in circulating lipoproteins and lipid loading capacities in genotype 1 patients affected by HCV infection but not for genotype 2 patients. Moreover, the rise in cholesterol level increased the risk for cardiovascular events in genotype 2 patients after successful eradication of HCV infection. The result indicates that DAA worsens the lipid profile of HCV genotype 2 patients with increased risk for cardiovascular events. This research also leverages data mining techniques to design and develop a prototype knowledge-based system to guide therapy and predict the prognosis of patients after DAAs treatment. The J48 algorithm identified HDL as an important factor in the classification of HCV genotypes.
論文目次 中文摘要 I
Abstract III
Acknowledgment V
致謝 VII
Tables XII
Figures XIII
Abbreviations XV
I. Introduction 1
1. Hepatitis C virus (HCV) 1
1.1. Background 1
1.2. Hepatitis C genotypes 1
1.3. HCV life cycle 2
2. Lipid metabolism 3
2.1. Lipoproteins 3
2.2. Apolipoproteins (Apo) 4
3. Chronic Hepatitis Viral infection and Metabolic Syndrome 4
3.1. The impact of lipoproteins in the HCV life cycle 4
3.2. Changes in lipid metabolism in chronic hepatitis C (CHC) patients 4
3.3. Cardiovascular risk indicators: Coronary risk index (CRI), Atherogenic indexes (AI) and Atherogenic indexes of plasma (AIP) 5
4. Hepatocellular Carcinoma (HCC) 5
5. Clinical anti-HCV therapy 6
5.1. HCV therapy development 6
5.2. The DAAs in this research 7
5.2.1. Grazoprevir/Elbasvir (Zepatier) 7
5.2.2. Paritaprevir and Dasabuvir (ProD) 8
5.2.3. Sofosbuvir 8
5.3. Changes in lipid metabolism in SVR patients with DAA treatment 8
5.4. Changes in lipid metabolism with interferon treatment 9
6. Machine learning applications in this study 9
6.1. Scope and Factors of Interest 10
6.2. Data Preparation 10
6.3. Modeling 10
6.4. Evaluation 11
6.5. Implementation 11
7. Study goal 11
II. Materials and methods 13
1. Study Population 13
2. Blood samples collection 14
3. Laboratory tests 14
4. VLDL, LDL, and HDL isolation 15
4.1. Preparation of the centrifuge solutions 15
4.2. Two consecutive density-gradient ultracentrifugation 15
5. Quantification of TG and Cholesterol by biochemical analysis 16
5.1. TG quantification 16
5.2. Chol quantification 17
6. Quantification of apoB by Enzyme-Linked Immunosorbent Assay (ELISA) 17
7. The formula for calculating the lipid change ratio 18
8. Data mining 18
9. Statistical analysis 19
III. Results 20
1. Baseline characteristics 20
2. γ GT level significantly declined after SVR 21
3. Fib-4 score values declined after SVR 21
4. Changes in fasting glucose, insulin and HOMA-IR levels 22
5. Changes in lipid parameters 23
5.1. TG and Total Chol levels after DAA treatment 23
5.2. Lipoprotein metabolic changes after DAA treatment 24
5.2.1. HDL level changes with DAA treatment 24
5.2.2. LDL level changes with DAA treatment 25
5.2.3. VLDL lipoprotein loading capacity and LDL-lipid changes with DAA treatment 25
5.2.4. VLDL and LDL TG/Chol ratios change with DAA treatment 27
5.2.5. The TG LDL/VLDL ratio changes with DAA treatment 29
5.3. Cardiovascular risk indicators: CRI, AI, and AIP 30
5.3.1. CRI 30
5.3.2. AI 30
5.3.3. AIP 31
6. Data Mining 31
IV. Discussion 34
1. Comparison with previous clinical outcomes 34
2. HCV induced glucose intolerance and insulin insensitivity that were resolved with viral clearance 34
3. HCV negatively modulating lipoprotein synthesis and secretion that resolves with viral clearance 35
4. Differential effects in lipid profile based on genotype 36
4.1. Changes in TG and TC concentrations 36
4.2. Changes in lipoprotein HDL and LDL levels 37
4.3. Improvement in lipoprotein loading capacities 38
5. The cardiovascular risk ratio 38
5. Data mining 39
6. Conclusion 40
V. References 41
VI. Tables 48
VII. Figures 51
VIII. Appendix 78

參考文獻 1. Bartenschlager, R., F.L. Cosset, and V. Lohmann, Hepatitis C virus replication cycle. J Hepatol, 2010. 53(3): p. 583-5.
2. Lindenbach, B.D. and C.M. Rice, The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol, 2013. 11(10): p. 688-700.
3. Scheel, T.K. and C.M. Rice, Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med, 2013. 19(7): p. 837-49.
4. Vespasiani-Gentilucci, U., et al., Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol, 2014. 20(11): p. 2825-38.
5. Younossi, Z.M., et al., Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther, 2013. 37(6): p. 647-52.
6. Siagris, D., et al., Serum lipid pattern in chronic hepatitis C: histological and virological correlations. J Viral Hepat, 2006. 13(1): p. 56-61.
7. Felmlee, D.J., et al., Hepatitis C virus, cholesterol and lipoproteins--impact for the viral life cycle and pathogenesis of liver disease. Viruses, 2013. 5(5): p. 1292-324.
8. Park, H.K., et al., Hepatitis C virus genotype affects survival in patients with hepatocellular carcinoma. BMC cancer, 2019. 19(1): p. 822-822.
9. Wang, J., et al., Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease. Lipids Health Dis, 2020. 19(1): p. 72.
10. Clark, P.J., et al., Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology, 2012. 56(1): p. 49-56.
11. Zayas, M., et al., Coordination of Hepatitis C Virus Assembly by Distinct Regulatory Regions in Nonstructural Protein 5A. PLoS Pathog, 2016. 12(1): p. e1005376.
12. Nguyen, P., et al., Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl), 2008. 92(3): p. 272-83.
13. Mahley, R.W., et al., Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res, 1984. 25(12): p. 1277-94.
14. Pechlaner, R., et al., Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III. J Am Coll Cardiol, 2017. 69(7): p. 789-800.
15. Yang, N. and Q. Qin, Apolipoprotein J: A New Predictor and Therapeutic Target in Cardiovascular Disease? Chin Med J (Engl), 2015. 128(18): p. 2530-4.
16. Syed, G.H., Y. Amako, and A. Siddiqui, Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab, 2010. 21(1): p. 33-40.
17. Yamaguchi, A., et al., Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci, 2005. 50(7): p. 1361-71.
18. Kim, K.H., et al., HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. Biochem Biophys Res Commun, 2007. 355(4): p. 883-8.
19. Kuo, Y.H., et al., Association between chronic viral hepatitis and metabolic syndrome in southern Taiwan: a large population-based study. Aliment Pharmacol Ther, 2018. 48(9): p. 993-1002.
20. Alberti, K.G., et al., Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 2009. 120(16): p. 1640-5.
21. Beiser, M.E., et al., Estimating the Prevalence of Advanced Fibrosis in Homeless Adults with Hepatitis C in Boston. J Health Care Poor Underserved, 2020. 31(1): p. 128-139.
22. Mendizabal, M., et al., Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-acting Antiviral Agents. Clin Gastroenterol Hepatol, 2020.
23. Wu, T.T., et al., Atherogenic index of plasma (AIP): a novel predictive indicator for the coronary artery disease in postmenopausal women. Lipids Health Dis, 2018. 17(1): p. 197.
24. Kazemi, T., et al., Cardiovascular Risk Factors and Atherogenic Indices in an Iranian Population: Birjand East of Iran. Clin Med Insights Cardiol, 2018. 12: p. 1179546818759286.
25. Ipsen, D.H., J. Lykkesfeldt, and P. Tveden-Nyborg, Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci, 2018. 75(18): p. 3313-3327.
26. Hayes, C.N., et al., Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses, 2018. 10(10).
27. Yoon, H., et al., Effects of metabolic syndrome on fibrosis in chronic viral hepatitis. Gut Liver, 2013. 7(4): p. 469-74.
28. Masetti, C., et al., Postsustained Virological Response Management in Hepatitis C Patients. Semin Liver Dis, 2020.
29. van der Meer, A.J., et al., Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis. JAMA, 2012. 308(24): p. 2584-2593.
30. Popescu, C.I., et al., Hepatitis C virus life cycle and lipid metabolism. Biology (Basel), 2014. 3(4): p. 892-921.
31. Flemming, J.A., et al., Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology, 2017. 65(3): p. 804-812.
32. Kwo, P.Y., The future of hepatitis C virus therapeutics. Gastroenterology & hepatology, 2014. 10(7): p. 433-435.
33. Ioannou, G.N., et al., Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System. Gastroenterology, 2016. 151(3): p. 457-471 e5.
34. Bell, A.M., et al., Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C. Int J Hepatol, 2016. 2016: p. 3852126.
35. Adinolfi, L.E., et al., Impact of hepatitis C virus clearance by direct-acting antiviral treatment on the incidence of major cardiovascular events: A prospective multicentre study. Atherosclerosis, 2020. 296: p. 40-47.
36. Zoratti, M.J., et al., Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: A systematic literature review and meta-analysis. EClinicalMedicine, 2020. 18: p. 100237.
37. Marrero, J.A., et al., Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology, 2018. 68(2): p. 723-750.
38. Feld, J.J., et al., Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection. Liver Int, 2017. 37(1): p. 5-18.
39. Flisiak, R., et al., Real-world effectiveness and safety of ombitasvir/paritaprevir/ritonavir +/- dasabuvir +/- ribavirin in hepatitis C: AMBER study. Aliment Pharmacol Ther, 2016. 44(9): p. 946-956.
40. Khaliq, S. and S.M. Raza, Current Status of Direct Acting Antiviral Agents against Hepatitis C Virus Infection in Pakistan. Medicina (Kaunas), 2018. 54(5).
41. Zarebska-Michaluk, D., Viral hepatitis C treatment shortening - what is the limit? Clin Exp Hepatol, 2019. 5(4): p. 265-270.
42. Charatcharoenwitthaya, P., et al., Real-world effectiveness and safety of sofosbuvir and nonstructural protein 5A inhibitors for chronic hepatitis C genotype 1, 2, 3, 4, or 6: a multicentre cohort study. BMC Gastroenterol, 2020. 20(1): p. 47.
43. Chu, S.Y., et al., Risk assessment of metabolic syndrome in adolescents using the triglyceride/high-density lipoprotein cholesterol ratio and the total cholesterol/high-density lipoprotein cholesterol ratio. Ann Pediatr Endocrinol Metab, 2019. 24(1): p. 41-48.
44. Sun, H.Y., et al., Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection. Gut, 2018. 67(7): p. 1342-1350.
45. Gitto, S., et al., Worsening of Serum Lipid Profile after Direct Acting Antiviral Treatment. Ann Hepatol, 2018. 17(1): p. 64-75.
46. Cheng, P.N., et al., Augmenting central arterial stiffness following eradication of HCV by direct acting antivirals in advanced fibrosis patients. Sci Rep, 2019. 9(1): p. 1426.
47. Mauss, S., et al., Short communication Effect of antiviral therapy for HCV on lipid levels. Antiviral therapy, 2017. 21: p. 81-88.
48. Lange, C.M., et al., Serum lipids in European chronic HCV genotype 1 patients during and after treatment with pegylated interferon-α-2a and ribavirin. European Journal of Gastroenterology & Hepatology, 2010. 22(11): p. 1303-1307.
49. Eyasu, K., W. Jimma, and T. Tadesse, Developing a Prototype Knowledge-Based System for Diagnosis and Treatment of Diabetes Using Data Mining Techniques. Ethiop J Health Sci, 2020. 30(1): p. 115-124.
50. Kourou, K., et al., Machine learning applications in cancer prognosis and prediction. Comput Struct Biotechnol J, 2015. 13: p. 8-17.
51. Izenman, A.J., Modern multivariate statistical techniques. Regression, classification and manifold learning, 2008. 10: p. 978-0.
52. Matthews, D.R., et al., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985. 28(7): p. 412-9.
53. Sterling, R.K., et al., Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology, 2006. 43(6): p. 1317-25.
54. Fossati, P. and L. Prencipe, Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem, 1982. 28(10): p. 2077-80.
55. MacLachlan, J., et al., Cholesterol oxidase: sources, physical properties and analytical applications. J Steroid Biochem Mol Biol, 2000. 72(5): p. 169-95.
56. Rajvanshi, C., et al., Use of liver enzymes as a surrogate marker for monitoring treatment of hepatitis C virus disease. Global Journal of Transfusion Medicine, 2019. 4(2): p. 224-226.
57. Butt, A.A., et al., Direct-Acting Antiviral Therapy for HCV Infection Is Associated With a Reduced Risk of Cardiovascular Disease Events. Gastroenterology, 2019. 156(4): p. 987-996 e8.
58. Frias, M., et al., Evaluation of hepatitis C viral RNA persistence in HIV-infected patients with long-term sustained virological response by droplet digital PCR. Sci Rep, 2019. 9(1): p. 12507.
59. Everhart, J.E. and E.C. Wright, Association of γ‐glutamyl transferase (GGT) activity with treatment and clinical outcomes in chronic hepatitis C (HCV). Hepatology, 2013. 57(5): p. 1725-1733.
60. Villela-Nogueira, C.A., et al., Gamma-Glutamyl Transferase (GGT) as an Independent Predictive Factor of Sustained Virologic Response in Patients With Hepatitis C Treated With Interferon-Alpha and Ribavirin. Journal of Clinical Gastroenterology, 2005. 39(8): p. 728-730.
61. Corey, K.E., et al., Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology, 2009. 50(4): p. 1030-7.
62. Poordad, F., et al., Long-term safety and efficacy results in hepatitis C virus genotype 1-infected patients receiving ombitasvir/paritaprevir/ritonavir + dasabuvir +/- ribavirin in the TOPAZ-I and TOPAZ-II trials. J Viral Hepat, 2020. 27(5): p. 497-504.
63. Eslam, M., et al., Use of HOMA-IR in hepatitis C. J Viral Hepat, 2011. 18(10): p. 675-84.
64. Bose, S.K. and R. Ray, Hepatitis C virus infection and insulin resistance. World journal of diabetes, 2014. 5(1): p. 52-58.
65. Ivanova, R., et al., Comparative analysis of serum lipids in patients with chronic hepatitis C, nonalcoholic fatty liver disease, and healthy controls. Atherosclerosis, 2016. 252: p. e154-e155.
66. Butt, A.A., et al., Changes in circulating lipids level over time after acquiring HCV infection: results from ERCHIVES. BMC Infect Dis, 2015. 15: p. 510.
67. Moriya, K., et al., Increase in the concentration of carbon 18 monounsaturated fatty acids in the liver with hepatitis C: analysis in transgenic mice and humans. Biochem Biophys Res Commun, 2001. 281(5): p. 1207-12.
68. Perlemuter, G., et al., Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. Faseb j, 2002. 16(2): p. 185-94.
69. Hu, B., et al., Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review. Cell Proliferation, 2020. 53(3): p. e12772.
70. Chan, A., K. Patel, and S. Naggie, Genotype 3 Infection: The Last Stand of Hepatitis C Virus. Drugs, 2017. 77(2): p. 131-144.
71. Piodi, A., et al., Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Hepatology, 2008. 48(1): p. 16-27.
72. Lee, C.-M., et al., Hepatitis C virus genotypes in southern Taiwan: prevalence and clinical implications. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2006. 100(8): p. 767-774.
73. Ramcharran, D., et al., Associations between serum lipids and hepatitis C antiviral treatment efficacy. Hepatology, 2010. 52(3): p. 854-63.
74. Kuo, Y.H., et al., Reversal of hypolipidemia in chronic hepatitis C patients after successful antiviral therapy. J Formos Med Assoc, 2011. 110(6): p. 363-71.
75. Jang, E.S., et al., The effect of antiviral therapy on serum cholesterol levels in chronic hepatitis C. Gut Liver, 2011. 5(3): p. 356-62.
76. FERNÁNDEZ-RODRÍGUEZ, C.M., et al., Long-term reversal of hypocholesterolaemia in patients with chronic hepatitis C is related to sustained viral response and viral genotype. Alimentary Pharmacology & Therapeutics, 2006. 24(3): p. 507-512.
77. Kawaguchi, Y. and T. Mizuta, Interaction between hepatitis C virus and metabolic factors. World journal of gastroenterology, 2014. 20(11): p. 2888-2901.
78. Pedersen, M.R., et al., Genotype specific peripheral lipid profile changes with hepatitis C therapy. World J Gastroenterol, 2016. 22(46): p. 10226-10231.
79. Meissner, E.G., et al., Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology, 2015. 61(3): p. 790-801.
80. Kono, Y., et al., High-density lipoprotein binding rate differs greatly between genotypes 1b and 2a/2b of hepatitis C virus. Journal of Medical Virology, 2003. 70(1): p. 42-48.
81. Hashimoto, S., et al. Rapid Increase in Serum Low-Density Lipoprotein Cholesterol Concentration during Hepatitis C Interferon-Free Treatment. PloS one, 2016. 11, e0163644 DOI: 10.1371/journal.pone.0163644.
82. Chang, M.L., et al., Distinct patterns of the lipid alterations between genotype 1 and 2 chronic hepatitis C patients after viral clearance. PLoS One, 2014. 9(8): p. e104783.
83. Shimizu, K., et al., Eradication of hepatitis C virus is associated with the attenuation of steatosis as evaluated using a controlled attenuation parameter. Sci Rep, 2018. 8(1): p. 7845.
84. Ridker, P.M., LDL cholesterol: controversies and future therapeutic directions. The Lancet, 2014. 384(9943): p. 607-617.
85. Enas, E.A., et al., Benefits & risks of statin therapy for primary prevention of cardiovascular disease in Asian Indians - a population with the highest risk of premature coronary artery disease & diabetes. The Indian journal of medical research, 2013. 138(4): p. 461-491.
86. Taylor, F., et al., Statins for the primary prevention of cardiovascular disease. The Cochrane database of systematic reviews, 2013. 2013(1): p. CD004816-CD004816.
87. Edwards, M.K., M.J. Blaha, and P.D. Loprinzi, Atherogenic Index of Plasma and Triglyceride/High-Density Lipoprotein Cholesterol Ratio Predict Mortality Risk Better Than Individual Cholesterol Risk Factors, Among an Older Adult Population. Mayo Clin Proc, 2017. 92(4): p. 680-681.
88. Wan, K., et al., The association between triglyceride/high-density lipoprotein cholesterol ratio and all-cause mortality in acute coronary syndrome after coronary revascularization. PloS one, 2015. 10(4): p. e0123521-e0123521.
89. Yue, W., et al., Machine Learning with Applications in Breast Cancer Diagnosis and Prognosis. Designs, 2018. 2: p. 13.

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