Liver Fibrosis Assessment in a Cohort of Greek HIV Mono-Infected Patients by Non-Invasive Biomarkers

Author(s): Theodoros Androutsakos*, Maria Schina, Abraham Pouliakis, Athanasios Kontos, Nikolaos Sipsas, Gregorios Hatzis

Journal Name: Current HIV Research

Volume 17 , Issue 3 , 2019

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Graphical Abstract:


Background: Non-alcoholic Fatty Liver Disease (NAFLD) is common in HIV-infected individuals. Liver biopsy remains the gold-standard procedure for the diagnosis of liver fibrosis, but both Transient Elastography (TE) and Non-invasive Biomarkers (NIBMs) have emerged as alternatives.

Objectives: Our study’s aim was to validate commonly used NIBMs for the assessment of liver fibrosis in a cohort of Greek HIV-mono-infected patients.

Methods: Inclusion criteria were confirmed HIV-infection and age>18 years and exclusion criteria HBV or HCV seropositivity, liver disease other than NAFLD, alcohol abuse, ascites, transaminases levels>4xULN(upper limit of normal) and Body-Mass index(BMI)>40. Liver stiffness (LS) measurement with TE and thorough laboratory work up and medical history were acquired at study entry. FIB-4, APRI, NFS, BARD, Forns and Lok scores were calculated for each patient.

Results: A total of 157 patients were eligible for this study. Significant liver fibrosis, compatible with Metavir score of F3-F4, was found in only 11(7%) patients. These findings were in accordance with those of the NIBMs; the BARD score constituting the only exception, allocating 102(65%) patients as having significant liver fibrosis. In order to obtain a balance between sensitivity and specificity new cut-offs for each NIBM were calculated; FIB-4 score yielded the best results, since by changing the cut-off to 1.49 a sensitivity and specificity balanced for both close to 85% was achieved.

Conclusion: Our findings suggest that NIBMs can be used for the evaluation of liver fibrosis in HIV mono-infected patients. New cut-offs for NIBMs should probably be calculated, to help distinguishing patients with significant from those with mild/no fibrosis.

Keywords: HIV infection, transient elastography, liver fibrosis, non-invasive biomarkers, HBV, HCV.

Mayor AM, Gómez MA, Ríos-Oliveras E, Hunter-Mellado RF. Mortality trends of HIV-infected patients after the introduction of highly active antiretroviral therapy: Analysis of a cohort of 3,322 HIV-infected persons. Ethn Dis 2005; 15(4 Suppl 5): S5-57-62.
Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: A collaborative analysis of 14 cohort studies. Lancet 2008; 372(9635): 293-9.
[] [PMID: 18657708]
Kasamba I, Baisley K, Mayanja BN, Maher D, Grosskurth H. The impact of antiretroviral treatment on mortality trends of HIV-positive adults in rural Uganda: A longitudinal population-based study, 1999-2009. Trop Med Int Health 2012; 17(8): e66-73.
[] [PMID: 22943381]
Slaymaker E, Todd J, Marston M, et al. How have ART treatment programmes changed the patterns of excess mortality in people living with HIV? Estimates from four countries in East and Southern Africa. Glob Health Action 2014; 7: 22789.
[] [PMID: 24762982]
Reniers G, Slaymaker E, Nakiyingi-Miiro J, et al. ALPHA Network. Mortality trends in the era of antiretroviral therapy: Evidence from the Network for Analysing Longitudinal Population based HIV/AIDS data on Africa (ALPHA). AIDS 2014; 28(Suppl. 4): S533-42.
[] [PMID: 25406756]
Eyawo O, Franco-Villalobos C, Hull MW, et al. Comparative Outcomes And Service Utilization Trends (COAST) study. Changes in mortality rates and causes of death in a population-based cohort of persons living with and without HIV from 1996 to 2012. BMC Infect Dis 2017; 17(1): 174.
[] [PMID: 28241797]
Cappell MS. Hepatobiliary manifestations of the acquired immune deficiency syndrome. Am J Gastroenterol 1991; 86(1): 1-15.
[PMID: 1986533]
Lefkowitch JH. Pathology of AIDS-related liver disease. Dig Dis 1994; 12(6): 321-30.
[] [PMID: 7712615]
Salmon-Ceron D, Lewden C, Morlat P, et al. Mortality 2000 study group. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol 2005; 42(6): 799-805.
[] [PMID: 15973779]
Piroth L. Liver steatosis in HIV-infected patients. AIDS Rev 2005; 7(4): 197-209.
[PMID: 16425960]
Puri P, Kumar S. Liver involvement in human immunodeficiency virus infection. Indian J Gastroenterol 2016; 35(4): 260-73.
[] [PMID: 27256434]
Shamanna SB, Naik RR, Hamide A. Causes of liver disease and its outcome in HIV-infected individuals. Indian J Gastroenterol 2016; 35(4): 310-4.
[] [PMID: 27435618]
Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53(2): 372-84.
[] [PMID: 20494470]
Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62(Suppl. 1): S47-64.
[] [PMID: 25920090]
Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis 2016; 20(2): 205-14.
[] [PMID: 27063264]
Calzadilla Bertot L, Adams LA. The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2016; 17(5)E774
[] [PMID: 27213358]
Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol 2017; 67(4): 862-73.
[] [PMID: 28642059]
Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis. PLoS One 2015; 10(10)e0140908
[] [PMID: 26512983]
Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int 2017; 37(Suppl. 1): 81-4.
[] [PMID: 28052624]
Haldar D, Kern B, Hodson J, et al. Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry Study. J Hepatol 2019; S0168-8278.
Sayiner M, Younossi ZM. Nonalcoholic Steatohepatitis Is Becoming a Top Indication for Liver Transplantation Worldwide. Liver Transpl 2019; 25(1): 10-1.
[] [PMID: 30472779]
Lemoine M, Barbu V, Girard PM, et al. Altered hepatic expression of SREBP-1 and PPARgamma is associated with liver injury in insulin-resistant lipodystrophic HIV-infected patients. AIDS 2006; 20(3): 387-95.
[] [PMID: 16439872]
Crum-Cianflone N, Collins G, Medina S, et al. Prevalence and factors associated with liver test abnormalities among human immunodeficiency virus-infected persons. Clin Gastroenterol Hepatol 2010; 8(2): 183-91.
[] [PMID: 19800985]
Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C virus-related liver disease: A cohort study. Ann Intern Med 2013; 158(9): 658-66.
[] [PMID: 23440167]
Macías J, Pineda JA, Real LM. Non-Alcoholic Fatty Liver Disease in HIV Infection. AIDS Rev 2017; 19(1): 35-46.
[PMID: 28182612]
Rockstroh JK. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV. Curr HIV/AIDS Rep 2017; 14(2): 47-53.
[] [PMID: 28284005]
Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352(1): 48-62.
[] [PMID: 15635112]
Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74(5): 1045-52.
[PMID: 1373735]
Sipsas NV, Kosmas N, Kontos A, Eftychiadis C, Agapitos E, Kordossis T. Fatal Nucleoside-Associated Lactic Acidosis in a Human Immunodeficiency Virus Type-1 Infected Obese Woman, Following a Very-Low-Calorie Diet. Scand J Infect Dis 2003; 35: 291-3.
[] [PMID: 12839166]
The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20(1 Pt 1): 15-20.
[PMID: 8020885]
Ratziu V, Charlotte F, Heurtier A, et al. LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128(7): 1898-906.
[] [PMID: 15940625]
Seeff LB, Everson GT, Morgan TR, et al. HALT–C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010; 8(10): 877-83.
[] [PMID: 20362695]
Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986; 2(2): 165-73.
[] [PMID: 3958472]
Cross TJ, Calvaruso V, Maimone S, et al. Prospective comparison of Fibroscan, King’s score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection. J Viral Hepat 2010; 17(8): 546-54.
[] [PMID: 19874477]
Pavlov CS, Casazza G, Nikolova D, et al. Transient elastography for diagnosis of stages of hepatic fibrosis and cirrhosis in people with alcoholic liver disease. Cochrane Database Syst Rev 2015. 1CD010542.
[] [PMID: 25612182]
Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016; 63(6): 1817-27.
[] [PMID: 26659452]
Ragazzo TG, Paranagua-Vezozzo D, Lima FR, et al. Accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI) imaging, the enhanced liver fibrosis (ELF) test, APRI, and the FIB-4 index compared with liver biopsy in patients with chronic hepatitis C. Clinics (São Paulo) 2017; 72(9): 516-25.
[] [PMID: 29069254]
Kamarajah SK, Chan WK, Nik Mustapha NR, Mahadeva S. Repeated liver stiffness measurement compared with paired liver biopsy in patients with non-alcoholic fatty liver disease. Hepatol Int 2018; 12(1): 44-55.
[] [PMID: 29372507]
Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019; 156(6): 1717-30.
[] [PMID: 30689971]
Chang PE, Goh GB, Ngu JH, Tan HK, Tan CK. Clinical applications, limitations and future role of transient elastography in the management of liver disease. World J Gastrointest Pharmacol Ther 2016; 7(1): 91-106.
[] [PMID: 26855815]
Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010; 51(3): 828-35.
[] [PMID: 20063276]
Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology 2007; 46(1): 32-6.
[] [PMID: 17567829]
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45(4): 846-54.
[] [PMID: 17393509]
Raszeja-Wyszomirska J, Szymanik B, Ławniczak M, et al. Validation of the BARD scoring system in Polish patients with nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol 2010; 10: 67.
[] [PMID: 20584330]
Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38(2): 518-26.
[] [PMID: 12883497]
Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology 2011; 53(3): 726-36.
[] [PMID: 21319189]
Martínez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology 2011; 53(1): 325-35.
[] [PMID: 21254180]
Lok AS, Ghany MG, Goodman ZD, et al. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort. Hepatology 2005; 42(2): 282-92.
[] [PMID: 15986415]
Forns X, Ampurdanès S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002; 36(4 Pt 1): 986-92.
[] [PMID: 12297848]
National Institute on Alcohol Abuse and Alcoholism. Helping patients who drink too much: A clinician’s guide NIH Publication no. 05-3769, Bethesda, MD.. 2005.
Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29(12): 1705-13.
[] [PMID: 14698338]
Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48(5): 835-47.
[] [PMID: 18334275]
Marozzi M. Testing for concordance between several criteria. J Stat Comput Simul 2014; 84(9): 1843-50.
Vogiatzi P, Pouliakis A, Siristatidis C. An artificial neural network for the prediction of assisted reproduction outcome. J Assist Reprod Genet 2019; 36(7): 1441-8.
[] [PMID: 31218565]
Makris GM, Pouliakis A, Siristatidis C, et al. Image analysis and multi-layer perceptron artificial neural networks for the discrimination between benign and malignant endometrial lesions. Diagn Cytopathol 2017; 45(3): 202-11.
[] [PMID: 28160459]
Kottaridi C, Kyrgiou M, Pouliakis A, et al. Quantitative Measurement of L1 Human Papillomavirus Type 16 Methylation for the Prediction of Preinvasive and Invasive Cervical Disease. J Infect Dis 2017; 215(5): 764-71.
[] [PMID: 28170039]
Zygouris D, Pouliakis A, Margari N, et al. Classification of endometrial lesions by nuclear morphometry features extracted from liquid-based cytology samples: a system based on logistic regression model. Anal Quant Cytopathol Histpathol 2014; 36(4): 189-98.
[PMID: 25291856]
Sebastiani G, Castera L, Halfon P, et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: an international study of 2411 cases. Aliment Pharmacol Ther 2011; 34(10): 1202-16.
[] [PMID: 21981787]
Charre C, Levrero M, Zoulim F, Scholtès C. Non-invasive biomarkers for chronic hepatitis B virus infection management. Antiviral Res 2019; 169104553
[] [PMID: 31288041]
Agbim U, Asrani SK. Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers. Expert Rev Gastroenterol Hepatol 2019; 13(4): 361-74.
[] [PMID: 30791772]
Myers RP, Benhamou Y, Imbert-Bismut F, et al. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients. AIDS 2003; 17(5): 721-5.
[] [PMID: 12646795]
Macías J, Girón-González JA, González-Serrano M, et al. Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes. Gut 2006; 55(3): 409-14.
[] [PMID: 16118349]
Al-Mohri H, Murphy T, Lu Y, Lalonde RG, Klein MB. Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and hepatitis C coinfection using a noninvasive marker. J Acquir Immune Defic Syndr 2007; 44(4): 463-9.
[] [PMID: 17211282]
Cacoub P, Carrat F, Bédossa P, et al. Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: the fibrovic study--ANRS HC02. J Hepatol 2008; 48(5): 765-73.
[] [PMID: 18314219]
Trang T, Petersen JR, Snyder N. Non-invasive markers of hepatic fibrosis in patients co-infected with HCV and HIV: Comparison of the APRI and FIB-4 index. Clin Chim Acta 2008; 397(1-2): 51-4.
[] [PMID: 18692034]
Bongiovanni M, Casana M. Non-invasive markers of liver fibrosis in HCV mono-infected and in HIV/HCV co-infected subjects. Med Chem 2008; 4(6): 513-9.
[] [PMID: 18991734]
Sanvisens A, Fuster D, Serra I, et al. Estimated liver fibrosis and its impact on all-cause mortality of HCV-monoinfected and HCV/HIV-coinfected drug users. Curr HIV Res 2011; 9(4): 256-62.
[] [PMID: 21675942]
Singal AG, Thomassen LV, Gretch DR, Shuhart MC. Use of the AST to platelet ratio index in HCV/HIV co-infected patients. Aliment Pharmacol Ther 2011; 33(5): 566-77.
[] [PMID: 21205257]
Rohrbach J, Stickel F, Schmid P, et al. Swiss HIV Cohort Study. Changes in biomarkers of liver disease during successful combination antiretroviral therapy in HIV-HCV-coinfected individuals. Antivir Ther (Lond) 2014; 19(2): 149-59.
[] [PMID: 24036684]
Schmid P, Bregenzer A, Huber M, et al. Swiss HIV Cohort Study. Progression of Liver Fibrosis in HIV/HCV Co-Infection: A Comparison between Non-Invasive Assessment Methods and Liver Biopsy. PLoS One 2015; 10(9)e0138838
[] [PMID: 26418061]
Bottero J, Lacombe K, Guéchot J, et al. Performance of 11 biomarkers for liver fibrosis assessment in HIV/HBV co-infected patients. J Hepatol 2009; 50(6): 1074-83.
[] [PMID: 19398234]
Kilonzo SB, Gunda DW, Kashasha F, Mpondo BC. Liver Fibrosis and Hepatitis B Coinfection among ART Naïve HIV-Infected Patients at a Tertiary Level Hospital in Northwestern Tanzania: A Cross-Sectional Study. J Trop Med 2017; 20175629130
[] [PMID: 28828009]
Sterling RK, King WC, Wahed AS, et al. HIV-HBV Cohort Study of the Hepatitis B Research Network. Evaluating non-invasive markers to identify advanced fibrosis by liver biopsy in HBV/HIV coinfected adults. Hepatology 2019. [Epub Ahead of Print]
[] [PMID: 31220357]
DallaPiazza M, Amorosa VK, Localio R, Kostman JR, Lo Re V III. Prevalence and risk factors for significant liver fibrosis among HIV-monoinfected patients. BMC Infect Dis 2010; 10: 116.
[] [PMID: 20465840]
Blackard JT, Welge JA, Taylor LE, et al. HIV mono-infection is associated with FIB-4 - A noninvasive index of liver fibrosis - in women. Clin Infect Dis 2011; 52(5): 674-80.
[] [PMID: 21248367]
Mendeni M, Focà E, Gotti D, et al. Evaluation of liver fibrosis: concordance analysis between noninvasive scores (APRI and FIB-4) evolution and predictors in a cohort of HIV-infected patients without hepatitis C and B infection. Clin Infect Dis 2011; 52(9): 1164-73.
[] [PMID: 21467023]
Price JC, Seaberg EC, Badri S, Witt MD, D’Acunto K, Thio CL. HIV monoinfection is associated with increased aspartate aminotransferase-to-platelet ratio index, a surrogate marker for hepatic fibrosis. J Infect Dis 2012; 205(6): 1005-13.
[] [PMID: 22291196]
Hasson H, Merli M, Galli L, et al. Non-invasive fibrosis biomarkers - APRI and Forns - are associated with liver stiffness in HIV-monoinfected patients receiving antiretroviral drugs. Liver Int 2013; 33(7): 1113-20.
[] [PMID: 23534616]
Tahiri M, Sodqi M, Lahdami FE, et al. Risk factors for liver fibrosis among human immunodeficiency virus monoinfected patients using the FIB4 index in Morocco. World J Hepatol 2013; 5(10): 584-8.
[] [PMID: 24179618]
Morse CG, McLaughlin M, Matthews L, et al. Nonalcoholic steatohepatitis and hepatic fibrosis in HIV-1-monoinfected adults with elevated aminotransferase levels on antiretroviral therapy. Clin Infect Dis 2015; 60(10): 1569-78.
[] [PMID: 25681381]
Matta B, Lee TH, Patel K. Use of Non-invasive Testing to Stage Liver Fibrosis in Patients with HIV. Curr HIV/AIDS Rep 2016; 13(5): 279-88.
[] [PMID: 27485838]
Oliveri F, Coco B, Ciccorossi P, et al. Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases. World J Gastroenterol 2008; 14(40): 6154-62.
[] [PMID: 18985805]
Arena U, Vizzutti F, Abraldes JG, et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut 2008; 57(9): 1288-93.
[] [PMID: 18448567]
Stebbing J, Farouk L, Panos G, et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol 2010; 44(3): 214-9.
[] [PMID: 19745758]
Gaia S, Carenzi S, Barilli AL, et al. Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis. J Hepatol 2011; 54(1): 64-71.
[] [PMID: 20932598]

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Year: 2019
Published on: 22 October, 2019
Page: [173 - 182]
Pages: 10
DOI: 10.2174/1570162X17666190809153245
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