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Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale? Cells 2021; 10:cells10051212. [PMID: 34063534 PMCID: PMC8156893 DOI: 10.3390/cells10051212] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 12/13/2022] Open
Abstract
After the introduction of antiretroviral treatment (ART) back in 1996, the lifespan of people living with HIV (PLWH) has been substantially increased, while the major causes of morbidity and mortality have switched from opportunistic infections and AIDS-related neoplasms to cardiovascular and liver diseases. HIV itself may lead to liver damage and subsequent liver fibrosis (LF) through multiple pathways. Apart from HIV, viral hepatitis, alcoholic and especially non-alcoholic liver diseases have been implicated in liver involvement among PLWH. Another well known cause of hepatotoxicity is ART, raising clinically significant concerns about LF in long-term treatment. In this review we present the existing data and analyze the association of LF with all ART drug classes. Published data derived from many studies are to some extent controversial and therefore remain inconclusive. Among all the antiretroviral drugs, nucleoside reverse transcriptase inhibitors, especially didanosine and zidovudine, seem to carry the greatest risk for LF, with integrase strand transfer inhibitors and entry inhibitors having minimal risk. Surprisingly, even though protease inhibitors often lead to insulin resistance, they do not seem to be associated with a significant risk of LF. In conclusion, most ART drugs are safe in long-term treatment and seldom lead to severe LF when no liver-related co-morbidities exist.
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Kirkegaard-Klitbo DM, Bendtsen F, Lundgren J, de Knegt RJ, Kofoed KF, Nielsen SD, Benfield T. Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls. J Infect Dis 2020; 224:443-452. [PMID: 33320268 DOI: 10.1093/infdis/jiaa763] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to estimate the prevalence and factors associated with liver fibrosis in PWH compared to population controls. METHODS This was a cross-sectional cohort study comparing 342 PWH with 2190 population controls aged 50-70 years.Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were computed by logistic regression. RESULTS The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM. In multivariate analysis, elevated LSM was associated with HIV (aOR, 1.84 [95% CI, 1.17-2.88]; P < .01); higher age (per decade: aOR, 3.34 [95% CI, 1.81-6.18]; P < .01); alanine aminotransferase (ALT) (per 10 IU/L: aOR, 1.25 [95% CI, 1.05-1.49]; P < .01); body mass index (BMI) (per 1 kg/m2: aOR, 1.17 [95% CI, 1.05-1.29]; P < .01), and previous exposure to didanosine (per year: aOR, 2.26 [95% CI, 1.01-5.06]; P = .04). CONCLUSIONS The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM.
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Affiliation(s)
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Lundgren
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Centre of Excellence for Health, Immunity and Infections, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Klaus Fuglsang Kofoed
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.,Department of Radiology, Rigshospitalet, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Benfield
- Department of Infectious Diseases, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Kirkegaard-Klitbo DM, Bendtsen F, Lundgren J, Nielsen SD, Benfield T. Poor Concordance Between Liver Stiffness and Noninvasive Fibrosis Scores in HIV Infection Without Viral Hepatitis. Clin Gastroenterol Hepatol 2020; 18:3049-3050. [PMID: 31648031 DOI: 10.1016/j.cgh.2019.10.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/06/2019] [Accepted: 10/11/2019] [Indexed: 02/07/2023]
Abstract
People living with human immunodeficiency virus (PLWH) are at higher risk of liver fibrosis compared with the general population. As liver fibrosis is independently associated with poor long-term liver related outcomes and mortality,1 early detection is extremely important. Liver biopsy is considered gold standard for the diagnosis of liver fibrosis. However, this invasive procedure is only suitable for a selected group of patients because of the risk of serious complications. We aimed to estimate the concordance between vibration-controlled transient elastography (VCTE) and simple noninvasive liver fibrosis scores-Fibrosis-4 index (FIB4), aspartate aminotransferase-to-platelet ratio index (APRI), and nonalcoholic fatty liver disease fibrosis score (NFS)-in PLWH without viral hepatitis.
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Affiliation(s)
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Jens Lundgren
- Center of Excellence for Health, Immunity and Infections, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Denmark
| | - Thomas Benfield
- Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
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Androutsakos T, Schina M, Pouliakis A, Kontos A, Sipsas N, Hatzis G. Causative factors of liver fibrosis in HIV-infected patients. A single center study. BMC Gastroenterol 2020; 20:91. [PMID: 32252653 PMCID: PMC7137262 DOI: 10.1186/s12876-020-01230-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 03/24/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Liver disease is a leading cause of morbidity and mortality among Human Immunodeficiency virus (HIV) infected patients; however no consensus exists on HIV-related risk factors for it. The aim of this study was to identify risk factors for liver fibrosis/cirrhosis in a cohort of Greek HIV-infected patients. METHODS Patients attending the HIV outpatient clinic of Pathophysiology Department at «Laiko» General Hospital in Athens, Greece, between December 2014 and December 2017 were eligible for inclusion. Inclusion criteria were confirmed HIV infection and age > 18 years. Exclusion criteria were Body-Mass index (BMI) > 40, liver metastases of malignant diseases and concurrent or previous chemotherapy. Liver stiffness (LS) was measured using Vibration Controlled Transient Elastography (TE) and laboratory tests were acquired in all patients. Patients were classified in 2 groups: those with mild or no fibrosis (equivalent to Metavir score F0-F2) and those with significant fibrosis (equivalent to Metavir score F3-F4). RESULTS A total of 187 consecutive patients were included in this study. Median TE value was 5.1 kilopascals (KPa) (range 2.8-26.3), with 92.5% (173/187) of the patients having no/mild fibrosis and 7.4% (14/187) significant fibrosis. On multivariate logistic regression analysis older patient's age, abnormal serum aspartate aminotransferase (AST) value, Hepatitis C virus (HCV) infection, alcohol abuse, CD4/CD8 ratio and an increased number of liver related events (LREs) were significantly correlated with liver fibrosis/cirrhosis. CONCLUSIONS In our cohort of HIV-infected individuals HCV/HIV co-infection, older age, alcohol abuse and CD4/CD8 ratio seem to correlate with fibrogenesis in the liver.
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Affiliation(s)
- Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
| | - Maria Schina
- Liver unit, Euroclinic of Athens, Athens, Greece
| | - Abraham Pouliakis
- Second Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Nikolaos Sipsas
- Infectious Diseases Unit, Laiko General Hospital, Athens, Greece.,Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregorios Hatzis
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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So-Armah KA, Lim JK, Lo Re V, Tate JP, Chang CCH, Butt AA, Gibert CL, Rimland D, Marconi VC, Goetz MB, Rodriguez-Barradas MC, Budoff MJ, Tindle HA, Samet JH, Justice AC, Freiberg MS. FIB-4 stage of liver fibrosis predicts incident heart failure among HIV-infected and uninfected patients. Hepatology 2017; 66:1286-1295. [PMID: 28543215 PMCID: PMC5609079 DOI: 10.1002/hep.29285] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/10/2017] [Accepted: 05/19/2017] [Indexed: 12/13/2022]
Abstract
UNLABELLED Liver fibrosis is common, particularly in individuals who are infected with human immunodeficiency virus (HIV). HIV-infected individuals have excess congestive heart failure (CHF) risk compared with uninfected people. It remains unknown whether liver fibrosis stage influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether 1) stage of liver fibrosis is independently associated with incident CHF and 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after April 1, 2003, in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease were followed until their first CHF event, death, last follow-up date, or December 31, 2011. Liver fibrosis was measured using the fibrosis 4 index (FIB-4), which is calculated using age, aminotransferases, and platelets. Cox proportional hazards regression models were adjusted for cardiovascular disease risk factors. Among 96,373 participants over 6.9 years, 3844 incident CHF events occurred. FIB-4 between 1.45 and 3.25 (moderate fibrosis) and FIB-4 > 3.25 (advanced fibrosis/cirrhosis) were associated with CHF (hazard ratio [95% confidence interval], 1.17 [1.07-1.27] and 1.65 [1.43-1.92], respectively). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status. CONCLUSION Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom cardiovascular disease risk is elevated and liver disease is common. (Hepatology 2017;66:1286-1295).
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Affiliation(s)
| | - Joseph K Lim
- Yale University School of Medicine, New Haven, CT
| | - Vincent Lo Re
- Philadelphia VA Medical Center, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Janet P Tate
- Yale University School of Medicine, New Haven, CT
- VA Connecticut Healthcare System, West Haven, CT
| | - Chung-Chou H Chang
- University of Pittsburgh Schools of Medicine and Public Health, Pittsburgh, PA
| | - Adeel A Butt
- Weill Cornell Medical College, NY
- VA Pittsburgh Healthcare System, PA
- Hamad Healthcare Quality Institute, Hamad Medical Corporation, Doha, Qatar
| | - Cynthia L Gibert
- VA Medical Center, Washington, DC
- George Washington University School of Medicine and Public Health, Washington, DC
| | - David Rimland
- Atlanta VA Medical Center, Atlanta, GA
- Emory University School of Medicine, Atlanta, GA
| | - Vincent C Marconi
- Atlanta VA Medical Center, Atlanta, GA
- Emory University School of Medicine, Atlanta, GA
- Rollins School of Public Health, Atlanta, GA
| | - Matthew B Goetz
- VA Greater Los Angeles Healthcare System, Los Angeles, CA
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | | | - Matthew J Budoff
- Harbor-UCLA Medical Center, Los Angeles, CA
- Los Angeles Biomedical Research Institute, Los Angeles, CA
| | | | - Jeffrey H Samet
- Boston University School of Medicine, Boston, MA
- Boston University School of Public Health, Boston, MA
- Boston Medical Center, Boston, MA
| | - Amy C Justice
- Yale University School of Medicine, New Haven, CT
- VA Connecticut Healthcare System, West Haven, CT
- Yale University School of Public Health, New Haven, CT
| | - Matthew S Freiberg
- Vanderbilt University School of Medicine, Nashville, TN
- Nashville Veterans Affairs Medical Center, Nashville, TN
- Tennessee Valley Healthcare System, Nashville, TN
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Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART). PLoS One 2017; 12:e0178685. [PMID: 28594920 PMCID: PMC5464588 DOI: 10.1371/journal.pone.0178685] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 05/17/2017] [Indexed: 12/16/2022] Open
Abstract
Hepatic steatosis can occur with any antiretroviral therapy (cART). Although single nucleotide polymorphisms (SNPs) have been identified to predispose to alcoholic and non-alcoholic fatty liver disease, their role for treatment-associated steatosis in HIV-positive patients remains unclear. We determined the frequency of PNPLA3 (rs738409), CSPG3/NCAN (rs2228603), GCKR (rs780094), PPP1R3B (rs4240624), TM6SF (rs8542926), LYPLAL1 (rs12137855) and MBOAT7 (rs626283) by RT-PCR in 117 HIV-positive patients on cART and stratified participants based on their “controlled attenuation parameter” (CAP) into probable (CAP: 215–300 dB/m) and definite (CAP >300 dB/m) hepatic steatosis. We analyzed CAP values and routine metabolic parameters according to the allele frequencies. Sixty-five (55.6%) and 13 (11.1%) patients were allocated to probable and definite steatosis. CAP values (p = 0.012) and serum triglycerides (p = 0.043) were increased in carriers of the GCKR (rs780094) A allele. Cox logistic regression identified triglycerides (p = 0.006), bilirubin (p = 0.021) and BMI (p = 0.068), but not the genetic parameters as risk factors for the occurrence of hepatic steatosis. Taken together, according to the limited sample size, this exploratory study generates the hypothesis that genetic polymorphisms seem to exert minor effects on the risk for fatty liver disease in HIV-positive patients on cART. Nevertheless, SNPs may modify metabolic complications once metabolic abnormalities have developed. Hence, subsequent analysis of a larger cohort is needed.
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