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Murnane PM, Afshar M, Chamie G, Cook RL, Ferguson T, Haque LY, Jacobson KR, Justice AC, Kim TW, Khalili M, Krupitsky E, McGinnis KA, Molina P, Muyindike WR, Myers B, Richards VL, So-Armah K, Stewart S, Sulkowski MS, Tien PC, Hahn JA. Using Phosphatidylethanol as an Adjunct to Self-Reported Alcohol Use Improves Identification of Liver Fibrosis Risk. Am J Gastroenterol 2024:00000434-990000000-01423. [PMID: 39480054 PMCID: PMC12041314 DOI: 10.14309/ajg.0000000000003178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 10/15/2024] [Indexed: 11/02/2024]
Abstract
INTRODUCTION Accurate assessment of alcohol use informs prevention and management of liver disease. We examined whether phosphatidylethanol (PEth, an alcohol metabolite) blood concentrations are associated with liver fibrosis risk independently of self-reported alcohol use, among persons with and without HIV. METHODS We pooled individual-level data from 12 studies from the United States, Russia, Uganda, and South Africa with PEth, Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), and fibrosis-4 (FIB-4) measurements. We conducted mixed-effects logistic regression of the relationship between PEth and AUDIT-C as continuous variables (after checking linearity), with high FIB-4 (≥2.67). We divided PEth (range 0-1,000) by 83.3 to put it on the same scale as AUDIT-C (0-12) to directly compare odds ratios. Adjusted models included sex, race/ethnicity, age, body mass index, HIV, and virologic suppression status. RESULTS Among 4,644 adults, the median age was 49 years (interquartile range [IQR]: 40-55), 998 (21%) were female, and 3,520 (76%) were living with HIV, among whom 2,386 (68%) were virologically suppressed. Median PEth was 13 ng/mL (IQR: <8-132.0) and median AUDIT-C was 3 (IQR: 1-6); 554 (12%) had high FIB-4. The adjusted odds ratios per 83.3 ng/mL difference in PEth and one-unit difference in AUDIT-C with high FIB-4 were 1.15 (95%CI: 1.08-1.22) and 1.03 (95%CI: 1.00-1.07), respectively. Findings were similar when PEth and AUDIT-C were treated as categorical variables. DISCUSSION PEth was independently associated with high FIB-4, with a larger odds ratio than that of the association of AUDIT-C. The use of PEth may improve identification of alcohol use and liver fibrosis prevention and management.
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Affiliation(s)
- Pamela M. Murnane
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Institute for Global Health Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Majid Afshar
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, WI, USA
| | - Gabriel Chamie
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Robert L. Cook
- Department of Epidemiology, University of Florida, Gainesville, FL, USA
| | - Tekeda Ferguson
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Lamia Y. Haque
- Department of Internal Medicine (Section of Digestive Diseases) and Program in Addiction Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Karen R. Jacobson
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Amy C. Justice
- VA Connecticut Healthcare System, United States Department of Veterans Affairs, West Haven, CT, USA
- Yale School of Medicine, New Haven, CT, USA
- Yale School of Public Health, New Haven, CT, USA
| | - Theresa W. Kim
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Mandana Khalili
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, CA, USA
| | - Evgeny Krupitsky
- First Pavlov State Medical University, St. Petersburg, Russia
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, St. Petersburg, Russia
| | - Kathleen A. McGinnis
- VA Connecticut Healthcare System, United States Department of Veterans Affairs, West Haven, CT, USA
| | - Patricia Molina
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Winnie R. Muyindike
- Department of Internal Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Bronwyn Myers
- Curtin enAble Institute, Faculty of Health Sciences, Curtin University, Australia
- Mental Health, Alcohol, Substance Use and Tobacco Research Unit, South African Medical Research Council, Tygerberg, South Africa
- Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
| | - Veronica L. Richards
- TSET Health Promotion Research Center, University of Oklahoma Health Sciences Center, Tulsa, Oklahoma, USA
| | - Kaku So-Armah
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Scott Stewart
- Department of Family Medicine, Division of Addiction Medicine, University at Buffalo, Buffalo, NY, USA
| | | | - Phyllis C. Tien
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- San Francisco VA Health Care System, San Francisco, CA, USA
| | - Judith A. Hahn
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Gasik RE, Madkour AS, Skeen SJ, Clum G, Francis T, Felker-Kantor E, Ferguson T, Welsh DA, Molina PE, Theall KP. The Impact of Childhood Adversity on Life Course Alcohol Use Patterns and Health Status Among People Living with HIV. AIDS Behav 2024; 28:2887-2898. [PMID: 38907764 PMCID: PMC11390825 DOI: 10.1007/s10461-024-04368-1] [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] [Accepted: 05/06/2024] [Indexed: 06/24/2024]
Abstract
Adverse childhood experiences (ACEs) and financial hardship are associated with increased likelihood of heavier alcohol use and health challenges in adulthood among persons living with HIV (PWH). We examined whether retrospectively captured lifetime drinking trajectories are a pathway through which childhood hardships affect current health in a sample of 365 adult PWH. Childhood economic hardship and ACEs were used as main predictors. Measures of alcohol use included age at first drink and lifetime drinking trajectories. Health indicators included health-related quality of life, frailty, number of comorbidities, and symptoms of anxiety, depression, and post-traumatic stress disorder (PTSD). Structural equation modeling (SEM) was applied to estimate both direct and indirect pathways between childhood hardship and physical and mental health. Participants were mostly male; Black (84%); and averaged 48 years of age. SEM results supported both direct and indirect pathways between childhood experiences and adult health. ACEs were connected to physical health directly and mental health both directly and indirectly through age at first drink and drinking heaviness during ages 10-20. Childhood economic hardship related to mental health indirectly through higher drinking levels during ages 10-20. Childhood adverse experiences, economic hardship, and early drinking patterns appear to accumulate, resulting in later life physical and mental health concerns for PWH. Findings support taking a life course approach to health. This includes considering individual trauma histories in HIV care engagement and taking preventative approaches which support the economic and social well-being of vulnerable children to improve health in subsequent decades.
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Affiliation(s)
- Rayna E Gasik
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
| | | | - Simone J Skeen
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
- Department of Psychology, Hunter College, City University of New York, New York, NY, USA
| | - Gretchen Clum
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
| | | | - Erica Felker-Kantor
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
| | - Tekeda Ferguson
- Department of Epidemiology, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - David A Welsh
- Section of Pulmonary/Critical Care, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Patricia E Molina
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Katherine P Theall
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
- Department of Epidemiology, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
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3
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Ramirez Bustamante CE, Agarwal N, Cox AR, Hartig SM, Lake JE, Balasubramanyam A. Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV. Endocr Rev 2024; 45:190-209. [PMID: 37556371 PMCID: PMC10911955 DOI: 10.1210/endrev/bnad028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 07/09/2023] [Accepted: 08/07/2023] [Indexed: 08/11/2023]
Abstract
Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.
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Affiliation(s)
- Claudia E Ramirez Bustamante
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Neeti Agarwal
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aaron R Cox
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sean M Hartig
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jordan E Lake
- Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA
| | - Ashok Balasubramanyam
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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Lynch EN, Russo FP. Liver Transplantation in People Living with HIV: Still an Experimental Procedure or Standard of Care? Life (Basel) 2023; 13:1975. [PMID: 37895356 PMCID: PMC10608432 DOI: 10.3390/life13101975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
Liver transplantation (LT) is the only curative treatment for various liver diseases, including acute liver failure, end-stage liver disease, and selected unresectable liver malignancies. Combination antiretroviral therapy has improved outcomes for people living with HIV (PLWH), transforming the status of acquired immune deficiency syndrome from a fatal disease to a chronic and manageable condition. These powerful antiviral therapies have not only increased the number of HIV+ enlisted patients by improving their survival but also made the use of HIV+ organs a viable option. In this review, we summarise current knowledge on the peculiarities of liver transplantation in PLWH. In particular, we focus on the indications, contraindications, specific considerations for treatment, and outcomes of LT in PLWH. Finally, we present available preliminary data on the use of HIV+ liver allografts.
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Affiliation(s)
- Erica Nicola Lynch
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, Padua University Hospital, 35128 Padua, Italy;
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, Padua University Hospital, 35128 Padua, Italy;
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Ruta S, Grecu L, Iacob D, Cernescu C, Sultana C. HIV-HBV Coinfection-Current Challenges for Virologic Monitoring. Biomedicines 2023; 11:1306. [PMID: 37238976 PMCID: PMC10215721 DOI: 10.3390/biomedicines11051306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
HIV-HBV coinfected patients have higher rates of liver-related morbidity, hospitalizations, and mortality compared to HBV or HIV mono-infected ones. Clinical studies have shown an accelerated progression of liver fibrosis and an increased incidence of HCC, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Antiviral therapy based on dually active antiretrovirals is highly efficient, but late initiation, global disparities in accessibility, suboptimal regimens, and adherence issues may limit its impact on the development of end-stage liver disease. In this paper, we review the mechanisms of liver injuries in HIV-HBV coinfected patients and the novel biomarkers that can be used for treatment monitoring in HIV-HBV coinfected persons: markers that assess viral suppression, markers for liver fibrosis evaluation, and predictors of oncogenesis.
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Affiliation(s)
- Simona Ruta
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Laura Grecu
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Diana Iacob
- Department for the Prevention and Control of Healthcare Associated Infections, Emergency University Hospital, 050098 Bucharest, Romania;
| | | | - Camelia Sultana
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
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Regan T, Gette J, McAfee N, Parker J. Substance use disparities by age, race, sex, and sexual orientation among persons living with HIV in the Southern U.S. Int J STD AIDS 2023:9564624231162150. [PMID: 36919911 DOI: 10.1177/09564624231162150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
BACKGROUND Alcohol and drug use is overrepresented among individuals living with Human Immunodeficiency Virus (HIV) and is associated with poor health outcomes. Determining the extent to which substance use differs between demographic profiles of people living with HIV (PLWH) would determine at-risk groups that would benefit from intervention. METHODS Cross-sectional screening data (N = 1307, Mage = 42.7 years, 66% male, 86% African American, 39% sexual minority) was examined from an HIV clinic in the southern U.S. largely treating underserved and low-income patients. Age, gender, race/ethnicity, sexual orientation, and their interactions were entered as predictors of substance use and related impairment in a series of zero-inflated negative binomial regressions. RESULTS African Americans reported more drug use (p = 0.004) and drug-related negative consequences (p = 0.003). Notably, alcohol-related negative consequences of African American heterosexuals were much higher at younger ages, compared to sexual minorities (regardless of race) and White heterosexuals of all age groups (p = 0.04). CONCLUSIONS Among PLWH in the U.S. South, African Americans may be uniquely at-risk with for problems related to drug-related functional impairment. Specifically, young heterosexual African Americans are at high risk for alcohol-related impairment. Implications are discussed.
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Affiliation(s)
- Timothy Regan
- Department of Mental Health, RinggoldID:25802Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Jordan Gette
- Center of Alcohol and Substance Use Studies, RinggoldID:242612Rutgers University, Piscataway, NJ, USA
| | - Nicholas McAfee
- Department of Psychiatry and Human Behavior, RinggoldID:12276University of Mississippi Medical Center, Jackson, MI, USA
| | - Jefferson Parker
- Department of Psychiatry and Human Behavior, RinggoldID:12276University of Mississippi Medical Center, Jackson, MI, USA
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Chen PH, Yenokyan K, Fojo AT, Hutton HE, Lesko CR, McCaul ME, Yang C, Cachay ER, Crane HM, Jacobson JM, Kim HN, Kitahata MM, Mayer KH, Moore RD, Napravnik S, Saag M, Lau B, Chander G. Alcohol consumption upon direct-acting antiviral therapy for hepatitis C among persons with human immunodeficiency virus in the United States. Drug Alcohol Depend 2022; 241:109673. [PMID: 36332596 PMCID: PMC9810271 DOI: 10.1016/j.drugalcdep.2022.109673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Direct-acting antivirals (DAA) are highly effective against hepatitis C virus (HCV) infection among persons with human immunodeficiency virus (PWH). However, alcohol use post-DAA treatment poses a continued threat to the liver. Whether the focus on liver health alone during HCV treatment can impact alcohol consumption is unclear. Therefore, we examined the change in alcohol use among HCV-coinfected PWH who received DAA therapy by non-addiction medical providers. METHODS In our longitudinal clinical cohort study, we identified HCV-coinfected PWH who received interferon-free DAA therapy between January 2014 and June 2019 in the Centers for AIDS Research Network of Integrated Clinical Systems. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) was the alcohol screening instrument. We used mixed-effects logistic regression models to estimate the longitudinal change in alcohol use upon DAA therapy. RESULTS Among 738 HCV-coinfected PWH, 339 (46 %) reported any alcohol use at the end of HCV treatment, including 113 (15 %) with high-risk use (i.e., AUDIT-C ≥3 for women, ≥4 for men). Concurrently, 280 (38 %) PWH noted active drug use, and 357 (48 %) were currently smoking. We observed no changes in the odds of any alcohol or high-risk alcohol use over time with DAA therapy. Findings were similar in the PWH subgroup with a history of alcohol use before DAA treatment. CONCLUSIONS For PWH with HCV, alcohol use did not change following interferon-free DAA treatment by non-addiction medical providers. Thus, clinicians should consider integrating targeted alcohol use interventions into HCV care to motivate reduced alcohol consumption and safeguard future liver health.
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Affiliation(s)
- Po-Hung Chen
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Karine Yenokyan
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Anthony T Fojo
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Heidi E Hutton
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Catherine R Lesko
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Mary E McCaul
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Cui Yang
- Department of Health, Behavior and Society, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Edward R Cachay
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego School of Medicine, San Diego, CA 92093, USA
| | - Heidi M Crane
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Jeffrey M Jacobson
- Division of Infectious Diseases, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - H Nina Kim
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Mari M Kitahata
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Kenneth H Mayer
- The Fenway Institute, Fenway Health, Boston, MA 02215, USA; Department of Global Health and Population, Harvard University T.C. Chan School of Public Health, Boston, MA 02115, USA
| | - Richard D Moore
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sonia Napravnik
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
| | - Michael Saag
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA
| | - Bryan Lau
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA; Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Geetanjali Chander
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
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Ahodantin J, Nio K, Funaki M, Zhai X, Wilson E, Kottilil S, Cheng L, Li G, Su L. Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy. JCI Insight 2022; 7:e152738. [PMID: 35639478 PMCID: PMC9310524 DOI: 10.1172/jci.insight.152738] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 05/25/2022] [Indexed: 11/17/2022] Open
Abstract
Liver diseases have become a major comorbidity health concern for people living with HIV-1 (PLWH) treated with combination antiretroviral therapy (cART). To investigate if HIV-1 infection and cART interact to lead to liver diseases, humanized mice reconstituted with progenitor cells from human fetal livers were infected with HIV-1 and treated with cART. We report here that chronic HIV-1 infection with cART induced hepatitis and liver fibrosis in humanized mice, associated with accumulation of M2-like macrophages (M2LMs), elevated TGF-β, and IFN signaling in the liver. Interestingly, IFN-I and TGF-β cooperatively activated human hepatic stellate cells (HepSCs) in vitro. Mechanistically, IFN-I enhanced TGF-β-induced SMAD2/3 activation in HepSCs. Finally, blockade of IFN-I signaling reversed HIV/cART-induced liver diseases in humanized mice. Consistent with the findings in humanized mice with HIV-1 and cART, we detected elevated markers of liver injury, M2LMs, and of IFN signaling in blood specimens from PLWH compared with those of healthy individuals. These findings identify the IFN-I/M2LM/HepSC axis in HIV/cART-induced liver diseases and suggest that inhibiting IFN-I signaling or M2LM may provide a novel therapeutic strategy for treating HIV/cART-associated liver diseases in PLWH treated with antiretroviral therapy.
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Affiliation(s)
- James Ahodantin
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kouki Nio
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Masaya Funaki
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Xuguang Zhai
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Eleanor Wilson
- Division of Clinical Care and Research, Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Shyamasundaran Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Liang Cheng
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Guangming Li
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Lishan Su
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Lyu H, Tang H, Liang Y, Huang S, Wang Y, Huang W, Zhou Y. Alcohol Consumption and Risk of Liver Fibrosis in People Living With HIV: A Systematic Review and Meta-Analysis. Front Immunol 2022; 13:841314. [PMID: 35371091 PMCID: PMC8971654 DOI: 10.3389/fimmu.2022.841314] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/28/2022] [Indexed: 11/16/2022] Open
Abstract
Objectives It is unclear if a high level of alcohol consumption is a risk factor for liver fibrosis for people living with HIV (PLWH). This study systematically summarizes the risk relationship between different alcohol consumption and the incidence of liver fibrosis among PLWH. Methods We identified potential studies by searching the PubMed, Embase, Web of Science Library, and CNKI databases up to September 26th, 2021. Observation studies in PLWH that evaluated the relationship between alcohol consumption and the risk of liver fibrosis and estimated the effect of alcohol with pooled odds ratios (pooled ORs) and 95% confidence intervals (CIs) were included. Results There were total 15 studies included in data analysis. Three studies were set up as cohort studies and the other twelve were cross-sectional studies. Our study was based on 22,676 individuals and 2,729 liver fibrosis cases from 15 studies. Alcohol abuse is a significant risk factor of liver fibrosis (pooled OR = 2.25, 95% CI: 1.59-3.17, p < 0.05) among PLWH. Daily alcohol consumption > 50 g can elevate the risk of liver fibrosis (pooled OR = 3.10, 95% CI: 2.02-4.73, p < 0.05) among PLWH. However, high-risk alcohol consumption determined by AUDIT-C (AUDIT-C ≥ 4) had little or no effect on subsequent liver fibrosis risk. Further, alcohol consumption > 50 g is also a risk factor to liver fibrosis in PLWH co-infected with HCV (pooled OR = 2.48, 95% CI: 1.62-3.80, p < 0.05) and in HIV mono-infected (pooled OR = 1.85, 95% CI: 1.00-3.43, p < 0.05). Conclusion Alcohol consumption is associated with an increased risk of liver fibrosis in PLWH. HCV co-infection with alcohol abuse could possibly induce a higher risk of liver fibrosis than HIV mono-infected patients. Systematic Review Registration PROSPERO, identifier (CRD42021272604).
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Affiliation(s)
- Hang Lyu
- Department of HIV Prevention, Zhuhai Center for Disease Control and Prevention, Zhuhai, China
| | - Haotong Tang
- Faculty of Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Yizhi Liang
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Shaoli Huang
- Zhejiang University-University of Edinburgh Institute, Zhejiang University, Jiaxing, China
| | - Yuyu Wang
- School of Medicine, Jinan University, Guangzhou, China
| | - Wenyan Huang
- Department of HIV Prevention, Zhuhai Center for Disease Control and Prevention, Zhuhai, China
- *Correspondence: Wenyan Huang , ; Yi Zhou,
| | - Yi Zhou
- Department of HIV Prevention, Zhuhai Center for Disease Control and Prevention, Zhuhai, China
- *Correspondence: Wenyan Huang , ; Yi Zhou,
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10
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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11
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Rafiemanesh H, Rahimi-Movaghar A, Shadloo B, Rostam-Abadi Y, Nedjat S, Yazdani K. Prevalence, pattern, and associated factors of alcohol use disorder among male treatment-seeking people with illicit drug use disorder in Tehran, Iran. JOURNAL OF SUBSTANCE USE 2022. [DOI: 10.1080/14659891.2021.2020346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Hosein Rafiemanesh
- Department of Epidemiology and Biostatistics Alborz University of Medical Sciences, Karaj, Iran
| | - Afarin Rahimi-Movaghar
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Behrang Shadloo
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Yasna Rostam-Abadi
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Saharnaz Nedjat
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Yazdani
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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12
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Discordant Liver Fibrosis Predictors in Virologically Suppressed People Living with HIV without Hepatitis Virus Infection. Diagnostics (Basel) 2021; 12:diagnostics12010014. [PMID: 35054179 PMCID: PMC8775200 DOI: 10.3390/diagnostics12010014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 12/17/2022] Open
Abstract
Severe liver fibrosis (LF) is associated with poor long-term liver-related outcomes in people living with HIV (PLWH). The study aimed to explore the prevalence and predictors of LF and the concordance between different non-invasive methods for the estimation of LF in HIV-infected individuals without hepatitis virus infection. We enrolled PLWH with HIV-1-RNA <50 copies/mL for >12 months, excluding individuals with viral hepatitis. LF was assessed by transient elastography (TE) (significant >6.65 kPa), fibrosis-4 (FIB-4) (significant >2.67), and AST-to-platelet ratio index (APRI) (significant >1.5). We included 234 individuals (67% males, median age 49 years, median time from HIV diagnosis 11 years, 38% treated with integrase strand transfer inhibitors). In terms of the TE, 13% had ≥F2 stage; FIB-4 score was >1.5 in 7%; and APRI > 0.5 in 4%. Higher body mass index, diabetes mellitus, detectable baseline HIV-1 RNA and longer atazanavir exposure were associated with higher liver stiffness as per TE. Predictors of higher APRI score were CDC C stage and longer exposure to tenofovir alafenamide, while HBcAb positivity and longer exposure to tenofovir alafenamide were associated to higher FIB-4 scores. Qualitative agreement was poor between FIB-4/TE and between APRI/TE by non-parametric Spearman correlation and kappa statistic. In our study, in the group of PLWH without viral hepatitis, different non-invasive methods were discordant in predicting liver fibrosis.
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13
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Rosen EM, Primeaux SD, Simon L, Welsh DA, Molina PE, Ferguson TF. Associations of Binge Drinking and Heavy Alcohol Use on Sugar and Fat Intake in a Cohort of Southern People Living with HIV. Alcohol Alcohol 2021; 57:226-233. [PMID: 34611697 DOI: 10.1093/alcalc/agab066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 11/12/2022] Open
Abstract
AIMS To assess whether binge drinking and heavy alcohol use are associated with increased sugar and fat consumption among a Southern cohort of people living with HIV (PWH). METHODS This was a cross-sectional analysis of PWH enrolled in the New Orleans Alcohol use in HIV (NOAH) Study (n = 215). Binge and heavy drinking were identified through a 30-day Alcohol Timeline-Followback and dietary intake was assessed through a 24-hour dietary recall. RESULTS Participants were 65.4% male, 83.3% Black, with a mean age of 49.2 ± 9.9. Heavy drinkers consumed more total calories than abstainers (P = 0.035) and low-to-moderate drinkers (P = 0.024), and binge drinkers consumed more calories than non-binge drinkers (P = 0.025). Binge and heavy drinkers had significantly higher intake of total and saturated fat in grams. However, substantially increased caloric intake among these participants led to non-significant associations for alcohol use with high total and saturated fat intake as a percent of total energy intake (%TEI). Binge drinkers had lower odds of consuming high sugar as a %TEI (odds ratio: 0.31 [0.14, 0.68]). Additionally, sugar intake predicted total and saturated fat intake, and this association was slightly higher among binge drinkers (total fat P-value: 0.12). CONCLUSIONS In this population of PWH, while binge and heavy drinking predicted higher caloric and fat intake in grams, binge drinkers were less likely to consume a high-sugar diet. This analysis suggests that interventions focused on reduced alcohol use may be especially beneficial in reducing metabolic disease burden in PWH if supplemented with information on incorporating lower energy-dense foods with reduced fat.
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Affiliation(s)
- Erika M Rosen
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112 USA.,Louisiana State University Health Sciences Center, School of Public Health, Department of Epidemiology, 2020 Gravier St, New Orleans, LA 70112, USA
| | - Stefany D Primeaux
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112 USA.,Louisiana State University Health Sciences Center, School of Medicine, Department of Physiology, 1901 Perdido St, New Orleans, LA 70112, USA.,Pennington Biomedical Research Center, Joint Diabetes, Endocrinology & Metabolism Program, 6400 Perkins Rd, Baton Rouge, LA 70808, USA
| | - Liz Simon
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112 USA.,Louisiana State University Health Sciences Center, School of Medicine, Department of Physiology, 1901 Perdido St, New Orleans, LA 70112, USA
| | - David A Welsh
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112 USA.,Louisiana State University Health Sciences Center, School of Medicine, Department of Pulmonology, 1901 Perdido St, New Orleans, LA 70112, USA
| | - Patricia E Molina
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112 USA.,Louisiana State University Health Sciences Center, School of Medicine, Department of Physiology, 1901 Perdido St, New Orleans, LA 70112, USA
| | - Tekeda F Ferguson
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112 USA.,Louisiana State University Health Sciences Center, School of Public Health, Department of Epidemiology, 2020 Gravier St, New Orleans, LA 70112, USA.,Louisiana State University Health Sciences Center, School of Medicine, Department of Physiology, 1901 Perdido St, New Orleans, LA 70112, USA
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14
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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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15
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Stein MD, Herman DS, Kim HN, Howell A, Lambert A, Madden S, Moitra E, Blevins CE, Anderson BJ, Taylor LE, Pinkston MM. A Randomized Trial Comparing Brief Advice and Motivational Interviewing for Persons with HIV-HCV Co-infection Who Drink Alcohol. AIDS Behav 2021; 25:1013-1025. [PMID: 33047258 DOI: 10.1007/s10461-020-03062-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2020] [Indexed: 12/15/2022]
Abstract
Alcohol use contributes to the progression of liver disease in HIV-HCV co-infected persons, but alcohol interventions have never addressed low levels of alcohol use in this population. We enrolled 110 persons consuming at least 4 alcoholic drinks weekly in a clinical trial comparing two active 18-month long interventions, delivered every 3 months by phone, brief advice about drinking versus a motivational intervention. Final assessment was at 24 months. MI had larger reductions in alcohol use days than the BA arm at all follow-up assessments. The treatment by time effect was not significant for days of drinking (p = 0.470), mean drinks per day (p = 0.155), or for the continuous FIB-4 index (p = 0.175). Drinking declined in both conditions from baseline, but given the small sample, we do not have sufficient data to make any conclusion that one treatment is superior to the other.Trial Registry Trial registered at clinicaltrials.gov; Clinical Trial NCT02316184.
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Affiliation(s)
- Michael D Stein
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, USA.
- Department of Health Law, Policy & Management, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
| | - Debra S Herman
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, USA
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - H Nina Kim
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Abigail Howell
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Audrey Lambert
- Department of Health Law, Policy & Management, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA
| | | | - Ethan Moitra
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Claire E Blevins
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, USA
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Bradley J Anderson
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, USA
| | | | - Megan M Pinkston
- Warren Alpert Medical School of Brown University, Providence, RI, USA
- The Miriam Hospital, Providence, RI, USA
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16
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Lin X, Li Y, Zhang X, Wei Y, Wen S, Lu Z, Huang Q, Wei J. Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF-κB signalling pathways. Cell Biochem Funct 2020; 39:77-87. [PMID: 32564421 DOI: 10.1002/cbf.3564] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/06/2020] [Accepted: 05/17/2020] [Indexed: 01/06/2023]
Abstract
The present study was to investigate the inhibitory effect and underlying mechanism of Tormentic acid (TA) on hepatic stellate cells (HSCs). HSC-T6 cells were stimulated with Platelet-derived growth factor-BB (PDGF-BB) and TA, and then cell proliferation, apoptosis, inflammatory factor, and collagen-related indicators were detected. In order to elucidate the potential mechanism, the PI3K/Akt/mTOR and NF-κB signalling pathways were also detected. The results showed that TA treatment markedly inhibited PDGF-BB-stimulated HSC-T6 cell activation, as evidenced by the inhibition of cell proliferation, migration and colony formation, as well as the decreased expression of TGF-β and α-SMA. TA treatment caused a significant increase in the activity of lactate dehydrogenase and significantly promoted cell apoptosis. TA treatment significantly reduced aspartate aminotransferase, alanine aminotransferase and total bilirubin activity. Importantly, TA inhibited the expression of collagen type I and III, alleviating the excessive deposition of extracellular matrix (ECM). Further experiments showed that TA administration significantly inhibited the phosphorylation of PI3K, Akt, FAK and mTOR and the protein expression of P70S6K, indicating the inhibition of the PI3K/Akt/mTOR pathway. Moreover, treatment with TA markedly decreased the phosphorylation of IκBα, NF-κB p65 and IKKα/β, thereby blocking the NF-κB signal transduction. In summary, this study demonstrates that TA significantly inhibits HSC activation and promotes cell apoptosis via the inhibition of the PI3K/Akt/mTOR and NF-κB signalling pathways. SIGNIFICANCE OF THE STUDY: Tormentic acid (TA) could inhibit HSC activation and alleviate collagen-based ECM deposition, suggesting that TA exerted anti-hepatic fibrosis. Further mechanism research revealed that the inhibition of TA on HSC activation might be through blocking the PI3K/Akt/mTOR and NF-κB signalling pathways. These findings provided a new cue to understand the protective effect of TA against liver fibrosis, which may provide a potential nature medicine for the treatment of liver fibrosis.
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Affiliation(s)
- Xing Lin
- Guangxi Medical University, Nanning, China
| | - Yan Li
- Guangxi Medical University, Nanning, China
| | | | | | | | - Zhongpeng Lu
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | - Quanfang Huang
- The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jinbin Wei
- Guangxi Medical University, Nanning, China
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