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The Aging Liver in the Aging HIV Patient

The Aging Liver in the Aging HIV Patient. Douglas T. Dieterich, M.D Professor of Medicine Division of Liver Diseases, Gastroenterology and Infectious Diseases Department of Medicine Mount Sinai School of Medicine New York, New York. The HIV-Infected Population is Aging.

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The Aging Liver in the Aging HIV Patient

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  1. The Aging Liver in the Aging HIV Patient Douglas T. Dieterich, M.D Professor of Medicine Division of Liver Diseases, Gastroenterology and Infectious Diseases Department of Medicine Mount Sinai School of Medicine New York, New York

  2. The HIV-Infected Population is Aging Persons 50 years and older increasing Among new HIV infections 4% in1995 vs 6% in 2000 vs 15% in 2005 Increasing number of persons 50 years and older living with HIV/AIDS in the US From 2004 to 2007, the prevalence of persons living with HIV/AIDS increased the most in those aged 40-49 years old In 2005, persons 50 years and older accounted for 35% of all deaths of persons living with AIDS CDC 2007. HIV/AIDS surveillance report, 2005.

  3. Persons Living with HIV/AIDS in USA (33 states) CDC Surveillance Program 50% 25.4% 19.7% 17.1% By 2015, 50% of the HIV population will be 50 and older CDC 2007. HIV/AIDS surveillance report 2005 Fauci AS. National HIV/AIDS and Aging Awareness Day

  4. HIV Results in Accelerated Age-related Conditions Development of frailty, muscle wasting Insulin resistance, diabetes and cardiovascular disease Chronic kidney disease Bone disease Cognitive impairment and dementia Non AIDS-defining malignancies Liver disease and HCC Effros RB et al. Clin Infect Dis 2008

  5. Consequences of HIV, Aging and the Liver Clinical manifestations of aging HIV and the liver Chronic elevations of liver enzymes Steatosis/steatohepatitis Increased drug-related toxicity More severe liver disease in aging patients with hepatitis B and C Later stage and less treatable HCC 1. Weber R. et al. arch Intern Med 2006.

  6. Consequences of HIV, Aging and the Liver Mortality associated with liver disease is high among HIV-infected patients 2nd cause of death in HIV-infected patients after AIDS-related complications 4-fold increase in morbidity and mortality due to liver diseases among older patients Weber R. et al. arch Intern Med 2006. 1. Weber R. et al. arch Intern Med 2006.

  7. Change in Causes of Death in Patients with HIV Reflects Aging Swiss HIV Cohort Study (SHCS) 446 deaths between 2005 and 2009 76% men Median age at death = 47 years Median duration of HIV infection = 14 years 93% received ART X median of 9.5 years CD4+ before death= 251 cells/mm3 45% co-infected with HCV 11% co-infected with HBV Ruppik M. et al. Changing patterns of causes of death in the SHCS 2005-2009. CROI 2011. Poster # 789. Available at: http://www.retroconference.org/2011/PDFs/789.pdf.

  8. Change in Causes of Death in Patients with HIV Reflects Aging Causes of death #1 Non-AIDS defining cancers (n=85, 19.1%) including HCC (n=13, 2.8%) #2 AIDS (n=73, 16.4%) #3 Liver Diseases (n=67, 15%) When deaths due to HCC were included among liver-related deaths (instead of non-AIDS defining cancers) Liver Diseases = #1 Cause of Death (17.9%) Ruppik M. et al. Changing patterns of causes of death in the SHCS 2005-2009. CROI 2011. Poster # 789. Available at: http://www.retroconference.org/2011/PDFs/789.pdf

  9. Age and HCC in HIV-Infected Patients • All HCC cases in HIV-infected patients from 1995-2010 with data on initial presentation (n = 163) • Diagnosed by AASLD criteria (Bruix & Sherman, Hepatology, 2005) • Patients were divided into • Age < 50 years n=66 (40%) • Age ≥ 50 years n=97 (60%) Braü et al. AASLD, Boston 2010, Poster # 1795

  10. Age and Survival of HIV-Infected Patients with HCC Braü et al. AASLD, Boston 2010, Poster # 1795.

  11. Age and HCC in HIV-Infected Patients • Compared to younger HIV-infected patients with HCC, patients ≥ 50 years • are more frequently black • tend to have chronic hepatitis C • tend to present more frequently with multiple rather than solitary tumors • tend to receive effective HCC therapy less often • tend toward shorter survival (p= 0.11) Braü et al. AASLD, Boston 2010, Poster # 1795.

  12. Age and HCC in HIV-Infected Patients • HCC mortality rates increased faster than rates for any other leading cause of cancer • HCC rate increased from • 2.7 per 100,000 persons in 2001 to • 3.2 in 2006, with an APC of 3.5% (annual percent increase, translates to 10% increase over 3 yr Reference

  13. Aging, HIV and the Immune System: Interactions Early immune senescence in HIV disease Aging and HIV seem to share common mechanisms by which they alter cellular immunity Immune activation and inflammation are characteristic of both aging and HIV infection In HIV infection, microbial translocation might contribute to premature aging by promoting immune activation And may have direct effects on the liver Desai S and Landay A. Curr HIV/AIDS Rep 2010 Balagopal A. et al. Gastroenterology 2008

  14. HIV and Microbial Translocation Primary target of HIV is CD4+T cell compartment Majority of CD4+ T cells are mucosal Gut = 80% of the entire T-cell population: Gut-Associated Lymphoid Tissue (GALT) Most of gut and peripheral CD4+ T cells are lost during the acute phase of HIV Depletion of gut CD4+ T cells persists into chronic phase and despite effective ART Bacteria and bacterial products such as LPS can cross over and reach the portal and systemic circulations Contributes to chronic immune activation in HIV Guadalupe M. et al. J Virol 2003; Mehandru S. et al. J Exp Med 2004; Brenchley JM et al. J Exp Med 2004; Poles MA et al. JAIDS 2006; Mehandru S. et al. PLos Med 2006

  15. Microbial Translocation in HIV HIV - HIV + Brenchley JM et al. Nature Medicine 2006.

  16. Early Immune Senescence in HIV Disease Viral replication Circulating antigen Antigen Antigen T cell CD4 CD4 T cell Clonal expansion Tcell HIV T cell T cell T cell T cell Microbial translocation Loss of CD28 on T cells Shortening of telomeres ? Inability to control mucosal dysregulation Activation Loss of naïve T cells Inflammation Thymic dysfunctionality CD57+ t cells Non-AIDS-defining co-morbidities End-stage senescent T cells Premature aging Desai S. and Landay A. Curr HIV/AIDS Rep 2010.

  17. Aging, HIV and the liver: Interactions • Aging and the liver • Decrease in liver volume • Impaired hepatic blood flow • Decreased amount of surface endoplasmic reticulum (SER) , the principal site of drug metabolism • Increased amount of fat, which alters metabolic rate • Decline in regenerative response of hepatocytes following liver injury Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003; Housset et al. Res Virol 1990; Banerjee et al. AIDS 1992; Blackard JT et al. J viral hepat. 2008; Hong F et al. Hepatology 2010.

  18. Aging, HIV and the liver: Interactions • Direct effect of HIV in the liver may contribute • Several liver cell types can be productively infected with HIV • Replication of HIV in hepatic stellate cells by detection of p24 ag and HIV mRNA • Pro-fibrogenic (collagen I) • Pro-inflammatory (MCP-1) Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003; Housset et al. Res Virol 1990; Banerjee et al. AIDS 1992; Blackard JT et al. J viral hepat. 2008; Hong F et al. Hepatology 2010.

  19. Hepatic Stellate Cell Activation: A Central Event in Liver Fibrosis Activated HSC with Fibrosis Normal Liver Friedman SL and Arthur, Science and Medicine, 2002

  20. Several Liver Cell Types Can Be Productively Infected with HIV Stellate cells express CXCR4 and CCR5 Activated human hepatic stellate cells support HIV gene expression HIV promotes stellate cell collagen I expression and secretion of MCP-1 HIV envelope protein induces cellular effects on parenchymal and non-parenchymal cells in the liver HIV-1 gp120 (X4) induces fibrogenic gene expression in human stellate cells Hong F, Hepatology, 2009; Schwabe R, Am J Physiol Gastrointest Liver Physiol, 2003; Tuyama et al., Hepatology, 2010; Vlahakis S, JID, 2003; Munshi N, JID, 2003; Bruno R, Gut, 2009.

  21. Chronic Elevation of Liver Enzymes in HIV Abnormal liver enzymes are frequently seen in HIV infected patients (15-43%) Risk factors Increased BMI, hypertension, ART exposure, severe alcohol use, HIV RNA level, low CD4+ cell count, and age No studies have compared the prevalence of liver enzymes elevation in younger vs older HIV-infected patients Pol S et al. Clin Infect Dis 2004; Maida I et al. J Acquir Immune Defic Syndr 2006; Sterling RK et al. Dig Dis Sci 2008; Kovari H et al. Clin Infect Dis 2010;

  22. Chronic Elevation of Liver Enzymes in HIV Steatosis/steatohepatitis is an emerging cause of chronic liver enzymes elevations in HIV 30 HIV-infected patients on ART with transaminase elevation > 6 months were biopsied Mean age 46y, duration of HIV infection 13 years 60% (18/30) had steatosis, 53% (16/30) had steatohepatitis Associated with insulin resistance 24 HIV-infected patients were biopsied Mean age 50, duration of HIV infection 17 years, mean duration of ART 12 years 37.5% (9/24) had steatohepatitis Ingiliz P et al. Hepatology 2009; Morse C. et al. CROI 2009, abstract #748

  23. Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV • 37% (83/225) of HIV patients with NAFLD based on CT-scans • Mean age 48 years • 72% male • Mean duration of HIV 13 years • Factors associated with steatosis • Elevated ALT/AST • Male sex • Elevated waist circumference • Cumulative NRTI exposure Guaraldi G. et al. Clin Infect Dis 2008. Crum-Cianflone N et al. J Acquir Immune Defic Syndr 2009.

  24. Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV • 31% (67/216) of HIV-infected patients with NAFLD based on US examination • Mean age 40 years • 94% male • Mean duration of HIV 10 years • 65% on ART • 165 patients with elevated liver enzymes and/or steatosis suggested at US • 55 underwent a liver biopsy • 36% (20/55) had biopsy-proven steatosis and 6 also had steatohepatitis Guaraldi G. et al. Clin Infect Dis 2008; Crum-Cianflone N et al. J Acquir Immune Defic Syndr 2009.

  25. The HIV Aging Liver and Steatosis Insulin Resistance Diabetes, Obesity Dyslipidemia EtOH Drugs ART (mitochondrial toxicity) STEATOSIS Fibrosis progression HIV (chronic inflam. state) Co-infection w/ Hepatitis C

  26. Drug-Induced Liver Injury In the post ART era, drug-induced liver injury has become a major problem in the management of HIV Mitochondrial toxicity and microvesicular steatosis with NRTIs Liver enzyme elevations with NNRTIs and PIs Aging increases susceptibility to drug toxicity Amount of SER + in P450 activity Decline in phase I drug metabolism Increase pill burden in older HIV patients Increased drug interactions and toxicity Jain MK. Clin Liver Dis 2007; Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003.

  27. Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART Case-series of HIV mono-infected patients with cryptogenic liver disease Signs and symptoms of portal hypertension Thrombocytopenia Hepatosplenomegaly Esophageal varices (EV) / EV bleeding Encephalopathy Liver enzymes usually normal. INR, bilirubin and albumin normal Prolonged exposure to ddI and median duration of HIV > 10 years Maida I et al. J Acquir Immune Defic Syndr 2006; Mallet V. et al. AIDS 2007; Schiano T. et al. Am J Gastroenterol 2007; Stebbing J. et al. J Acquir Immnue Defic Syndr 2009.

  28. Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART NRH LIVER BIOPSY Nodular Regenerative Hyperplasia (NRH) or HepatoPortal Sclerosis (HPS) Non cirrhotic portal hypertension HPS

  29. Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART In January of 2010, the United States Food and Drug Administration issued a statement that patients using Didanosine are at risk for a rare but potentially fatal liver disorder, non-cirrhotic portal hypertension

  30. HCV Co-Infected Patients Are Aging 1st cause of non-AIDS-related-deaths: LIVER Risk factors for liver deaths: lower CD4+ T cell count, IVDU, HCV, HBV and age (RR 1.3 per 5 years older) Patients with chronic HCV get older Recent multiple cohort model of HCV prevalence and disease progression (in the US) estimated the burden of HCV and cirrhosis for the next decades Weber R et al. Arch Intern Med 2006; Davis GL et al. Gastroenterology 2010; Balagopal A et al. Gastroenterology 2008.

  31. HCV-Related Cirrhosis Is Projected to Peak Over the Next 10 Years 1,200,000 25% of patients with HCV currently have cirrhosis 1,000,000 800,000 600,000 37% of patients with HCV projected to develop cirrhosis by 2020, peaking at 1 million Patients, N 400,000 200,000 0 1990 2000 2010 2020 2030 Year Adapted from Davis GL, et al. Gastroenterology2010.

  32. HCV-Related Cirrhosis Complications are Expected to Peak Over the Next 10 Years Projected Number of Cases of HCC andDecompensated Cirrhosis due to HCV 160,000 140,000 120,000 Decompensated cirrhosis 100,000 Cases (n) 80,000 60,000 40,000 Hepatocellular cancer 20,000 0 1950 1960 1970 1980 1990 2000 2010 2020 2030 Year Davis GL, et al. Gastroenterology2010.

  33. Baseline Fibrosis Stage According to Age in HCV/HIV Co-Infection F0-F2 F3-F4 70 62 60 50 46 44 40 36 Patients (%) 32 30 20 15 10 0 31-40 <30 ≥41 Age (yrs) Soriano V. J Hep. 2006.

  34. Liver fibrosis is Accelerated in HIV/HCV Co-Infected Patients And age at HCV infection is one of the risk factors associated with rapid progression Why? Decreased immunity HIV replication in stellate cells ART toxicity? Steatosis/steatohepatitis Liver disease progression may be associated with microbial translocation Balagopal A. et al. Gastroenterology 2008.

  35. HIV-related Microbial Translocation and Progression of Hepatitis C HIV-related CD4+ T-cell depletion is associated with microbial translocation Markers of microbial translocation (LPS, sCD14) are strongly associated with HCV-related liver disease progression Levels of LPS are elevated prior to recognition of cirrhosis Balagopal A et al. Gastroenterology 2008; Brenchley JM et al. Nature Medicine 2006.

  36. HIV-related Gut CD4+ T cell Depletion and Microbial Translocation Contributes to HCV Progression Balagopal A et al. Gastroenterology 2008

  37. Role of Microbial translocation in liver fibrosis? Bacterial translocation Following HIV infection: gut permeability LPS level in portal/systemic circulation Kupffer cells are a target of LPS Hepatic stellate cells activation (TLR4 dependent) Liver fibrogenesis Seki E. et al. Nature Medicine. 2007;13(11):1324-32. Paik et al. Hepatology 2003. Seki E. et al. Nature Medicine. 2007;13(11):1324-32.

  38. Conclusions Liver is a major target of the aging process that occurs in HIV-infected patients The causes are multiple Chronic immune activation Accelerated senescence HIV effect on stellate cells leading to liver fibrosis Microbial Translocation leading to progressive liver disease as a result of loss of GALT early in HIV infection Worsening of chronic hepatitis Fatty liver disease related to insulin resistance and ART Recognize the clinical importance of the aging liver and tailor treatment accordingly

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