Presentation on theme: "The Aging Liver in the Aging HIV Patient"— Presentation transcript:
1The Aging Liver in the Aging HIV Patient Douglas T. Dieterich, M.DProfessor of MedicineDivision of Liver Diseases,Gastroenterology and Infectious DiseasesDepartment of MedicineMount Sinai School of MedicineNew York, New YorkAging is becoming a hot topic in HIV.We used to say the liver did not age, well we now have evidence that this is not the case.So for the next 30 minutes or so, I will review with you some of what we know occurs in the liver of aging HIV persons.
2The HIV-Infected Population is Aging Persons 50 years and older increasingAmong new HIV infections4% in1995 vs 6% in 2000 vs 15% in 2005Increasing number of persons 50 years and older living with HIV/AIDS in the USFrom 2004 to 2007, the prevalence of persons living with HIV/AIDS increased the most in those aged years oldIn 2005, persons 50 years and older accounted for 35% of all deaths of persons living with AIDSTo start, some interesting numbers about the aging HIV populationThis is in part due to the increased survival in the post ART era.CDC HIV/AIDS surveillance report, 2005.
3Persons Living with HIV/AIDS in USA (33 states) CDC Surveillance Program 50%25.4%19.7%17.1%By 2015, 50% ofthe HIV populationwill be 50 and olderCDC HIV/AIDS surveillance report 2005Fauci AS. National HIV/AIDS and Aging Awareness Day
4HIV Results in Accelerated Age-related Conditions Development of frailty, muscle wastingInsulin resistance, diabetes and cardiovascular diseaseChronic kidney diseaseBone diseaseCognitive impairment and dementiaNon AIDS-defining malignanciesLiver disease and HCCWe now recognize that HIV is associated withEffros RB et al. Clin Infect Dis 2008
5Consequences of HIV, Aging and the Liver Clinical manifestations of aging HIV and the liverChronic elevations of liver enzymesSteatosis/steatohepatitisIncreased drug-related toxicityMore severe liver disease in aging patients with hepatitis B and CLater stage and less treatable HCCWe see an increasing numberEven in the HAART era1. Weber R. et al. arch Intern Med 2006.
6Consequences of HIV, Aging and the Liver Mortality associated with liverdisease is high among HIV-infected patients2nd cause of death in HIV-infected patients after AIDS-related complications4-fold increase in morbidity and mortality due to liver diseases among older patientsWe see an increasing numberEven in the HAART eraWeber R. et al. arch Intern Med 2006.1. Weber R. et al. arch Intern Med 2006.
7Change in Causes of Death in Patients with HIV Reflects Aging Swiss HIV Cohort Study (SHCS)446 deaths between 2005 and 200976% menMedian age at death = 47 yearsMedian duration of HIV infection = 14 years93% received ART X median of 9.5 yearsCD4+ before death= 251 cells/mm345% co-infected with HCV11% co-infected with HBVRuppik M. et al. Changing patterns of causes of death in the SHCS CROI 2011.Poster # 789. Available at:
8Change in Causes of Death in Patients with HIV Reflects Aging #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 CROI 2011.Poster # 789. Available at:
9Age and HCC in HIV-Infected Patients All HCC cases in HIV-infected patients from with data on initial presentation (n = 163)Diagnosed by AASLD criteria (Bruix & Sherman, Hepatology, 2005)Patients were divided intoAge < 50 years n=66 (40%)Age ≥ 50 years n=97 (60%)Braü et al. AASLD, Boston 2010, Poster # 1795
10of HIV-Infected Patients with HCC Age and Survivalof HIV-Infected Patients with HCCBraü et al. AASLD, Boston 2010, Poster # 1795.
11Age and HCC in HIV-Infected Patients Compared to younger HIV-infected patients with HCC, patients ≥ 50 yearsare more frequently blacktend to have chronic hepatitis Ctend to present more frequently with multiple rather than solitary tumorstend to receive effective HCC therapy less oftentend toward shorter survival (p= 0.11)Braü et al. AASLD, Boston 2010, Poster # 1795.
12Age and HCC in HIV-Infected Patients HCC mortality rates increased faster than rates for any other leading cause of cancerHCC rate increased from2.7 per 100,000 persons in 2001 to3.2 in 2006, with an APC of 3.5% (annual percent increase, translates to 10% increase over 3 yrReference
13Aging, HIV and the Immune System: Interactions Early immune senescence in HIV diseaseAging and HIV seem to share common mechanisms by which they alter cellular immunityImmune activation and inflammation are characteristic of both aging and HIV infectionIn HIV infection, microbial translocation might contribute to premature aging by promoting immune activationAnd may have direct effects on the liverDesai S and Landay A. Curr HIV/AIDS Rep 2010Balagopal A. et al. Gastroenterology 2008
14HIV and Microbial Translocation Primary target of HIV is CD4+T cell compartmentMajority of CD4+ T cells are mucosalGut = 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 HIVDepletion of gut CD4+ T cells persists into chronic phase and despite effective ARTBacteria and bacterial products such as LPS can cross over and reach the portal and systemic circulationsContributes to chronic immune activation in HIVGuadalupe 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
15Microbial Translocation in HIV HIV infection leads to CD4+ T cell depletion and this predominantly takes place in the GALT or gut associated lymphoid tissue which is the main reservoir of T-cells.Th-17 cells, the host defense against bacterial infections, are preferentially lost and this results in increase permeability of the gut membrane, the leaky gut.Microbes and microbial products can translocate and reach the portal and systemic circulation. This is measured by serum LPS. Microbial translocation is a cause of chronic immune activation.HIV +Brenchley JM et al. Nature Medicine 2006.
16Early Immune Senescence in HIV Disease Viral replicationCirculating antigenAntigenAntigenCD4CD4T cellT cellTcellClonalexpansionHIVT cellT cellT cellT cellMicrobialtranslocationLoss of CD28on T cellsShortening oftelomeres?Inability tocontrolmucosaldysregulationActivationLoss ofnaïveT cellsEven with ART, there is residual ongoing replication that continues to activate immune cells. Microbial translocation adds to circulating antigen.This immune activation is central in the HIV aging pathway.InflammationThymic dysfunctionalityCD57+ t cellsNon-AIDS-definingco-morbiditiesEnd-stage senescentT cellsPremature agingDesai S. and Landay A. Curr HIV/AIDS Rep 2010.
17Aging, HIV and the liver: Interactions Aging and the liverDecrease in liver volumeImpaired hepatic blood flowDecreased amount of surface endoplasmic reticulum (SER) , the principal site of drug metabolismIncreased amount of fat, which alters metabolic rateDecline in regenerative response of hepatocytes following liver injuryWe used to think that the liver was not aging because of its regenerative capacity, now we have evidence that it does.The liver SER is the principal site of drug metabolism. Decreased amount of SER coupled with an overall decrease in P450 activity contribute to the decline in phase I drug metabolism seen with aging and partly explains the increased susceptibility to drug-induced liver injury (DILI) in this group.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.
18Aging, HIV and the liver: Interactions Direct effect of HIV in the liver may contributeSeveral liver cell types can be productively infected with HIVReplication of HIV in hepatic stellate cells by detection of p24 ag and HIV mRNAPro-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.
19Hepatic Stellate Cell Activation: A Central Event in Liver Fibrosis Activated HSCwith FibrosisNormal LiverFriedman SL and Arthur, Science and Medicine, 2002
20Several Liver Cell Types Can Be Productively Infected with HIV Stellate cells express CXCR4 and CCR5Activated human hepatic stellate cells support HIV gene expressionHIV promotes stellate cell collagen I expression and secretion of MCP-1HIV envelope protein induces cellular effects on parenchymal and non-parenchymal cells in the liverHIV-1 gp120 (X4) induces fibrogenic gene expression in human stellate cellsHong 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.
21Chronic Elevation of Liver Enzymes in HIV Abnormal liver enzymes are frequently seen in HIV infected patients (15-43%)Risk factorsIncreased BMI, hypertension, ART exposure, severe alcohol use, HIV RNA level, low CD4+ cell count, and ageNo studies have compared the prevalence of liver enzymes elevation in younger vs older HIV-infected patientsPol 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;
22Chronic Elevation of Liver Enzymes in HIV Steatosis/steatohepatitis is an emerging cause of chronic liver enzymes elevations in HIV30 HIV-infected patients on ART with transaminase elevation > 6 months were biopsiedMean age 46y, duration of HIV infection 13 years60% (18/30) had steatosis,53% (16/30) had steatohepatitisAssociated with insulin resistance24 HIV-infected patients were biopsiedMean age 50, duration of HIV infection 17 years, mean duration of ART 12 years37.5% (9/24) had steatohepatitisIngiliz P et al. Hepatology 2009; Morse C. et al. CROI 2009, abstract #748
23Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV 37% (83/225) of HIV patients with NAFLD based on CT-scansMean age 48 years72% maleMean duration of HIV 13 yearsFactors associated with steatosisElevated ALT/ASTMale sexElevated waist circumferenceCumulative NRTI exposureData on prevalence of steatosis and steatohepatitis among HIV-infected patients are limited mostly b/cHIV mono-infected patients don’t usually undergo a liver biopsy. Data from a cross sectional study identified steatosis in 31% of 216 patients based on US examination.In this study, factors associated with steatosis on ultrasound examination included increased waist circumference, elevated TG levels, and lower HDL.This is consistent with prevalence rates of steatosis in the general population of about 17-33% (this is US data), however, the mean age of the general population in these studies is higher than in the studies of HIV-infected patients.Guaraldi G. et al. Clin Infect Dis Crum-Cianflone N et al. J Acquir Immune Defic Syndr 2009.
24Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV 31% (67/216) of HIV-infected patients with NAFLD based on US examinationMean age 40 years94% maleMean duration of HIV 10 years65% on ART165 patients with elevated liver enzymes and/or steatosis suggested at US55 underwent a liver biopsy36% (20/55) had biopsy-proven steatosis and 6 also had steatohepatitisData on prevalence of steatosis and steatohepatitis among HIV-infected patients are limited mostly b/cHIV mono-infected patients don’t usually undergo a liver biopsy. Data from a cross sectional study identified steatosis in 31% of 216 patients based on US examination.In this study, factors associated with steatosis on ultrasound examination included increased waist circumference, elevated TG levels, and lower HDL.This is consistent with prevalence rates of steatosis in the general population of about 17-33% (this is US data), however, the mean age of the general population in these studies is higher than in the studies of HIV-infected patients.Guaraldi G. et al. Clin Infect Dis 2008; Crum-Cianflone N et al. J Acquir Immune Defic Syndr 2009.
25The HIV Aging Liver and Steatosis Insulin ResistanceDiabetes, ObesityDyslipidemiaEtOHDrugsART(mitochondrial toxicity)STEATOSISFibrosis progressionHIV(chronic inflam. state)Co-infection w/Hepatitis C
26Drug-Induced Liver Injury In the post ART era, drug-induced liver injury has become a major problem in the management of HIVMitochondrial toxicity and microvesicular steatosis with NRTIsLiver enzyme elevations with NNRTIs and PIsAging increases susceptibility to drug toxicityAmount of SER + in P450 activityDecline in phase I drug metabolismIncrease pill burden in older HIV patientsIncreased drug interactions and toxicityThe liver SER is the principal site of drug metabolism. Decreased amount of SER coupled with an overall decrease in P450 activity contribute to the decline in phase I drug metabolism seen with aging and partly explains the increased susceptibility to drug-induced liver injury (DILI) in this group.Jain MK. Clin Liver Dis 2007; Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003.
27Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART Case-series of HIV mono-infected patients with cryptogenic liver diseaseSigns and symptoms of portal hypertensionThrombocytopeniaHepatosplenomegalyEsophageal varices (EV) / EV bleedingEncephalopathyLiver enzymes usually normal. INR, bilirubin and albumin normalProlonged exposure to ddI and median duration of HIV > 10 yearsParenchymal liver function is normalMaida I et al. J Acquir Immune Defic Syndr 2006; Mallet V. et al. AIDS 2007; Schiano T. et al. Am JGastroenterol 2007; Stebbing J. et al. J Acquir Immnue Defic Syndr 2009.
28Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART NRHLIVER BIOPSYNodular Regenerative Hyperplasia (NRH) orHepatoPortal Sclerosis (HPS)Non cirrhotic portal hypertensionNRH and HPS may be part of a spectrum reflecting chronological progression of a single diseaseHPS
29Non 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 hypertensionNon cirrhotic portal hypertension is the topic of the next presentation by Dr Vincent Soriano so I will leave it to him to explain the details about this relatively new clinical entity.
30HCV Co-Infected Patients Are Aging 1st cause of non-AIDS-related-deaths: LIVERRisk 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 olderRecent multiple cohort model of HCV prevalence and disease progression (in the US) estimated the burden of HCV and cirrhosis for the next decadesWeber R et al. Arch Intern Med 2006; Davis GL et al. Gastroenterology 2010; Balagopal A et al.Gastroenterology 2008.
31HCV-Related Cirrhosis Is Projected to Peak Over the Next 10 Years 1,200,00025%of patients with HCV currently have cirrhosis1,000,000800,000Patients, N600,000Key PointThe proportion of patients currently infected with HCV that progress to cirrhosis is expected to increase from 25% in 2010 to 37% by 2020.NotesDavis and colleagues developed a multi-cohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy.In 1989, cirrhosis among patients with chronic HCV represented only 5% of all cases, both diagnosed and undiagnosed.A sharp rise was seen in 1990 that corresponded to advancing patient age and a lengthening of their duration of infection.In 1998 cirrhosis was associated with 10% of all chronic HCV cases and that proportion had doubled to 20% by 2006.Current projections indicate that cirrhosis will affect approximately 37% of chronic HCV patients by 2020, peaking at 1 million cases.ReferenceDavis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:37%of patients with HCV projected to develop cirrhosis by 2020, peaking at 1 million400,000200,00019902000201020202030YearAdapted from Davis GL, et al. Gastroenterology 2010.
32HCV-Related Cirrhosis Complications are Expected to Peak Over the Next 10 Years Projected Number of Cases of HCC and Decompensated Cirrhosis due to HCV160,000140,000120,000Decompensated cirrhosis100,000Cases (n)80,000Key PointThe rates of decompensated cirrhosis and HCC associated with chronic HCV infection are estimated to peak in , which will greatly impact individual and public health.NotesAccording to the model by Davis et al, the US prevalence of decompensated cirrhosis associated with chronic HCV infection began to increase after 1995 and is currently estimated to represent 11.7% of cases of cirrhosis. The number of cases also will continue to increase throughSimilarly, the model showed the prevalence of HCC began to increase after 1990: 37,697 cases of HCC occurred during the decade of , increasing to 86,765 cases during and 130,366 cases during Should the risk of HCC in individuals with HCV infection and fibrosis remain unchanged, the incidence of chronic HCV infection–associated HCC is projected to peak in 2019 at about 14,000 cases per year.ReferenceDavis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:60,00040,000Hepatocellular cancer20,000195019601970198019902000201020202030YearDavis GL, et al. Gastroenterology 2010.
33Baseline Fibrosis Stage According to Age in HCV/HIV Co-Infection 70F0-F2F3-F462605046444036Patients (%)3230Baseline Fibrosis Stage According to Age in HCV/HIV CoinfectionThese data are from a retrospective analysis of baseline biopsies from HIV-infected patients who were not receiving any HCV therapy during the analyzed trials.More rapid liver disease progression is seen in this population, leading to cirrhosis and end-stage liver disease complications (including hepatocellular carcinoma) at younger ages, and justifying HCV therapy as a priority in HCV/HIV coinfected patients.ReferenceSoriano V. Treatment of chronic hepatitis C in HIV-positive individuals: selection of candidates. J Hep. 2006;44:S44-S48.20151031-40<30≥41Age (yrs)Soriano V. J Hep
34Liver fibrosis is Accelerated in HIV/HCV Co-Infected Patients And age at HCV infection is one of the risk factors associated with rapid progressionWhy?Decreased immunityHIV replication in stellate cellsART toxicity?Steatosis/steatohepatitisLiver disease progression may be associated with microbial translocationBalagopal A. et al. Gastroenterology 2008.
35HIV-related Microbial Translocation and Progression of Hepatitis C HIV-related CD4+ T-cell depletion is associated with microbial translocationMarkers of microbial translocation (LPS, sCD14) are strongly associated with HCV-related liver disease progressionLevels of LPS are elevated prior to recognition of cirrhosisBalagopal A et al. Gastroenterology 2008; Brenchley JM et al. Nature Medicine 2006.
36HIV-related Gut CD4+ T cell Depletion and Microbial Translocation Contributes to HCV Progression Balagopal A et al. Gastroenterology 2008
37Role of Microbial translocation in liver fibrosis? Following HIV infection: gut permeabilityLPS level in portal/systemic circulationKupffer cells are a target of LPSHepatic stellate cells activation (TLR4 dependent)Liver fibrogenesisBacterial translocationIn the study referenced here, mice that were treated with antibiotics had a decrease in plasma LPS and significant reduction in hepatic fibrosis.Seki E. et al. Nature Medicine. 2007;13(11):Paik et al. Hepatology Seki E. et al. Nature Medicine. 2007;13(11):
38ConclusionsLiver is a major target of the aging process that occurs in HIV-infected patientsThe causes are multipleChronic immune activationAccelerated senescenceHIV effect on stellate cells leading to liver fibrosisMicrobial Translocation leading to progressive liver diseaseas a result of loss of GALT early in HIV infectionWorsening of chronic hepatitisFatty liver disease related to insulin resistance and ARTRecognize the clinical importance of the aging liver and tailor treatment accordingly