The 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 Medicine New York, New York

The HIV-Infected Population is Aging

• Persons 50 years and older increasing• Among new HIV infections

o 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.

Persons Living with HIV/AIDS in USA (33 states) CDC Surveillance Program

17.1%

19.7%

25.4%

50%

CDC 2007. HIV/AIDS surveillance report 2005Fauci AS. National HIV/AIDS and Aging Awareness Day

By 2015, 50% of the HIV populationwill be 50 and older

HIV Results in Accelerated Age-related Conditions

• Development of frailty, muscle wastingo Insulin resistance, diabetes and

cardiovascular diseaseo Chronic kidney diseaseo Bone diseaseo Cognitive impairment and dementiao Non AIDS-defining malignancies

o Liver disease and HCC

Effros RB et al. Clin Infect Dis 2008

Consequences of HIV, Aging and the Liver

• Clinical manifestations of aging HIV and the livero Chronic elevations of liver enzymeso Steatosis/steatohepatitiso Increased drug-related toxicityo More severe liver disease in aging patients with

hepatitis B and Co Later stage and less treatable HCC

1. Weber R. et al. arch Intern Med 2006.

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

1. Weber R. et al. arch Intern Med 2006.

Weber R. et al. arch Intern Med 2006.

Change in Causes of Death in Patients with HIV Reflects Aging

• Swiss HIV Cohort Study (SHCS)o 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.

Change in Causes of Death in Patients with HIV Reflects Aging

• Causes of deatho #1 Non-AIDS defining cancers (n=85, 19.1%)

including HCC (n=13, 2.8%)o #2 AIDS (n=73, 16.4%)o #3 Liver Diseases (n=67, 15%)

• When deaths due to HCC were included among liver-related deaths (instead of non-AIDS defining cancers)

o 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

Age and HCC in HIV-Infected Patients

• All HCC cases in HIV-infected patients from 1995-2010 with data on initial presentation (n = 163) o Diagnosed by AASLD criteria (Bruix & Sherman,

Hepatology, 2005)o Patients were divided into

Age < 50 years n=66 (40%) Age ≥ 50 years n=97 (60%)

Braü et al. AASLD, Boston 2010, Poster # 1795

Braü et al. AASLD, Boston 2010, Poster # 1795.

Age and Survival of HIV-Infected Patients with HCC

Age and HCC in HIV-Infected Patients

• Compared to younger HIV-infected patients with HCC, patients ≥ 50 years1.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.

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 o 2.7 per 100,000 persons in 2001 too 3.2 in 2006, with an APC of 3.5% (annual

percent increase, translates to 10% increase over 3 yr

Reference

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 o And may have direct effects on the liver

Desai S and Landay A. Curr HIV/AIDS Rep 2010Balagopal A. et al. Gastroenterology 2008

HIV and Microbial Translocation

• Primary target of HIV is CD4+T cell compartment • Majority of CD4+ T cells are mucosal

o 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 o 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

Microbial Translocation in HIV

HIV +

Brenchley JM et al. Nature Medicine 2006.

HIV -

Early Immune Senescence in HIV Disease

CD4 CD4

T cell

T cell

T cell

Tcell

T cell

T cell

T cell

Viral replication Circulating antigen

Clonal expansion

Antigen Antigen

Microbialtranslocation

?Inability tocontrolmucosaldysregulation

Loss of naïveT cells

HIV

Thymic dysfunctionality

Activation

Inflammation

Non-AIDS-definingco-morbidities

Premature aging

CD57+ t cells

Loss of CD28on T cellsShortening of telomeres

End-stage senescent T cells

Desai S. and Landay A. Curr HIV/AIDS Rep 2010.

Aging, HIV and the liver: Interactions

• Aging and the livero Decrease in liver volumeo Impaired hepatic blood flowo Decreased amount of surface endoplasmic

reticulum (SER) , the principal site of drug metabolism

o Increased amount of fat, which alters metabolic rateo 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.

Aging, HIV and the liver: Interactions

• Direct effect of HIV in the liver may contributeo Several liver cell types can be productively

infected with HIV

o 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.

Hepatic Stellate Cell Activation: A Central Event in Liver Fibrosis

Normal LiverActivated HSC with Fibrosis

Friedman SL and Arthur, Science and Medicine, 2002

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.

Chronic Elevation of Liver Enzymes in HIV

• Abnormal liver enzymes are frequently seen in HIV infected patients (15-43%)

• Risk factorso 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;

Chronic Elevation of Liver Enzymes in HIV

• Steatosis/steatohepatitis is an emerging cause of chronic liver enzymes elevations in HIVo 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

o 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

Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV

• 37% (83/225) of HIV patients with NAFLD based on CT-scanso Mean age 48 yearso 72% maleo Mean duration of HIV 13 years

• Factors associated with steatosiso Elevated ALT/ASTo Male sex o Elevated waist circumferenceo Cumulative NRTI exposure

Guaraldi G. et al. Clin Infect Dis 2008. Crum-Cianflone N et al. J Acquir Immune Defic Syndr 2009.

Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV

• 31% (67/216) of HIV-infected patients with NAFLD based on US examinationo Mean age 40 years o 94% male o Mean duration of HIV 10 years o 65% on ART

• 165 patients with elevated liver enzymes and/or steatosis suggested at USo 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.

The HIV Aging Liver and Steatosis

HIV(chronic inflam.

state)

ART(mitochondrial

toxicity)

Fibrosis progression

Insulin ResistanceDiabetes, ObesityDyslipidemia

EtOHDrugs

Co-infection w/Hepatitis C

STEATOSIS

Drug-Induced Liver Injury

• In the post ART era, drug-induced liver injury has become a major problem in the management of HIVo Mitochondrial toxicity and microvesicular

steatosis with NRTIso Liver enzyme elevations with NNRTIs and PIs

• Aging increases susceptibility to drug toxicityo Amount of SER + in P450 activityo Decline in phase I drug metabolism

• Increase pill burden in older HIV patients o Increased drug interactions and toxicity

Jain MK. Clin Liver Dis 2007; Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003.

Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART

• Case-series of HIV mono-infected patients with cryptogenic liver diseaseo Signs and symptoms of portal hypertension

Thrombocytopenia Hepatosplenomegaly Esophageal varices (EV) / EV bleeding Encephalopathy

o 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.

Non Cirrhotic Portal Hypertension: Long-Term Liver Complication of ART

• LIVER BIOPSYo Nodular Regenerative

Hyperplasia (NRH) or o HepatoPortal Sclerosis

(HPS) Non cirrhotic portal

hypertension

NRH

HPS

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

HCV Co-Infected Patients Are Aging

• 1st cause of non-AIDS-related-deaths: LIVERo 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 oldero 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.

HCV-Related Cirrhosis Is Projected to Peak Over the Next 10 Years

Patients, N

1,200,000

1,000,000

800,000

600,000

400,000

0

200,000

1990 2000 2010 2020 2030

Year

25%of patients with HCV

currently have cirrhosis

37%of patients with HCV projected to develop cirrhosis by 2020,

peaking at 1 million

Adapted from Davis GL, et al. Gastroenterology 2010.

HCV-Related Cirrhosis Complications are Expected to Peak Over the Next 10 Years

Davis GL, et al. Gastroenterology 2010.

Projected Number of Cases of HCC andDecompensated Cirrhosis due to HCV

1950 1960 1970 1980 1990 2000 2010 2020 2030

Year

Cases (n)

160,000

0

140,000

120,000

100,000

80,000

60,000

40,000

20,000

Decompensated cirrhosis

Hepatocellular cancer

Baseline Fibrosis Stage According to Age in HCV/HIV Co-Infection

Soriano V. J Hep. 2006.

31-40<30 ≥41Age (yrs)

Patients (%)

F0-F2

F3-F462

44

32

15

36

46

0

10

20

30

40

50

60

70

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?o Decreased immunityo HIV replication in stellate cellso ART toxicity?o Steatosis/steatohepatitiso Liver disease progression may be

associated with microbial translocation

Balagopal A. et al. Gastroenterology 2008.

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 progressiono Levels of LPS are elevated prior to

recognition of cirrhosis

Balagopal A et al. Gastroenterology 2008; Brenchley JM et al. Nature Medicine 2006.

HIV-related Gut CD4+ T cell Depletion and Microbial Translocation Contributes to

HCV Progression

Balagopal A et al. Gastroenterology 2008

Role of Microbial translocation in liver fibrosis?

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.

Bacterial translocation

Paik et al. Hepatology 2003. Seki E. et al. Nature Medicine. 2007;13(11):1324-32.

Conclusions

• Liver is a major target of the aging process that occurs in HIV-infected patients

• The causes are multipleo Chronic immune activationo Accelerated senescence o HIV effect on stellate cells leading to liver fibrosiso Microbial Translocation leading to progressive liver disease

as a result of loss of GALT early in HIV infection o Worsening of chronic hepatitiso Fatty liver disease related to insulin resistance and ART

• Recognize the clinical importance of the aging liver and tailor treatment accordingly