The Aging Liver in the Aging HIV Patient

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 (n85, 19.1)
  including HCC (n13, 2.8)
• 2 AIDS (n73, 16.4)
• 3 Liver Diseases (n67, 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 lt 50 years n66 (40)
• Age 50 years n97 (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 CD4T 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 gt 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 gt 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. Gastroenterology
2010.
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. Gastroenterology 2010.
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
lt30
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?

• 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

Bacterial translocation
Seki E. et al. Nature Medicine.
200713(11)1324-32.
Paik et al. Hepatology 2003. Seki E. et al.
Nature Medicine. 200713(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