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
• 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
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
HIV Results in Accelerated
Age-related Conditions
• Development of frailty, muscle wasting
Insulin resistance, diabetes and
cardiovascular disease
o Chronic kidney disease
o Bone disease
o Cognitive impairment and dementia
o Non AIDS-defining malignancies
o
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 liver
o
o
o
o
o
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
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 AIDSrelated 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
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 death
o
#1 Non-AIDS defining cancers (n=85, 19.1%)
including HCC (n=13, 2.8%)
o
o
#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 nonAIDS 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)
Diagnosed by AASLD criteria (Bruix & Sherman,
Hepatology, 2005)
o Patients were divided into
o
 Age < 50 years n=66 (40%)
 Age ≥ 50 years n=97 (60%)
Braü et al. AASLD, Boston 2010, Poster # 1795
Age and Survival
of HIV-Infected Patients with HCC
Braü et al. AASLD, Boston 2010, Poster # 1795.
Age and HCC
in HIV-Infected Patients
• Compared to younger HIV-infected
patients with HCC, patients ≥ 50 years
1. are more frequently black
2. tend to have chronic hepatitis C
3. tend to present more frequently with multiple rather
than solitary tumors
4. tend to receive effective HCC therapy less often
5. 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 to
o 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 2010
Balagopal 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;
Microbial Translocation in HIV
HIV -
HIV +
Brenchley JM et al. Nature Medicine 2006.
Early Immune Senescence
in HIV Disease
Viral replication
CD4 CD4
Circulating
antigen
Antigen
Antigen
T cell
T cell
HIV
T cell
Clonal
T cell expansio
n
T cell T cell
Microbial
translocation
?
Inability to
control
mucosal
dysregulation
Tcell
Loss of CD28
on T cells
Shortening of
telomeres
Activation
Loss of
naïve
T cells
Inflammation
Thymic dysfunctionality
CD57+ t cells
Non-AIDS-defining
co-morbidities
Premature aging
Desai S. and Landay A. Curr HIV/AIDS Rep
2010.
End-stage senescent
T cells
Aging, HIV and the liver:
Interactions
• Aging and the liver
o
o
o
o
o
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.
Aging, HIV and the liver:
Interactions
• Direct effect of HIV in the liver may
contribute
o
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)
chmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003; Housset et al. Res Virol 1990;
anerjee 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 Liver
Friedman SL and Arthur, Science and Medicine, 2002
Activated HSC
with Fibrosis
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 factors
o 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 HIV
o
30 HIV-infected patients on ART with transaminase
elevation > 6 months were biopsied




o
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
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
o Elevated ALT/AST
o Male sex
o Elevated waist circumference
o Cumulative NRTI exposure
o
o
o
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 examination
o
o
o
o
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
o
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
Insulin Resistance
Diabetes, Obesity
Dyslipidemia
EtOH
Drugs
ART
(mitochondrial
toxicity)
STEATOSIS
Fibrosis progression
HIV
(chronic inflam.
state)
Co-infection w/
Hepatitis C
Drug-Induced Liver Injury
• In the post ART era, drug-induced liver injury has
become a major problem in the management of HIV
o Mitochondrial toxicity and microvesicular
steatosis with NRTIs
o Liver enzyme elevations with NNRTIs and PIs
• Aging increases susceptibility to drug toxicity
o Amount of SER + in P450 activity
o 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 disease
o 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 BIOPSY
o 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, noncirrhotic portal hypertension
HCV Co-Infected Patients Are Aging
• 1st cause of non-AIDS-related-deaths: LIVER
o 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
o 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
1,200,000
25%
1,000,000
of patients with HCV
currently have cirrhosis
800,000
600,000
Patients, N
37%
of patients with HCV projected
to develop cirrhosis by 2020,
peaking at 1 million
400,000
200,000
0
1990
2000
Adapted from Davis GL, et al. Gastroenterology 2010.
2010
Year
2020
2030
HCV-Related Cirrhosis Complications are
Expected to Peak Over the Next 10 Years
Projected Number of Cases of HCC and
Decompensated 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
Davis GL, et al. Gastroenterology 2010.
1980
1990
Year
2000
2010
2020
2030
Baseline Fibrosis Stage According to
Age in HCV/HIV Co-Infection
F0-F2
70
60
62
F3-F4
50
46
44
40
Patients (%)
30
36
32
20
15
10
0
<30
31-40
Age (yrs)
Soriano V. J Hep. 2006.
≥41
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 immunity
o HIV replication in stellate cells
o ART toxicity?
o Steatosis/steatohepatitis
o 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 HCVrelated liver disease progression
o 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
Bacterial translocation
LPS level in portal/systemic circulation
Kupffer cells are a target of LPS
Hepatic stellate cells activation (TLR4 dependent)
Liver fibrogenesis
Paik et
Seki
E. al.
et al.
Hepatology
Nature Medicine.
2003. Seki
2007;13(11):1324E. et al. Nature Medicine. 2007;13(11):132432.
Conclusions
• Liver is a major target of the aging process that occurs in HIVinfected patients
• The causes are multiple
o Chronic immune activation
o Accelerated senescence
o HIV effect on stellate cells leading to liver fibrosis
o Microbial Translocation leading to progressive liver disease
 as a result of loss of GALT early in HIV infection
o Worsening of chronic hepatitis
o Fatty liver disease related to insulin resistance and ART
• Recognize the clinical importance of the aging liver and tailor
treatment accordingly