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
Aging 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.

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 years old
In 2005, persons 50 years and older accounted for 35% of all deaths of persons living with AIDS
To start, some interesting numbers about the aging HIV population
This is in part due to the increased survival in the post ART era.
CDC 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 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
We now recognize that HIV is associated with
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
We see an increasing number
Even in the HAART era
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
We see an increasing number
Even in the HAART era
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 CROI 2011.
Poster # 789. Available at:

8. Change 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:

9. Age 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 into
Age < 50 years n=66 (40%)
Age ≥ 50 years n=97 (60%)
Braü et al. AASLD, Boston 2010, Poster # 1795

10. of HIV-Infected Patients with HCC
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 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.

16. Early Immune Senescence in HIV Disease
Viral replication
Circulating antigen
Antigen
Antigen
CD4
CD4
T cell
T cell
Tcell
Clonal
expansion
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
Even 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.
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
We 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.

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
Data on prevalence of steatosis and steatohepatitis among HIV-infected patients are limited mostly b/c
HIV 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.

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
Data on prevalence of steatosis and steatohepatitis among HIV-infected patients are limited mostly b/c
HIV 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.

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
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.
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
Parenchymal liver function is normal
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
NRH and HPS may be part of a spectrum reflecting chronological progression of a single disease
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
Non 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.

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
Patients, N
600,000
Key Point
The proportion of patients currently infected with HCV that progress to cirrhosis is expected to increase from 25% in 2010 to 37% by 2020.
Notes
Davis 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.
Reference
Davis 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 million
400,000
200,000
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 and Decompensated Cirrhosis due to HCV
160,000
140,000
120,000
Decompensated cirrhosis
100,000
Cases (n)
80,000
Key Point
The rates of decompensated cirrhosis and HCC associated with chronic HCV infection are estimated to peak in , which will greatly impact individual and public health.
Notes
According 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 through
Similarly, 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.
Reference
Davis 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:
60,000
40,000
Hepatocellular cancer
20,000
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-Infection70
F0-F2
F3-F4 62 60 50 46 44 40 36
Patients (%) 32 30
Baseline Fibrosis Stage According to Age in HCV/HIV Coinfection
These 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.
Reference
Soriano V. Treatment of chronic hepatitis C in HIV-positive individuals: selection of candidates. J Hep. 2006;44:S44-S48. 20 15 10
31-40
<30
≥41
Age (yrs)
Soriano V. J Hep

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
In 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):

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