HIV, AGING and the LIVER - Virology...

Presented at the 6th International Workshop on HIV & Hepatitis Co-infection,

31 May – 2 June 2010, Tel Aviv, Israel

HIV, AGING and the LIVER

MarieMarie--Louise C. Louise C. VachonVachon, M.D., , M.D., M.ScM.Sc..Infectious Diseases / Liver DiseasesInfectious Diseases / Liver Diseases

Mount Sinai School of MedicineMount Sinai School of Medicine

Presenter

Presentation Notes

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.



The HIV-Infected Population is Aging

Increasing number of persons 50 years and older among new HIV infections1

44% in1995 vs

6% in 2000 vs

15% in 2005

Increasing number of persons 50 years and older living with HIV/AIDS in the US4From 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.

1. CDC 2007. HIV/AIDS surveillance report, 2005.

Presenter

Presentation Notes

To start, some interesting numbers about the aging HIV population This is in part due to the increased survival in the post ART era.



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

0

20000

40000

60000

80000

100000

120000

140000

2001 2003 2006

> 50 yo> 65 yo

17.1%

19.7%

25.4%

50%

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

It is expected that

by 2015, 50% of

the HIV population

will be 50 and older



Complex Interactions between HIV and Aging Result in Accelerated Age-related Conditions

4Development of frailty, muscle wasting4 Insulin resistance, diabetes and cardiovascular disease4Chronic kidney disease4Bone disease4Cognitive impairment and dementia4HIV-related and unrelated malignancies

4Liver 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 liver4Chronic elevations of liver enzymes4Steatosis/steatohepatitis4 Increased drug-related toxicity4More severe liver disease in aging patients with hepatitis

B and C

Mortality associated with liver disease is high among HIV-infected patients1

42nd

cause of death

in HIV-infected patients after AIDS-

related complications44-fold increase

in morbidity and mortality due to liver

diseases among older patients1. Weber R. et al. arch Intern Med 2006.

Presenter

Presentation Notes

We see an increasing number Even in the HAART era



Clinical case: Michelle

48 yo, AA woman

Referred in 2002 for suspicion of cirrhosis4HIV diagnosed in 1989 (nadir CD4+

T-cell: 220)

4No HBV/HCV co-infection4On didanosine + stavudine /PI, HIV RNA

undetectable4BMI 20, severe lipoatrophy4Thrombocytopenia (plt=80) and CT-SCAN of the

abdomen showed signs of portal hypertension

Presenter

Presentation Notes

This is one of our patients who was referred to us in 2002



Complex interactions between aging, HIV, the immune system and the liver: role of

microbial translocation



Aging, HIV and the Immune System: Interactions

Early immune senescence in HIV disease1

4Aging and HIV seem to share common mechanisms by which they alter cellular immunity

4 Immune activation and inflammation are characteristic of both aging and HIV infection

4 In HIV infection, microbial translocation might contribute to premature aging by promoting immune activation –

And may have direct effects on the liver2

1. Desai S and Landay A. Curr HIV/AIDS Rep 2010; 2. Balagopal A. et al. Gastroenterology 2008.



Microbial Translocation in HIV

HIV +

Brenchley

JM et al. Nature Medicine 2006;12(12): 1365-71.

HIV -

Presenter

Presentation Notes

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.



Early Immune Senescence in HIV Disease

CD4 CD4

T cell

T cell

T cell

T cell

T cell

T cell

T cell

Viral replication Circulating antigen

Clonal

expansion

Antigen Antigen

Microbialtranslocation

?Inability to

controlmucosal

dysregulation

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

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

Presenter

Presentation Notes

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.



Aging, HIV and the liver: interactions

Aging and the liver1,2

4

Decrease in liver volume

4

Impaired hepatic blood flow

4

Decreased amount of surface endoplasmic reticulum (SER)

4

Decline in regenerative response of hepatocytes

following liver injury

HIV and the liver3,4,5,6

4

Several liver cell types can be productively infected with HIV

4

Replication of HIV in hepatic stellate

cells by detection of

p24 ag

and HIV mRNA–

Pro-fibrogenic

(collagen I)

–

Pro-inflammatory (MCP-1)

1. Schmucker DL. Exp Gerontol. 2005; 2. Maclean AJ et al. J Pathol 2003; 3. Housset et al. Res Virol 1990; 4. Banerjee et al. AIDS 1992; 5. Blackard JT et al. J viral hepat. 2008; 6. Hong F et al. Hepatology 2010.

Presenter

Presentation Notes

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.



Clinical Manifestations of Aging Liver in HIV



Chronic Elevation of Liver Enzymes in HIV

Abnormal liver enzymes are frequently seen in HIV infected patients (15-43%)1,2,3,4

Risk factors4 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

1. Pol S et al. Clin Infect Dis 2004; 2. Maida I et al. J Acquir Immune Defic Syndr 2006; 3. Sterling RK et al. Dig Dis Sci 2008; 4. 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 HIV1,2

430 HIV-infected patients on ART with transaminase elevation (> 6 months) were biopsied1

–

Mean age 46, duration of HIV infection 13 years–

18/30 had steatosis, 16/30 had steatohepatitis

–

Associated with insulin resistance424 HIV-infected patients were biopsied2

–

Mean age 50, duration of HIV infection 17 years, mean duration of ART 12 years

–

9/24 had steatohepatitis

(37.5%)

1. Ingiliz P et al. Hepatology 2009; 2. Morse C. et al. CROI 2009, abstract #748



Steatosis and Steatohepatitis

67/216 (31%) of HIV-infected patients with NAFLD based on US examination2

4

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 US4

55 underwent a liver biopsy–

20 of them (36%) had biopsy-proven steatosis

and 6 also had steatohepatitis

83/225 (37%) of HIV patients with NAFLD based on CT-

scans1

4

Mean age 48 years, 72% male, mean duration of HIV 13 years

Factors associated with steatosis4

Elevated ALT/AST, male sex, elevated waist circumference, and cumulative NRTI exposure

1. Guaraldi G. et al. Clin Infect Dis 2008. 2. Crum-Cianflone N et al. J Acquir Immune Defic Syndr 2009.

Presenter

Presentation Notes

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.



The HIV aging liver: Steatosis

STEATOSIS

HIV

(chronic inflam. state)

ART

(mitochondrial toxicity)

Fibrosis progression

Insulin Resistance,

Diabetes, Obesity,

Dyslipidemia EtOH

Drugs

Co-infection w/

Hepatitis C and B



Drug-induced Toxicity

In the post ART era, drug-induced toxicity has become a major problem in the management of HIV1

4Mitochondrial toxicity and microvesicular

steatosis with NRTIs

4Liver enzyme elevations with NNRTIs

and PIs

Aging increases susceptibility to drug toxicity2,3

4 amount of SER + in P450 activity–

Decline in phase I drug metabolism

Increase pill burden in older HIV patients 4 Increased drug interactions and toxicity

1. Jain MK. Clin Liver Dis 2007; 2. Schmucker DL. Exp Gerontol. 2005; 3. Maclean AJ et al. J Pathol 2003

Presenter

Presentation Notes

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.



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

Case-series of HIV mono-infected patients with cryptogenic liver disease1,2,3,4

4Signs and symptoms of portal hypertension–

Thrombocytopenia

–

Hepatosplenomegaly–

Esophageal

varices (EV) / EV bleeding

–

Encephalopathy4Liver enzymes usually normal. INR, bilirubin

and

albumin normal4Prolonged exposure to ddI

and median duration of

HIV > 10 years1. Maida I et al. J Acquir Immune Defic Syndr 2006; 2. Mallet V. et al. AIDS 2007; 3. Schiano T. et al. Am J Gastroenterol 2007; 4. Stebbing J. et al. J Acquir Immnue Defic Syndr 2009.

Presenter

Presentation Notes

Parenchymal liver function is normal




LIVER BIOPSY4

Nodular Regenerative Hyperplasia (NRH) or

4

HepatoPortal

Sclerosis

(HPS),–

Non cirrhotic portal hypertension

NRH

HPS

Presenter

Presentation Notes

NRH and HPS may be part of a spectrum reflecting chronological progression of a single disease




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

Presenter

Presentation Notes

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.



HCV Co-Infected Patients Are Aging

1st

cause of non-AIDS-related-deaths: LIVER1

4Risk 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 older2

4A recent multiple cohort model of HCV prevalence and disease progression (in the US) estimated the burden of HCV and cirrhosis for the next decades

1. Weber R et al. Arch Intern Med 2006; 2. Davis GL et al. Gastroenterology 2010; 3. Balagopal A et al. Gastroenterology 2008



The total number of patients with cirrhosis is expected

to peak in 2020, but the proportion of patients with

cirrhosis will climb up to 45% in 2030*

The total number of cases of hepatic decompensation

and HCC is also expected to peak in 2020*

Davis GL et al. Gastroenterology 2010. Figure 2 and Figure 4.* Not including treatment effect in model

Presenter

Presentation Notes

When treatment effect of new HCV treatment is included in the model (assuming 80% chance of response and ½ of the patients treated), the model estimated that cirrhosis would be reduced by 15% after 10 years, or 30% if all would receive treatment. This is for HCV mono-infected patients, such a model was not done in coinfected.



Baseline Fibrosis Stage According to Age in Baseline Fibrosis Stage According to Age in HCV/HIV HCV/HIV CoinfectionCoinfection

SorianoSoriano

V. V. J J HepatologyHepatology 2006.2006.

3131--4040<30<30 ≥≥4141Age (yrs)Age (yrs)

Pat

ient

s (%

)P

atie

nts

(%)

F0F0--F2F2F3F3--F4F46262

4444

3232

1515

36364646

001010202030304040505060607070

Presenter

Presentation Notes

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.�



Liver fibrosis is accelerated in HIV/HCV coinfected patients

Why?4Decreased immunity4HIV replication in stellate

cells

4ART toxicity?4Steatosis/steatohepatitis4Liver disease progression may be associated

with microbial translocation1

1. Balagopal A. et al. Gastroenterology 2008.



HIV-related Microbial Translocation and Progression of Hepatitis C1

HIV-related CD4+ T-cell depletion associated with microbial translocation2

Markers of microbial translocation were strongly associated with HCV-related liver disease progression4Levels of LPS were elevated prior to recognition of

cirrhosis

1. Balagopal A et al. Gastroenterology 2008; 2. Brenchley JM et al. Nature Medicine 2006;12(12): 1365- 71



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

Balagopal A et al. Gastroenterology 2008



Hepatic Hepatic StellateStellate

Cell Activation: Cell Activation: A Central Event in Liver FibrosisA Central Event in Liver Fibrosis

Normal LiverNormal LiverActivated HSC Activated HSC with Fibrosiswith Fibrosis

Friedman SL and Arthur, Science and Medicine, 2002



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

Presenter

Presentation Notes

In the study referenced here, mice that were treated with antibiotics had a decrease in plasma LPS and significant reduction in hepatic fibrosis.



Clinical case: Michelle

• No significant fibrosis, no cirrhosis. No significant steatosis.

Liver biopsy 2002: Hepatoportal sclerosis (HPS)

Presenter

Presentation Notes

Consistent with hepatoportal sclerosis



Dx: Non cirrhotic portal hypertension

Upper endoscopy: grade 3 varices: banded.

Trace ascites. No encephalopathy.

ART modified: tenofovir

DF + lamivudine

+ efavirenz

2 years later, ALT increases to 3X ULN

She had gained about 20 pounds in 1 year

Liver biopsy 2004



Liver biopsy 2004: Steatosis

Only 2 portal tracts, portal vein branches not assessed



Since 2002

Still on TDF + lamivudine

+ efavirenz

Lost weight and ALT in the 30s

Bi-annual upper EGD: varices grade 1-2 in 02/2010, no bleeding, no further banding necessary



Conclusion

The liver is a major target of the aging process that occurs in HIV-infected patients

The causes are multiple:4Chronic immune activation4Accelerated senescence 4HIV effect on stellate

cells and liver fibrosis

4Microbial Translocation leading to progressive liver disease

4Worsening of chronic hepatitis

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



1st International Workshop on HIV & Aging 4-5 October 2010, Baltimore, MD, USA4Abstract submission deadline August 7, 2010


31 May – 2 June 2010, Tel Aviv, Israel P-35

Take care of your patients livers and they will all be Take care of your patients livers and they will all be smiling!smiling!

HIV, AGING and the LIVER - Virology...

Documents

Transcript of HIV, AGING and the LIVER - Virology...