The Long and Winding Road of HIV Complications: Aging with HIV Luis A. Espinoza, MD Associate Professor of Clinical Medicine University of Miami Miller.

The Long and Winding Road of HIV

Complications: Aging with HIV

Luis A. Espinoza, MDAssociate Professor of Clinical Medicine

University of Miami Miller School of Medicine

Faculty, Florida/Caribbean AETC

Disclosure of Financial Relationships

This speaker has the following financial relationships with commercial entities to

disclose:• Consultant: Gilead, Tibotec, ViiV – Terminated

• Speaker’s Bureau: Abbott, Boehringer, Gilead, Tibotec – Terminated

This speaker will not discuss any off-label use or investigational product during the program.

This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

HIV and Aging

Objectives• Discuss the evolving complications being

seen in the aging HIV population• Improve patient education in reduction of

risk factors in disease seen in the aging population

• Implement appropriate recommendations in screening and monitoring in the aging HIV population

As estimated by the CDC: The percentage of HIV infected individuals older than 50 years, in the year 2015 will be:

A. 20%

B. 25%

C. 30%

D. 40%

E. > 50%

A. B. C. D. E.

0%

13%

45%

32%

10%

Prevalence of HIV Infection in US

From: www.cdc.gov/hiv/topics/over50

Estimated Percentage of New Cases of HIV/AIDS by Age, 2005

From: www.cdc.gov/hiv/topics/over50

Aging and Comorbidities

• Common disorders in older adults– Cardiovascular disease– Hypertension– Metabolic disorders, obesity– Neurocognitive decline– Hepatic and/or renal impairment– Bone fractures/Osteopenia/osteoporosis– Malignancies

Biology of Aging in Humans

Vijg and Campisi, Nature 2008

Telomeres and

TelomeraseAppendix C: Human

Embryonic Stem Cells and Human Embryonic Germ

Cells . In Stem Cell Information. Bethesda,

MD: NIH US DHHS, 2010

Telomeres and Telomerase

Human Telomeric and Subtelomeric Regions

http://AtlasGeneticsOncology.org/Deep/SubTelomereID20025.html June 2009

Telomeres, senescence and organismal aging

http://AtlasGeneticsOncology.org/Deep/SubTelomereID20025.html June 2009

Haematopoietic stem cells experience functional decline with aging

Sahin and DePinho, Nature 2010

Aging of the Immune System “Immunosenescence”

T cell characteristics that predict morbidity/mortality in the very old:

• Reduced regenerative capacity (stem cells, thymus)• Low naïve/memory T cell ratios• Low CD4/CD8 ratio• Increased T cell activation• Increased inflammatory markers (IL-6, CRP)• Clonal expression of CD28-CD57+ T cells• Expanded CMV specific T cell responses• Reduced T cell proliferation

Weng N. Immunity, 2006;24:495-499

Cao W. JAIDS 2009; 50:137-147

Linton PJ. Nat Immunol. 2004; 2:133-139

Barrier to HIV Diagnosis in Older Adult

• Physicians are less likely to discuss HIV related risk factors with older adults

• HIV-associated symptoms and other illnesses

• Late presentation for diagnosis and care• CDC recommendations

Patel D. Curr Inf Dis Rep 2011 Gebo KA. Drugs Aging 2006

Lindau ST. NEJM 2007 MMWR Recomm Rep 2006

Risk for Older HIV-Uninfected Adults

• National Survey of Sexual Health and Behavior (2008)

Among all persons aged 50 years or older, condoms were not used during most recent intercourse with:

91.5% of casual partners

76.0% of friends

69.6% of new acquaintances

33.3% of transactional sexual partners

Schick V et al. J Sex Med. 2010;7(Suppl 5):315-329

Issues Specific toOlder Persons With HIV Disease

• Unprotected sex– No concern about pregnancy– “I’m too old to catch HIV”

• Delay in testing• Limited incomes• Immune restoration • Comorbid illnesses• Polypharmacy• Insufficient data on drug interactions in older

population

Luther VP, et al. Clin Geriatr Med. 2007;23:567-583.Illa L, et al. AIDS Behav. 2008;12:935-942.

NIH Statement on National HIV/AIDS and Aging Awareness Day - September 18, 2010

“Older HIV-infected adults face unique health challenges stemming from age-related changes to the body accelerated by HIV infection, the side effects of long-term treatment for HIV, the infection itself and often, treatments for age-associated illnesses”

NIH statement on National HIV/AIDS and Aging Awareness Day Sept. 18, 2010http://www.nih.gov/news/health/sep2010/niaid-09.htm.

Barriers to HIV Managementin Older Adults

• Age as independent predictor on clinical progression on HAART

• Significantly slower CD4 cell reconstitution• Older patients are more susceptible to the

adverse events of therapy• Older patients have greater number of co-morbid

conditions• Viral suppression and adherence

Kirk JB: J Am Geriatr Soc. 2009;57:2129-2138Hinkin, CH: AIDS 2001; 15:1576-9Grabar,S: JAC; Jan 2006; 57:4-7

Time to AIDS Diagnosis After a Diagnosisof HIV Infection in 2008 (40 States)

< 20 (n=2246) 20 to 34 (n=16,557)

35 to 49 (n=16,287)

> 50 (n=6,894)

0

10

20

30

40

50

60

70

80

90

15.424.1

38.645.9

84.675.9

61.454.1

< 12 months (overall:32.8%)> 12 months (overall: 67.2%)

Age at HIV Diagnosis

AID

S di

agno

sis

Aft

er

Dia

gnos

is o

f HIV

Infe

ction

(%)

CDC. HIV Surveillance Report, 2009. http://www.cdc.gov/hiv/surveillance/resources/reports/2009report/.

Survival After AIDS Diagnosis(1998-2005)

0

0.2

0.4

0.6

0.8

1

Prop

ortio

n Su

rviv

ing

0 12 24 36 48 60 72 84 96 108

Months After AIDS Diagnosis

<1313-2425-3435-4445-54

>55

Age atTime of

Diagnosis

CDC. HIV Surveillance Report, 2009. Available at: http://www.cdc.gov/hiv/surveillance/resources/reports/2009report/.

Factors of and Obstacles to Successful Aging With HIV

Vance DE, et al. Clin Interv Aging. 2011;6:181-192

Successful Aging

• Length of life– Number of years one remains alive– Decreased compared to general population– Lower in men, IVDU, lower initial CD4 count

• Biological Health– How well is the interaction and function of

the different systems of the body– Compromise of the immune system– Bacterial translocation and alcohol

Vance DE, et al. Clin Interv Aging. 2011;6:181-192

Successful Aging

• Cognitive efficiency– Optimal neurological integrity– Cognitive decline versus same-aged peers– Substance use

• Mental Health– Emotional equilibrium– HIV and poor mental health– HIV and stigma– Coping with HIV while aging

Vance DE, et al. Clin Interv Aging. 2011;6:181-192

Aging in HIV Infection

• Chronic inflammatory stimulation• Bone fractures/Osteoporosis/Osteopenia• Increase in cardiovascular disease• Increased rates of non-AIDS associated

malignancies• Faster neurocognitive decline• Functional decline

Polypharmacy in Older HIV-Infected PatientsVariables Total Age Group P Value

< 50 50-64 >65

Non-ART medication, n (%)

Antihypertensives (not ACE inhibitors)

785 (9.7) 300 (5.4) 341 (15.9) 144 (33.4) <0.001

Antihypertensives(ACE inhibitors)

874 (10.7) 311 (5.6) 415 (19.3) 148 (34.3) <0.001

Lipid-lowering agents 1013 (12.4) 324 (5.8) 511 (23.8) 178 (41.3) <0.001

Oral antidiabetics 170 (2.1) 49 (0.9) 82 (3.8) 39 (9.1) <0.001

Insulin 118 (1.5) 39 (0.7) 52 (2.4) 27 (6.3) <0.001

Antiplatelets drugs 473 (5.8) 110 (2.0) 233 (10.8) 130 (30.2) <0.001

Antidepressants 792 (9.7) 514 (9.3) 240 (11.2) 38 (8.8) 0.140

Hasse B, et al. 18th CROI; 2011; Boston, MA. Abstract 792

Inflammation and Aging: Therapeutic Strategies

• Reduce inflammation– Residual HIV replication (ART intensification?)– Prednisone, HU, cyclosporine, mycophenolic acid– Chronic/persistent co-infections (HCV, CMV)– Microbial translocation (sevelamer, colostrum)– CCR5 inhibitors– Chloroquine (reduced PDC mediated IFNα)– NSAIDs (COX-2 inhibitors)

Inflammation and Aging: Therapeutic Strategies

• Enhance T-cell renewal– GH, IL-7, stem cell transplant, perfenidone,

leuprolide (Lupron®)

• Anti-aging interventions– Caloric restrictions– Sirtuin activators, Telomerase activators– Vitamin D, omega-3 fatty acids, sirolimus

(Rapamycin®)

Treating HIV Does Not Fully restore Life expectancy

Losina et al. CID 2009

T cell activation in human immunodeficiency virus (HIV)-infected and HIV-uninfected adults

Hunt P W et al. J Infect Dis. 2003;187:1534-1543© 2003 by the Infectious Diseases Society of America

Comorbidities Associated With Aging and HIV Infection

Hypertension Diabetes Vascular disease

Pulmonary disease

Renal Disease05

101520253035404550

40-49 Years 50-59 Years > 60 Years

Perc

ent o

f Pre

vale

nce

Goulet JL, et al. Clin Infect Dis. 2007;45:1593-1601

Diabetes Mellitus in HIV and Aging

• Incidence is higher in HIV-infected patients• Most important prevention is to avoid

excess weight gain.• It could be related to the use of certain

antiretrovirals• Screening for glucose intolerance should

be performed regularly

Summary Report from the HIV and Aging Consensus Project

JAGS 60:974-979, May2012

Cardiovascular Disease in HIV and Aging

• HIV-infected patients have greater 10-year risk of cardiovascular disease

• Higher rates of atherosclerosis independent of viral load, ARV or extent of immunodeficiency (SMART)

• Smoking• Dyslipidemia and metabolic syndrome• Overweight

Brooks et al. Am J Public Health 2012;102:1516-1526

Pathogenesis of CV Disease in HIV

HIV cART HIV

InsulinResistance

Lipodystrophy InflammationDyslipidemia

DiabetesMellitus

CVDEndothelial dysfunction

van Wijk at al. Int J Vasc Med. 2012; ID201027

Risk Factors Contributing to Development of Kidney Disease

Modifiable risk factors• Diabetes mellitus• High blood pressure• Kidney stones• Inflammation (eg GMN)• Allergic reaction to med

(eg, antibiotics)• Medications (eg, NSAIDs)• Drug abuse• Use of creatine, hGH

testosterone

Non-modifiable risk factors• Age• Family history of kidney

disease• Trauma or accident• Presence of other

diseases:– HIV/AIDS, hepatitis C, lupus,

sickle cell anemia, cancer, congestive heart failure

http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p7_risk_g13.htm

HIV and Age as Renal Risk Factor

• Among 2159 HIV-infected patients enrolled in ACTG studies• 30% of patients had low baseline glomerular

filtration rate (GFR)• Median age was significantly higher in

patients with low versus normal GFR• 42 versus 36 years, respectively; P<.0011

Kalayjian R. 14th CROI. 2007. Abstract 827.

HIV and Age as Renal Risk Factor

• In the EuroSIDA cohort, the rate of chronic renal failure at baseline ranged from 3.5% to 4.7% depending on the method of GFR calculation• By multivariate analysis, age was a strong

predictor of chronic renal failure at baseline• OR 5.47, 95% CI 4.4-6.72; P<.00012

Mocroft A. AIDS. 2007;21(9):1119-1127.

Bone Health in HIV and Aging

• Among HIV-infected adults up to 60% have osteopenia, and up to 15% osteoporosis

• Higher rates of fragility fractures• Rates of fracture 60% greater on those

with nadir CD4 < 200• BMD assessment

Triant VA. J Clin Endocrinol Metab 2008:93(9):3499-3504

Sharma A. AIDS. 2010;24(15):2337-2345

BMD is Lower in HIV-Infected Women > 40 Years of Age

Femur neck and lumbar spine

Femoral neck only Lumbar Spine only0

5

10

15

20

25

3027

12

2119

7

15

HIV InfectedControl

Perc

ent W

ith L

ow B

MD

Arnsten JH, et al. Clin Infect Dis. 2006;42:1014-1020

BMD is Lower in HIV-Infected Older Men

Femoral Neck Total Hip Lumbar Spine0

0.2

0.4

0.6

0.8

1

1.2

1.4 HIV infected (n=230)Control (n=159)

BMD

at F

irst

DEX

A (g

/cm

2)

Sharma A et al. AIDS. 2010, 24:2337-2345Osteopenia incidence per 100 person-years at risk was 2.6 for HIV-uninfectedMen and 7.2 for HIV-infected men

Frailty in HIV and Aging

• Weakness• Low physical activity• Slow motor performance• Weight loss• Weak grip strength• Factors associated with frailty: higher

depression score, unemployment, greater comorbid conditions, past OIs

Brooks et al. Am J Public Health.2012;102:1516-1526

Psychiatric and Neurocognitive Disorders

• Alcohol and drug use• Thought and mood disorders• Depression and suicide• Decrease memory

• UPDRS motor scores were 40.7% in HIV infected vs 15.7% in HIV-– Slowness of hand movement, body bradykinesia,

tremor

Valcour V at al. J Neurovirol. 2008;14:362-367Vance et al. Clin Interv Aging 2011:6 181-192

Neurocognitive Complications in HIV

42%

53%

5%

Asymptomatic Neurocognitive Impairment (ANI)

Mild Neurocognitive Disorder (MND)

HIV-associated Dementia (HAD)

Valcour V, et al. CROI 2012. Abstract 498

Cancer in HIV and AgingPatel P. Ann Intern Med. 2008;148(10):728-736

• Higher incidence among HIV-infected– Anal– Vaginal– Hodgkin’s lymphoma– Liver– Lung– Melanoma– Oropharyngeal– Leukemia– Colorectal– Renal

Higher Cancer Risk in HIV infection

• Kaposi’s sarcoma 199-fold• Non-Hodgkin lymphoma 15-fold• Anal cancer 55-fold• Hodgkin lymphoma 19-fold• Melanoma 1.8-fold• Liver cancer 1.8-fold

Silverberg MJ. CEBP. Dec2011 20:2551-2559

Cancer Screening

• Cervical cancer• Colon cancer• Anal cancer• Liver cancer• Skin cancer• Cancer screening should be in

accordance with current guidelines for the general population

Cancer Screening

• Cervical cancer– PAP smear upon starting care and again in

six months– If abnormal: Colposcopy and biopsy

• Anal cancer– RR increases 37-fold among HIV+ men– RR increased 60-fold among HIV+ MSM

USPSTF, CDC, HIVMA Recommendations

Aberg JA et al. CID 2004 39(5)609-29

Frisch M et al. J NCI 2000 92(18)1500-10

Colorectal Cancer Screening

Series10

10

20

30

40

50

60

70

80

90

43

5.3 2.6

17.2

55.649.3

66.6

17.5

7.9

27.5

77.8

65.6

HIV +HIV -

Prop

ortio

n Te

sted

(%)

Fecal OccultBlood Test

Reinhold JP et al. Am J Gastroenterol. 2005;100:1805-1812

FlexibleSigmoidoscopy

Air ContrastBarium Enema

Colonoscopy At least 1 CRCScreening Test

UTD with at least 1CRC Screening TestPerformed

Summary• HIV population is aging• Providers should ask all patients about high-

risk behaviors and educate them on the risks

• Management of older HIV-infected patients may be complicated by comorbidities

• Comorbidities attributed to increasing age may overlap with morbidity from HIV disease and toxicity from ART

Summary• Current ARV therapies are effective in reducing

progression of the disease and mortality• Life expectancy is shorter than normal despite

optimal ART. – It appears to be predicted by lower CD4 and higher

inflammation.

• Markers of inflammation and T cell activation remain higher in ART than non-HIV infected

• Early diagnosis, and probably early therapy initiation, may improve outcomes in this population