Comorbidities in an Aging HIV Positive Population

1
Comorbidities in an Aging HIV Positive Population

• Speaker Name
• Location
• Date

2
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

3
HAART An Aging HIV Positive Population

• The success of HAART has dramatically enhanced
  life expectancy among HIV positive individuals1
• By 2015, it is estimated that more than one-half
  of all HIV positive individuals in the US will be
  aged gt50 years2

1Munoz A, et al. AIDS. 199711S69-76. 2Statement
from Senator Gordon H. Smith. Aging hearing HIV
over fifty, exploring the new threat. Available
at http//aging.senate.gov/events/hr141gs.pdf.
Accessed September 25, 2008.
4
Age Distribution (in years) of HIV Positive
Individuals Living in the United States
Adapted from CDC Surveillance Report 2006
5
Rate of HIV Related Deaths Have Declined Since
1999

• 1 out of 4 deaths of patients with AIDS was
  non-HIV related
• The proportion of deaths due to non-HIV related
  causes increased over this time period

Sackoff JE, et al. Ann Interm Med.
2006145397-406.
6
Comorbidities Associated with an Aging HIV
Positive Population

• Age related comorbidities are important in HIV
  positive individuals
• Renal1
• Lipodystrophy2
• Insulin Resistance / Diabetes3
• Cardiovascular4
• These comorbidities in HIV positive patients may
  be increasingly important in determining the
  course of therapy in an aging patient population

1Gupta SK, et al. Clinical Infectious Disease.
2005 401559-1585., 2Falutz J., Nat Clin Pract
Endocrinol Metab. 2007 Sep3(9)651-61.
3Florescu, D. Antiretroviral Therapy. 2007.
12149-162. 4Schambelan M et al. Circulation.
2008118e48-e53.
7
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

8
Case Study Treatment-Experienced Patient

• Patient is a 63-year-old African American man who
  presents to the office for routine follow-up
• HIV positive for 6 years and has been on a BID
  boosted PI-based antiretroviral regimen since
  diagnosis
• No history of prior treatment intolerance or
  virologic failures
• He describes mild long-standing fatigue and
  infrequent episodes of diarrhea
• Current labs
• CD4 436 cells/mm3, VL lt50 copies/mL,
• WBC 5.2 cells/µL, Hgb 14.1g/dL, Platelet
  count 236,000
• TC 212 mg/dL, TG 190 mg/dL, LDL 123 mg/dL,
  HDL 41 mg/dL
• FBG 120mg/dl, Creatinine 1.2 mg/dL, BUN 6
  mg/dL, Normal LFTs
• eGFR (C-G method) 78.8 mL/min/1.73 m2

9
Case Study Treatment-Experienced Patient

• Current meds ARV regimen, statin, PRN
  antidiarrheal
• No history of diabetes, HTN, tobacco use, or
  family history of CAD
• Physical exam lipoatrophy of face, arms, and
  legs Waist circumference 39
• Patient is starting a new job and has concerns
  about his current ARV regimen

10
Case Study Treatment-Experienced Patient

• How does this patients age affect your initial
  evaluation?
• How do his physical exam and lab values factor
  into treatment decisions?
• What are the similarities and differences in how
  you would manage this patient compared to a
  younger patient?

11
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

12
Prevalence of Chronic Kidney Disease in the
General Population Increases with Age
Eight year cross-sectional Norwegian survey
subjects 20 yrs of age
45
lt30
GFR (mL/min/1.73 m2)
45-59
30-44
N 65,605
Prevalence ()
Age (Years)
Adapted from Hallan SI, et al. BMJ. 2006
3331047-1050.
13
Renal Disease in HIV Positive Patients

• Kidney disease is an important complication of
  HIV infection in the era of antiretroviral
  therapy1
• In a retrospective study of 487 consecutive HIV
  positive patients with normal renal function, the
  initial prevalence of CKD was 22
• After 5 years of follow-up, 6 had progressed to
  CKD
• Older age was a multivariate predictor of CKD for
  this cohort

1Gupta SK, et al. Clinical Infectious Disease.
2005 401559-1585.2Gupta SK, et al. Clinical
Nephrology. 2004. 611-6.
14
Kidney Disease in HIV Positive Patients

• The spectrum of kidney disease in HIV includes
• HIV-associated nephropathy
• Immune complex kidney disease
• Medication nephrotoxicity
• Kidney disease related to co-morbid conditions
• Diabetes, hypertension, and hepatitis virus
  co-infection

Wyatt, CM. AJM. 2007. 120488-49.
15
Risk Factors for Kidney Disease in the HIV
Positive Population
Ethnicity
Family History
Age
CKD Risk
Hyper- tension
HIV
ART
Diabetes
Hepatitis C
Modifiable
Nonmodifiable
Gupta SK, et al. Clinical Infectious Disease.
2005 401559-1585.
16
IDSA Initial Evaluation Recommendations

• Obtain baseline GFR
• All patients at the time of HIV diagnosis should
  be assessed for existing kidney disease with a
  screening urinalysis for proteinuria and a
  calculated estimate of renal function
• Annual screening
• If there is no evidence of proteinuria at initial
  evaluation, patients at high risk for the
  development of proteinuric renal disease should
  undergo annual screening
• Renal function should be estimated on a yearly
  basis to assess for changes over time
• When to consider a nephrology consult
• Additional evaluations and referral to a
  nephrologist are recommended for patients with
  proteinuria of grade 1 by dipstick analysis or
  GFRlt60 mL/min per 1.73m2

Gupta SK, et al. Clinical Infectious Disease.
2005 401559-1585.
17
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

18
The Causation of Lipodystrophy Is Multi-Factorial
in HIV Positive Patients
19
Potential Clinical Impact of Lipodystrophy

• Morphological1
• Quality of life
• Patient adherence
• Metabolic2
• Insulin resistance
• Impaired glucose tolerance
• Type 2 diabetes
• Hypertriglyceridemia
• Hypercholesterolemia
• Increased free fatty acids (FFA)
• Decreased high density lipoprotein (HDL)

1Falutz J., Nat Clin Pract Endocrinol Metab. 2007
Sep3(9)651-61. 2Behrens G, et al.
Lipodystrophy syndrome. HIV Medicine. 15th ed.
2007. Available at http//www.hivmedicine.com/hiv
medicine2007.pdf. Accessed September 25, 2008.
20
Therapeutic Options for Managing Lipodystrophy

• Lifestyle changes
• Reduce saturated fat/ cholesterol intake
• Increase physical activity
• Cease smoking
• Evaluate ARVs
• Manage chronic co-morbid conditions
• e.g. hypertension, hyperlipidemia, diabetes

Falutz J., Nat Clin Pract Endocrinol Metab. 2007
Sep3(9)651-61.
21
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

22
Insulin Resistance and Diabetes in the HIV
Positive Population

• An increased prevalence of insulin resistance,
  glucose intolerance and diabetes has been
  reported in HIV infections in the HAART era1
• Diabetes in HIV positive men with HAART exposure
  gt 4X HIV-seronegative men2
• Risk factors for HIV positive individuals
  developing diabetes include3

• Male sex
• Greater BMI

• Certain ARVs
• Older age
• Ethnic background (African American)

1Florescu, D. Antiretroviral Therapy. 2007.
12149-162.2Brown, TT. Arch Intern Med. 2005.
1651179-1184.3DeWit, D. Diabetes Care. 2008.
31(6)1224-1229.
23
Diabetes Diagnostic Criteria
Florescu, D. Antiretroviral Therapy. 2007.
12149-162.
24
Complications of Insulin Resistance

• Insulin resistance occurs as part of a metabolic
  syndrome that may lead to the development of
• Type II diabetes
• Atherosclerosis
• Hypertension

Florescu, D. Antiretroviral Therapy. 2007.
12149-162.
25
Diagnosis and Management of InsulinResistance in
HIV-Infected Patients

• Fasting serum glucose measurement
• At baseline and 3-6 months after starting
  HAART
• Yearly thereafter
• Oral glucose tolerance test
• At the first visit in patients with family
  history of diabetes or obesity
• Repeat when there is clinical suspicion of
  impaired glucose tolerance
• Lifestyle modification
• Diabetic education
• Self-monitoring of blood glucose
• Aerobic and resistance training

Florescu, D. Antiretroviral Therapy. 2007.
12149-162.
26
ß-Cell function and glucagon in Type 2 diabetes

• Loss of ß-cell function and glucagon
  over-secretion both play key roles in Type 2
  diabetes development
• Progressive ß-cell decline is coupled with
  inadequate insulin secretion
• Glucagon is not suppressed during the
  postprandial period
• Hepatic glucose production is increased during
  the fasting period and is not suppressed during
  the postprandial period

27
Incretin therapies

• Physiologic defects associated with Type 2
  diabetes
• ß-cell dysfunction
• Inadequate insulin secretion and glucagon
  over-secretion
• The role of incretins in normal physiology
• Approaches to incretin therapy
• GLP-1 analogues
• DPP-4 inhibitors

28
GLP-1 effects in humans

• Stimulates glucose- dependent
• insulin secretion

Suppresses glucagonsecretion

• Slows gastric emptying

• Leads to a reduction offood intake

GLP-1 is secreted fromL-cells of the jejunum
and ileum

• Improves insulin sensitivity

Long-term effectsin animal models
That in turn

• Increase of ß-cell mass and improved ß-cell
  function

Drucker. Curr Pharm Des. 2001 Drucker. Mol
Endocrinol. 2003
29
GLP-1 enhancement
GLP-1 secretion is impaired in Type 2
diabetes Natural GLP-1 has extremely short
half-life
Drucker. Curr Pharm Des. 2001 Drucker. Mol
Endocrinol. 2003
30
Oral Hypoglycemic Agents First- Generation
Sulfonylureas
Drugs

• chlorpropamide (Diabinese)
• tolbutamide

31
Oral Hypoglycemic AgentsSecond-Generation
Sulfonylureas
Drugs

• glimepiride (Amaryl)
• glipizide (Glucotrol, Glucotrol XL)
• glyburide (DiaBeta, Glynase, Micronase)

32
Oral Hypoglycemic Agents Meglitinides
Drugs

• nateglinide (Starlix)
• repaglinide (Prandin)

33
Oral Hypoglycemic Agents Glitazones/Thiazolidinedi
ones
Drugs

• pioglitazone (Actos)
• rosiglitazone (Avandia)

34
Oral Hypoglycemic Agents
Drug List

• Enzyme inhibitors
• acarbose (Precose)
• miglitol (Glyset)
• Biguanide
• metformin (Glucophage, Riomet)

35
Oral Hypoglycemic Agents Combinations
Drugs

• glipizide-metformin (Metaglip)
• glyburide-metformin (Glucovance)
• rosiglitazone-metformin (Avandamet)

36
Human Insulins
Drug List

• NPH isophane insulin (Humulin N)
• insulin aspart (NovoLog)
• insulin glargine (Lantus)
• insulin lispro (Humalog)
• regular insulin (Humulin R)

37
Action Profiles of Bolus Basal Insulins
lispro/aspart 46 hours

• BOLUS INSULINS

• BASAL INSULINS

regular 6-10 hours
NPH 1220 hours
detemir 6-23 hours (dose dependant)
Plasma Insulin levels
glargine 20-26 hours
Hours
Note action curves are approximations for
illustrative purposes. Actual patient response
will vary.
Mayfield, JA.. et al, Amer. Fam. Phys. Aug.
2004, 70(3) 491 Plank, J. et.al. Diabetes Care,
May 2005 28(5) 1107-12
38
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

39
Cardiovascular Disease in the HIV Positive
Population

• Cardiovascular (CV) disease has emerged as a
  health concern in the aging HIV-positive
  population as HAART can provide durable clinical
  benefit and improved survival
• Contributes to more than 10 of deaths among HIV
  positive individuals
• Factors that affect CV risk are similar for HIV
  positive and negative individuals
• Risk may vary among ARV agents

DAD Study Group. The Lancet. 2008.
371(9622)1417-26.
40
MI Rates in HIV Positive and HIV Negative Patients
AMI rate by age group
Cohorts (HIV 3851, HIV- 1,044,589) were
identified in the Research Patient Data Registry.
The primary outcome was AMI.
Triant VA,et al. J Clin Endocrinol Metab.
2007922506-2512.
41
HIV Related Factors that May Contribute to
Cardiovascular Disease
Endothelial Dysfunction
Persistent Inflammation
Lipid Disorders
HAART

Vascular Disease in HIV Positive Patients
ART-Associated Lipodystrophy
Insulin Resistance
Oxidative Stress
Viremia
Adapted from Dube M, et al. Circulation.
2008118e36-e40.
42
IDSA Guidelines General Approach to CV Risk in
HIV Positive Patients
Obtain fasting lipid profile, prior to starting
antiretrovirals and within 3 to 6 months of
starting new regimen
Count number of CHD risk factors and determine
level of risk.If 2 risk factors, perform a
10-year risk calculation
Intervene for modifiable nonlipid risk factors,
including diet and smoking
If above the lipid threshold based on risk group
despite vigorous lifestyle interventions,
consider altering antiretroviral therapy or
lipid-lowering drugs
IF LIPID-LOWERING DRUGS ARE NECESSARY
Serum LDL cholesterol above threshold, or
triglycerides 200-500 mg/dL with elevated
non-HDL cholesterol STATINS
Serum triglycerides gt500 mg/dLFIBRATES
OR
Dubé MP et al. Clin Infect Dis. 200337613-627.

IDSA Infectious Diseases Society of
America.
43
Calculating Framingham Risk
Available at http//hp2010.nhlbihin.net/atpiii/ca
lculator.asp?usertypeprof. Accessed September
25, 2008.
44
Summary

• Due to advances in HAART, HIV positive patients
  are growing older and living longer
• HIV positive individuals may experience common
  comorbidities as they grow older
• Renal dysfunction
• Lipodystrophy
• Insulin resistance / Diabetes
• Cardiovascular disease
• Comorbidities may be increasingly important in
  therapeutic decisions involving aging HIV
  positive patients

45
Comorbidities Associated With anAging HIV
Positive Population

• I. Epidemiology
• II. Introduction to Case Study
• III. Comorbidities
• Renal
• Lipodystrophy
• Insulin Resistance / Diabetes
• Cardiovascular
• IV. Case Study Facilitation

46
Case Study Treatment-Experienced Patient

• Patient is a 63-year-old African American man who
  presents to the office for routine follow-up
• HIV positive for 6 years and has been on a BID
  boosted PI-based antiretroviral regimen since
  diagnosis
• No history of prior treatment intolerance or
  virologic failures
• He describes mild long-standing fatigue and
  infrequent episodes of diarrhea
• Current labs
• CD4 436 cells/mm3, VL lt50 copies/mL,
• WBC 5.2 cells/µL, Hgb 14.1g/dL, Platelet
  count 236,000
• TC 212 mg/dL, TG 190 mg/dL, LDL 123 mg/dL,
  HDL 41 mg/dL
• FBG 120mg/dl, Creatinine 1.2 mg/dL, BUN 6
  mg/dL, Normal LFTs
• eGFR (C-G method) 78.8 mL/min/1.73 m2

47
Case Study Treatment-Experienced Patient

• Current meds ARV regimen, statin, PRN
  antidiarrheal
• No history of diabetes, HTN, tobacco use, or
  family history of CAD
• Physical exam lipoatrophy of face, arms, and
  legs Waist circumference 39
• Patient is starting a new job and has concerns
  about his current ARV regimen

48
Case Study Treatment-Experienced Patient

• How does this patients age affect your initial
  evaluation?
• How do his physical exam and lab values factor
  into treatment decisions?
• What are the similarities and differences in how
  you would manage this patient compared to a
  younger patient?