Comorbidities in an Aging HIV
Positive Population
Speaker Name
Location
Date
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
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 >50
years2
1Munoz
A, et al. AIDS. 1997;11:S69-76.
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.
2Statement
Age Distribution (in years) of HIV Positive
Individuals Living in the United States
Estimated Number of Persons Living with HIV/AIDS
110,000
100,000
90,000
2003
2006
80,000
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0
<13
13-14 15-19
20-24 25-29 30-34
Adapted from CDC Surveillance Report 2006
35-39 40-44 45-49
Age Group (Years)
50-54 55-59 60-64
>65
Rate of HIV Related Deaths Have Declined Since 1999
Age-adjusted AIDS mortality rate by underlying cause of death
Rate per 10,000
persons with AIDS
900
800
Overall deaths
700
HIV-related deaths
Non-HIV-related deaths
600
500
400
300
200
100
1999
2000
2001
2002
2003
2004
Years
• 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. 2006;145:397-406.
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; 40:1559-1585.,
J., Nat Clin Pract Endocrinol Metab. 2007 Sep;3(9):651-61.
3Florescu, D. Antiretroviral Therapy. 2007. 12:149-162.
4Schambelan M et al. Circulation. 2008;118:e48-e53.
2Falutz
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
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 <50 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
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
Case Study: Treatment-Experienced Patient
• How does this patient’s 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?
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
Prevalence of Chronic Kidney Disease in the
General Population Increases with Age
Eight year cross-sectional Norwegian survey subjects ≥20 yrs of age
Prevalence (%)
50
GFR (mL/min/1.73 m2):
40
45
45-59
30-44
<30
N = 65,605
30
20
10
0
20-29
30-39
40-49
50-59
60-69
Age (Years)
Adapted from Hallan SI, et al. BMJ. 2006; 333:1047-1050.
70-79
80-89
90+
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 2%2
– After 5 years of follow-up, 6% had progressed to CKD
– Older age was a multivariate predictor of CKD for this cohort
1Gupta
2Gupta
SK, et al. Clinical Infectious Disease. 2005; 40:1559-1585.
SK, et al. Clinical Nephrology. 2004.; 61:1-6.
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 coinfection
Wyatt, CM. AJM. 2007. 120;488-49.
Risk Factors for Kidney Disease in the HIV Positive
Population
Ethnicity
Family
History
Age
HIV
CKD
Risk
ART
= Modifiable
= Nonmodifiable
Hypertension
Diabetes
Hepatitis C
Gupta SK, et al. Clinical Infectious Disease. 2005; 40:1559-1585.
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 GFR<60
mL/min per 1.73m2
Gupta SK, et al. Clinical Infectious Disease. 2005; 40:1559-1585.
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
The Causation of Lipodystrophy Is MultiFactorial in HIV Positive Patients
Host
Age
Race
Gender
Body composition
Virus
Viral Load
Nadir CD4 levels
CDC Disease Category
Duration of HIV infection
Therapy
Duration of treatment
Certain ARVs
Adapted from Lichtenstein KA. JAIDS. 2005;39:395–400.
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 Sep;3(9):651-61.
2Behrens
G, et al. Lipodystrophy syndrome. HIV Medicine. 15th ed. 2007. Available at:
http://www.hivmedicine.com/hivmedicine2007.pdf. Accessed September 25, 2008.
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 Sep;3(9):651-61.
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
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 > 4X
HIV-seronegative men2
• Risk factors for HIV positive individuals developing
diabetes include3:
• Certain ARVs
• Older age
• Ethnic background (African American)
1Florescu,
D. Antiretroviral Therapy. 2007. 12:149-162.
TT. Arch Intern Med. 2005. 165:1179-1184.
3DeWit, D. Diabetes Care. 2008. 31(6):1224-1229.
2Brown,
• Male sex
• Greater BMI
Diabetes Diagnostic Criteria
Test
Test
Fasting plasma glucose
Fasting plasma glucose
OGTT
Random plasma glucose
Oral Glucose Tolerance Test
Random plasma glucose
Florescu, D. Antiretroviral Therapy. 2007. 12:149-162.
Criteria
Criteria
≥ 126 mg/dL (≥ 6.99 mmol/L), confirmed by
repeat testing or
Plasma
glucose
2 hours
75testing
g oral or
≥ 126
mg/dL,
confirmed
by after
repeat
glucose ≥ 200 mg/dL (≥ 11.10 mmol/L)
≥ 200 mg/dL (≥ 11.10 mmol/L) with polyuria
and polydipsia
Plasma glucose 2 hours after 75 g oral
glucose ≥ 200 mg/dL
≥ 200 mg/dL with polyuria and polydipsia
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. 12:149-162.
Diagnosis and Management of Insulin
Resistance 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. 12:149-162.
β-Cell function and glucagon
in Type 2 diabetes
• Loss of β-cell function and glucagon oversecretion both play key roles in Type 2 diabetes
development
• Progressive β-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
Incretin therapies
Physiologic defects associated with Type 2 diabetes
β-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
GLP-1: effects in humans
After food ingestion…
• Stimulates glucose- dependent
• insulin secretion
Suppresses glucagon
secretion
• Slows gastric emptying
GLP-1 is secreted from
L-cells of the jejunum
and ileum
That in turn…
• Leads to a reduction of
food intake
• Improves insulin sensitivity
Long-term effects
in animal models:
• Increase of β-cell mass
and improved β-cell function
Drucker. Curr Pharm Des. 2001
Drucker. Mol Endocrinol. 2003
GLP-1 enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
•
Exenatide(byetta)
.Liraglutide(Victosa)
Injectables
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
Block DPP-4, the
enzyme that degrades
GLP-1:
• Sitagliptin(januvia)
.Saxagliptin(onglyza)
Oral agents
Drugs
Oral Hypoglycemic Agents
First- Generation
Sulfonylureas
• chlorpropamide (Diabinese)
• tolbutamide
Drugs
Oral Hypoglycemic Agents
Second-Generation
Sulfonylureas
• glimepiride (Amaryl)
• glipizide (Glucotrol, Glucotrol XL)
• glyburide (DiaBeta, Glynase, Micronase)
Drugs
Oral Hypoglycemic Agents
Meglitinides
• nateglinide (Starlix)
• repaglinide (Prandin)
Drugs
Oral Hypoglycemic Agents
Glitazones/Thiazolidinediones
• pioglitazone (Actos)
• rosiglitazone (Avandia)
Drug
List Oral Hypoglycemic
Agents
Enzyme inhibitors:
• acarbose (Precose)
• miglitol (Glyset)
Biguanide:
• metformin (Glucophage, Riomet)
Drugs
Oral Hypoglycemic Agents
Combinations
• glipizide-metformin (Metaglip)
• glyburide-metformin (Glucovance)
• rosiglitazone-metformin (Avandamet)
Drug
List Human Insulins
•
•
•
•
•
NPH isophane insulin (Humulin N)
insulin aspart (NovoLog)
insulin glargine (Lantus)
insulin lispro (Humalog)
regular insulin (Humulin R)
Action Profiles of Bolus & Basal
Insulins
lispro/aspart 4–6 hours
regular 6-10 hours


BOLUS INSULINS
BASAL INSULINS
NPH 12–20 hours
detemir ~ 6-23 hours (dose dependant)
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
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
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
D:A:D Study Group. The Lancet. 2008. 371(9622):1417-26.
MI Rates in HIV Positive and HIV Negative Patients
AMI rate by age group
Events per
1000 Person-Years
100
HIV+
80
HIV–
60
40
20
0
18-34
35-44
45-54
55-64
65-74
Age Group (Years)
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. 2007;92:2506-2512.
HIV Related Factors that May Contribute to
Cardiovascular Disease
Persistent
Inflammation
Endothelial
Dysfunction
Lipid Disorders
HAART
Vascular Disease in
HIV Positive Patients
ART-Associated
Lipodystrophy
= ART
Insulin
Resistance
Viremia
= HIV Infection
= HIV Infection & ART
Adapted from Dube M, et al. Circulation. 2008;118:e36-e40.
Oxidative Stress
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
Dubé MP et al. Clin Infect Dis. 2003;37:613-627.
OR
Serum triglycerides >500 mg/dL:
FIBRATES
IDSA = Infectious Diseases Society of America.
Calculating Framingham Risk
Available at: http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof. Accessed September 25, 2008.
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
Comorbidities Associated With an
Aging HIV Positive Population
I. Epidemiology
II. Introduction to Case Study
III. Comorbidities
•
Renal
•
Lipodystrophy
•
Insulin Resistance / Diabetes
•
Cardiovascular
IV. Case Study Facilitation
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 <50 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
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
Case Study: Treatment-Experienced Patient
• How does this patient’s 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?