Comorbidities in an Aging HIV Positive Population Fernando Garcia, MD Valley AIDS Council HalingenTExas

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 2

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 Objective: To establish that HAART has increased the life expectancy of HIV positive individuals, and the percentage of these patients >50 years of age is increasing. Transition: Show the data demonstrating the increase in average age in the HIV positive population over time. 1Munoz A, et al. AIDS. 1997;11:S69-76. 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.

Age Distribution (in years) of HIV Positive Individuals Living in the United States Objective: Graphically depict the aging of the HIV positive population. Transition: Not only are people living longer, but fewer people are dying from AIDS-related conditions Adapted from CDC Surveillance Report 2006

Rate of HIV Related Deaths Have Declined Since 1999 Overall deaths HIV-related deaths Non-HIV-related deaths 900 800 700 600 500 400 300 200 100 1999 2000 2001 2002 2003 2004 Years Rate per 10,000 persons with AIDS Age-adjusted AIDS mortality rate by underlying cause of death Objective: Illustrate that the percentage of overall deaths for non-AIDS defining illnesses in HIV positive patients is increasing over time. Background A population-based analysis was conducted from 1999 through 2004 utilizing the New York City HIV/AIDS Reporting System and Vital Statistics Registry (N=68,669). The population included patients ≥13 years of age who received a diagnosis of AIDS; were alive at any time between 1999 and 2004; and, among those who died, had a known underlying cause of death (98.2%). Transition: Setting up why certain co-morbidities are important to factor into to treating HIV infected patients. 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. 5

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 Objective: Summary slide, creating a call to action for considering common age related comorbidities when treating HIV positive patients. Transition: Introduce case study 1Gupta SK, et al. Clinical Infectious Disease. 2005; 40:1559-1585., 2Falutz 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.

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 7

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 Objective: Introduce a 63 y/o HIV patient who has slightly elevated risk for both cardiovascular disease and renal disease. Transition to physical exam and reason for patient visit.

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 Objective: Complete medical history and describe patient visit to provider Transition: Questions to consider for this patient.

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 11

Prevalence of Chronic Kidney Disease in the General Population Increases with Age Eight year cross-sectional Norwegian survey subjects ≥20 yrs of age GFR (mL/min/1.73 m2): 45-59 45 30-44 <30 N = 65,605 Prevalence (%) Objective: The proportion of the general population with chronic kidney disease increases dramatically with age. Transition: Describe how CKD manifests in HIV positive patients Age (Years) Adapted from Hallan SI, et al. BMJ. 2006; 333:1047-1050.

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 Objective: Highlight the fact that kidney disease is prevalent in the aging HIV positive population. Transition: How does this compare to the general (non-HIV positive) population? 1Gupta SK, et al. Clinical Infectious Disease. 2005; 40:1559-1585. 2Gupta 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 co-infection Objective: Causation of kidney disease in HIV positive patients is multi-factorial Transition: There are many risk factors associated with CKD Wyatt, CM. AJM. 2007. 120;488-49.

Risk Factors for Kidney Disease in the HIV Positive Population Ethnicity Family History Age CKD Risk HIV Hyper- tension Diabetes, HTN, Hep C and HIV are listed as "modifiable", not because they are curable per se, but can be controlled. ART Diabetes = Modifiable Hepatitis C = Nonmodifiable 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 Objective: That physicians follow guidelines to screen and monitor patients appropriately for kidney disease Transition: On to the lipodystrophy section 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 17

The Causation of Lipodystrophy Is Multi-Factorial in HIV Positive Patients Objective: Development of lipodystrophy is multifactorial with host, viral and certain treatments contributing to fat redistribution. Transition: The clinical significance of lipodystrophy is (listed on the next slide).

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) Objective: The downstream complications of lipodystrophy are more than just cosmetic effects Transition: How can you avoid or manage lipodystrophy 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 Objective: Summary slide of a variety of options that should be considered when managing a patient with lipodystrophy Transition: On to diabetes section 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 21

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: Objective: HIV positive patients are at a higher risk for diabetes than the general population Transition: How do we define insulin resistance, impaired glucose tolerance in diabetes Certain ARVs Older age Ethnic background (African American) Male sex Greater BMI 1Florescu, D. Antiretroviral Therapy. 2007. 12:149-162. 2Brown, TT. Arch Intern Med. 2005. 165:1179-1184. 3DeWit, D. Diabetes Care. 2008. 31(6):1224-1229.

Diabetes Diagnostic Criteria Objective: To define IFG, IGT and DM. Transition: Downstream effects of insulin resistance comprise Florescu, D. Antiretroviral Therapy. 2007. 12:149-162.

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 Objective: Insulin resistance leads to more serious complications Transition: How to screen for and manage insulin resistance 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 Objective: Call to action of diagnosis and management of insulin resistance in HIV positive patients Transition: On to the cardiovascular section Florescu, D. Antiretroviral Therapy. 2007. 12:149-162.

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 26

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 Objective: Establish cardiovascular disease as an important comorbidity in HIV postive individuals Transition: Show MI rates for HIV +/- individuals D:A:D Study Group. The Lancet. 2008. 371(9622):1417-26.

MI Rates in HIV Positive and HIV Negative Patients Age Group (Years) Events per 1000 Person-Years 20 40 60 80 100 18-34 35-44 45-54 55-64 65-74 HIV+ HIV– AMI rate by age group Objective: As stated Transition: There are a number of contributing factors to CV disease in HIV positive individuals 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 Insulin Resistance Objective: As stated Transition: Utilize the guidelines to manage CV risk and lipid disorders Viremia Oxidative Stress = HIV Infection = ART = HIV Infection & ART Adapted from Dube M, et al. Circulation. 2008;118:e36-e40.

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 Objective: To follow current CV guidelines established for HIV positive patients. Transition: How to calculate CV risk. 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 >500 mg/dL: FIBRATES OR Dubé MP et al. Clin Infect Dis. 2003;37:613-627. IDSA = Infectious Diseases Society of America.

Calculating Framingham Risk Objective: Calculate 10 year CV risk in all HIV positive patients at baseline Transition: Conclusion 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 33

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 Objective: Introduce a 63 y/o HIV patient who has slightly elevated risk for both cardiovascular disease and renal disease. Transition to physical exam and reason for patient visit.

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 Objective: Complete medical history and describe patient visit to provider Transition: Questions to consider for this patient.

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?