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1 Current HIV Issues in the US: Case Studies in Managing Long-Term Non-ADS Co-Morbidities Ann Khalsa, MD, MSEd, AAHIVS Centro de Salud Familiar La Fe CARE Center Texas-Oklahoma AIDS Education and Training Center El Paso, Texas, USA =背景の写真は、 Dr Khalsaが2006年エイズ学会(熊本)来日時に日本で写した紅葉の写真だそうです= 2 Outline Cases Co-Morbidities • Francisco • Richard • Juan • Renal and Bone • Bone and Androgens • Diabetes Case: Francisco Introduction • 48 y/o Hispanic MSM • HIV+ since 1992 on multiple ARVs with multiple 3-class mutations • VL<50, CD4>500 on TDF-FTC-LPVr x 3yrs • Complications: – Hyperlipidemia, hypertension, GERD on Omega 3 FFA, ACE inhibitor, PPI • New onset CrCl: 45 (eGFR) 3 Case: Francisco Question #1 • Which tests should be ordered to evaluate his renal insufficiency? 1. 2. 3. 4. 5. Spot urine protein:creatinine ratio Serum and urine phosporous Serum and urine glucose 24 hour urine creatinine clearance 1, 2 and 3 4 5 Case Francisco Q#1 Results Test Result Normal Urine spot prt:creat ratio 425 mg/g <200 mg/g creat Urine spot creatinine 135 mg/dL N/A Urine random phosphorous 118 mg/dL N/A Serum creatinine 1.8 mg/dL ~< 1.5 mg/dL Serum phosphate 2.0 ng/dL 2.5-4.5 mg/dL Fractional Excretion of Phosphorous (FE PO4): INTERPRETATION: (Ur PO4 x Ser Cr x 100) / (Ser PO4 x Ur Cr) Serum PO4 & FEPO4: (118 x 1.8 x 100) / (2.0 x 135) = 79% = Tubular, eg. Fanconi’s Elevated FE PO4 = >5% 6 Kidney Disease in HIV • Acute Kidney Injury – Example hospitaliztion complication – Infections, medications, liver failure • ARV Nephrotoxicity – TDF: proximal tubulopathy – IDV, ATV: crystalluria, nephrolithiasis • HIV Associated (HIVAN) – Advanced HIV, blacks (MYH9 gene) • Comorbid Disease – HBV, HCV, DM, HTN End Stage Renal Disease 7 Tenofovir Toxicity: Proximal Tubulopathy Classic Presentation Phosphate wasting Metabolic acidosis Euglycemic glycosuria Evaluation FE PO4 Serum bicarbonate Serum & urine glucose Creatinine clearance Proteinuria MDRD, CG GFR Spot Ur Prt:Creat • Most have sub-clinical abnormalities; 1-2% serious toxicity • Risks: Pre-existing renal insufficiency, genetic predisposition, concommitant meds (ddI, PI-rtv) Case Francisco Question #2 • Which of the following are important in the managment of his CKD? 1. Consider non-TDF antiretroviral regimen 2. Optimize ACE / ARB inhibitor therapy to control blood pressure and proteinuria 3. Evaluate for other co-morbidities potentially underlying his CKD 4. All of the above 8 Case Francisco Q#2 Management • Co-Mobidities: – No diabetes mellitus – Hepatitis B & C serologies negative • ARV Allergies / Resistance: – NNRTI: 181C, EFV allergy – NRTI: 151M mutation complex – PI: 10I,71V,73S,77I,90M: 1st generation PIs, Ø DRV mut • Medication changes: – TDF RLT; FTC dose monitored (CrCl normalized) – ACE inhibitor increased (BP & proteinuria normalized) – NSAID discontinued 9 Case Francisco Question #3 • Given his CKD with phosphate wasting what other studies should be performed? 1. Serum 25-OH vitamin D 2. DEXA bone density scan 3. 1 and 2 10 11 Case Francisco Q#3 Results Bone Mineral Density (BMD) Dual Energy X-ray Absorptiometry (DEXA) Scores T-Score Z-Score L1 -1.8 -0.7 L2 -1.7 -1.7 L3 -2.2 -2.2 Vitamin D Level 25-OH Vitamin D Result Normal 24 ng/ml 32-100 ng/ml Case Francisco Question #4 • Does this patient have osteoporosis? 1. Yes 2. No 3. Can’t tell 12 13 Osteoporosis Definitions • WHO Definition (DEXA): – Osteoporosis:T-Score -2.5 Std.Dev. – Osteopenia : T-Score -1.0 to -2.5 SD – Normal: T-Score -1.0 SD • Increase risk of fracture by 1.5-3.0 fold for each 1.0 SD decrease • Z-Score used in men <50 yrs, and premenopausal women Case Francisco Question #5 • Does this patient have Vitamin D deficiency? 1. Yes 2. No 3. Can’t tell 14 15 Vitamin D Deficiency • Definitions – Deficiency: – Insufficiency: 25 OH Vit D <20 ng/ml 25 OH Vit D 20-30 ng/ml • Vitamin D Replacement (“filling up the tank”) – Ergocalciferol 50,000 units orally twice weekly for 6-12 weeks ( 600,000 units total) • Vitamin D Maintenance – Cholecalciferol 800-2000 IU daily – Ergocalciferol 50,000 units every 2-4 weeks 16 Osteomalacia • Most important differential diagnosis for low BMD • Impaired bone mineralization • Symptoms: Weakness, fracture, pain, anorexia, weight loss • Major causes: severe vitamin D deficiency, phoaphate wasting • Treatment: vitamin D, phosphate; not bisphosphonates Case Richard Introduction • 51 y/o heterosexual male • Co-morbidities: – Hepatitis C with cirrhosis – Alcoholism • HIV well-controlled on AZT-3TC-EFV • Complications: – Hyperlipidemia, severe lipoatrophy with low BMI – Diabetes mellitus on glipizide 10mg bid, HgbA1c 6.8% 17 Case Richard Question #1 • Should this patient be screened for osteoporosis? 1. Yes 2. No 3. Dont know 18 Indications for Osteoporosis Screening in HIV • • • • • • • • • Low BMI Hypogonadism / postmenopausal Vitamin D deficiency: Osteomalacia Corticosteroid exposure Alcoholism Smoking Aging ? TDF exposure, ? VL AUC (yrs untreated HIV) 19 20 FRAX WHO Fracture Risk Assessment Tool: 10Year Risk of Fracture Risk Factors Age Gender Weight & height Previous fracture Parent hip fracture Current smoking Glucocorticosteroids exposure Rheumatoid arthritis Secondary osteoporosis Alcohol Femoral neck BMD Parameters W: 65 yrs, M: 70 yrs; 50-70 yrs if risks Female Low BMI As an adult, spontaneous or low trauma (dose dependent) >3 months @ 5mg prednisolone/day Confirmed diagnosis Presence of associated condition 3 units daily (8-10g/u) Gm/cm2 http://www.shef.ac.uk/FRAX/ 21 Case Richard Q#1 Results Bone Mineral Density (BMD) Dual Energy X-ray Absorptiometry (DEXA) Scores L1-L4 Femoral Neck Total Hip T-Score -1.9 -2.8 -2.0 Z-Score -1.6 -2.0 -1.7 Case Richard Question #2 • Does this patient have osteoporosis? 1. Yes 2. No 3. Can’t tell 22 23 Osteoporosis Definitions • WHO Definition (DEXA): – Osteoporosis:T-Score -2.5 Std.Dev. – Osteopenia : T-Score -1.0 to -2.5 SD – Normal: T-Score -1.0 SD • Increase risk of fracture by 1.5-3.0 fold for each 1.0 SD decrease • Z-Score used in men <50 yrs, and premenopausal women Case Richard Question #3 • What is the next step? 1. 2. 3. 4. Treat with a bisphosphonate Treat with calcium and viatmin D Evaluate for secondary causes of low BMD All (1, 2 and 3) 24 25 Causes of Secondary Low BMD COMMON IN HIV Vitamin D Deficiency 25-OH Vitamin D Level Phosphate Wasting Serum phosphate (urine fractional excretion) Hypogonadism M: testosterone; W: menstrual history; FSH/LH ADDITIONAL BASIC WORK-UP Hyperparathyroidism PTH, serum calcium Subclinical Hyperthyroidism TSH OTHERS • • • • Deficiencies: Calcium, Celiac Disease, Malabsorption, Malnutrition Endocrine: Cushing’s Syndrome, Adrenal Insufficiency, Diabetes Inflammation: HIV, Rheumatoid Arthritis, Inflammatory Bowel Disease, Heme & CA: Hemophilia, Lymphoma, Multiple Myeloma, Thalassemia 26 Case Richard Q#3 Results Test Result Normal 25-OH Vitamin D 36 ng/ml >30 ng/ml Serum phosphate 3.5 ng/dL 2.5-4.5 mg/dL PTH Serum Calcium TSH 18 pg/ml 9.4 mg/dL 0.99 mU/L 8.5-10.5 mg/dL 0.45-4.5 mU/L Testosterone? Case Richard Question #4 • What is the best test for evaluation of hypogonadism in HIV? 1. 2. 3. 4. Random total testosterone Morning total testosterone Random free testosterone Morning free testosterone 27 28 Regulation of Testosterone Only 2% is Free Testosterone Adapted from Braunstein GD. Basic and Clinical Endocrinology. 5th edition. Stanford, Conn: Appleton & Lange; 1997:422-452. 29 Alterations in SHBG Decreased SHBG Increased SHBG •Moderate obesity •Nephrotic Syndrome •Hypothyroidism •Glucocorticoids, progestins, anabolic steroids •Aging •Hepatic cirrhosis •Hyperthyroidism •Anticonvulsants •Estrogens •HIV Diagnosis of Androgen-Deficiency in Symptomatic HIV+ Men: Obtain “Morning Free Testosterone” 30 Case Richard Q#4 Results Test Result Normal 25-OH Vitamin D 36 ng/ml >30 ng/ml Serum phosphate 3.5 mg/dL 2.5-4.5 mg/dL PTH Serum Calcium TSH 18 pg/ml 9.4 mg/dL 0.99 mU/L 8.5-10.5 mg/dL 0.45-4.5 mU/L AM Free Testosterone 32 ng/dL 46-224 ng/dL Case Richard Question #5 • What is the next step? 1. Start testosterone enanthate 200 mg IM every 2 weeks 2. Start testosterone gel 1%, 5 g daily 3. Measure LH & FSH 4. Measure serum prolactin 5. Obtain pituitary MRI 31 32 Select Causes of Low Testosterone PRIMARY (Testicular) •Congenital •Chemo / radiation •Mumps / viruses •Trauma •Certain drugs SECONDARY (CNS) •Acute illnesses •Pituitary tumor / infiltration •Hemochromatosis •Cushing’s Syndrome •Cirrhosis •Morbid obesity •Certain drugs MIXED • AIDS • Liver failure • Uremia • Alcoholism • Aging • Corticosteroids Suggested Monitoring During Testosterone Treatment Test Symptom Assessment Testosterone Level PSA/DRE Hematocrit 33 1-2 3-6 Annually Goal/Comments months months Response versus X X X adverse effects Acute illnesses Mid-normal range X X X Urology eval: PSA >4 ng/ml or >1.4 rise in 12 months X X Hold therapy when hct >54 until safe level Case Richard Question #6 • You start patient on testosterone gel 1% (5 g/d) and calcium 1200 mg/d and vitamin D 800 IU/d. What else do you recommend? 1. No additional treatment. Repeat DEXA in 1 year. 2. Start bisphosphonate therapy 3. Start recombinant PTH therapy 34 35 Osteoporosis Therapies BISPHOSPHONATES Alendronate Risedronate Ibandronate Dose Frequency Daily Weekly Daily Annually (IV) Monthly Quarterly (IV) Adverse Effects • GI: Dyspepsia, pain, nausea • Jaw osteonecrosis (oversuppression of osteoclasts ?) Daily Weekly Zolendronate RECOMBINANT PARATHYROID HORMONE Teriparatide • Stimulates osteoblastic bone formation • Dose: daily subcutaneous injection • Reserved for patients with fractures on bosphosphonates or continued bone loss Osteoporosis Overall Management • Lifestyle changes: – Smoking cessation, alcohol reduction, weight bearing exercise • Rx options – Bisphosphonates – Hormones: estrogen or testosterone – Parathyroid hormones • Calcium + Vitamin D – 1200 mg calcium + 800 IU vitamin D 36 Case: Juan Introduction - 1 • 53 yr Hispanic MSM • HIV+ x 20 yrs, on ART since 2000 – VL <50: TDF-FTC-EFV – Mild lipoatrophy: face, buttocks, legs • Co-morbidities: – Mild HTN, normal lipids and renal, no smoking – Strong family history DM – BMI 27 kg/m2 37 Case: Juan Question #1 The patient’s labs show fasting glucose of 110 mg/dl. What should you do next? 1.Repeat a fasting glucose level 2.Order a 2 hour oral glucose tolerance test 3.Check a HgbA1c level 38 Case Juan Results • Plasma Fasting Glucose 108 mg/dL • 2 hour oral glucose tolerance test 167mg/dL • Hemoglobin A1c 6.4% 39 American Diabetes Association Definitions Test Pre-Diabetes Diabetes 1 Plasma Fasting Glucose (IFG: Impaired F.G.) 100-125 mg/dL, confirmed 125 mg/dL, confirmed 2 2 hour Oral Glucose Tolerance Test (OGTT) (IGT: Impaired G.T.) 140-199 mg/dL 200 mg/dL 3 Random plasma glucose -- 200 mg/dL w/ symptoms 4 HgbA1c 6.5% * 6.0-6.5% HgbA1c for Diabetes Diagnosis – Caveats: • Confirm with repeat measurement, unless #3 present • If hemoglobinopathy or increased RBC turnover: • Not valid, so diagnose with #1 and 2 40 HgbA1c Underestimates Glycemia in HIV+ Patients 450 HIV (n=100) - - - Control (n=200) 400 Glucose (mg/dL) 350 300 250 200 150 HgbA1c Discordance = 29mg/dL 100 50 0 4 5 6 7 8 9 HgbA1c (%) Kim P, et al. Diabetes Care, 2009; 32:1591-1593. 10 11 12 13 14 41 Case: Juan Question #2 The patient is diagnosed with “Pre-Diabetes”. You recommend? 1.Lifestyle modifications to lose 5-10% of body weight 2.Lifestyle modifications plus metformin 3.Lifestyle modifications plus pioglitazone 42 43 Evlauation of Glucose Disorders in HIV-Infected Patients Fasting Glucose (at HIV diagnosis, ARV initiation, and annually therafter < 100 mg/dL 100-125 mg/dL 125 mg/dL Repeat FG 125 mg/dL 2 hr OGTT No Yes 200 mg/dL < 140 mg/dL 140-199 mg/dL Normal Pre-DM: IFG alone Pre-DM: IFG/IGT Diabetes Mellitus Repeat FG annually Lifestyle Modifications Lifestyle Modifications Consider Metformin: if other risks Consider Pioglitazone: if lipoatrophy Lifestyle Modifications Rx: Metformin or Pioglitazone Brown, Clinical Care Options, 2008. 44 Metformin • Associated with 31% reduction in diabetes1 • Recommended for pre-diabetes (IFG & IGT) with any of the following:2 <60 yrs, BMI >35kg/m2, FH DM (1st-degree relative), Triglycerides, HDL cholesterol, HTN, A1c >6.0% • Contraindications / Complications: – – – – Renal insufficiency Hepatic failure Lactic acidosis with antiretrovirals Worsening of lipoatrophy3 1) Knowler WC, et al. NEJM 2002;346:393-403. 2) Nathan, Diabetes Care 2007. 3) Kohli et al, HIV Med. 2007;8:42-426. 45 Pros and Cons of Glitazones PROS CONS • Decreases risk of developing DM (82% risk)1 • CVD benefit (pioglit.) • Modest lipoatrophy benefit (~200-500gm) • • • • • • 1: Knowler, Diabetes, 2005 Expensive Weight gain Fluid retention CVD risk (rosiglit.) Osteoporosis Liver toxicity 46 Diabetes Risk Factors HIV-associated risk factors Classic type 2 diabetes risk factors • Obesity (abdominal) • Physical Inactivity • Genetic – Family history – Race/ethnicity • Older age • Dyslipidemia Insulin Resistance • Peripheral lipoatrophy • Reduced adiponectin • Increased liver/muscle fat • Inflammatory cytokines • Low testosterone • Oxidant stress • HCV infection • Protease inhibitors 47 Take-Home Application Pointers Co-Morbidity Management Renal Disease • Regularly monitor urinalysis and creatinine clearance; • Evaluate with FE PO4; spot urine protein:creatinine • Optimize management of DM, HTN, HVC, HBV • Adjust ARVs and other medications • ACE-I/ARB Osteoporosis • Screen based on age, hromonal status & risk factors • Evaluate for Vit. D (25-OH) and secondary causes • Manage with calcium, vit. D, wt-exercise; d/c smoking & alcohol; bisphosphonates 48 Take-Home Application Pointers Co-Morbidity Management Hypogonadism • Screen (free am test.) based on symptoms & risks • Evaluate for primary & secondary causes • Monitor treatment: Hct., PSA & exam, levels Diabetes • Monitor fasting glucose; OGTT &/or HgbA1c • Prevent / treat: diet, exercise, ? ARV changes • Pioglitazone for lipoatrophy, Metformin for other risks Cardiovascular Disease • • • • Agressive lifestyle changes (especially smoking) Manage co-morbidities (DM, HTN, lipids) Additive lipid-lowering therapies Aspirin daily, ? ARV selection or changes