Complicações Metabólicas e Ósseas da Infecção pelo HIV: Sugar and Bones

Transcription

1 Slide 1 Complicações Metabólicas e Ósseas da Infecção pelo HIV: Sugar and Bones Todd T. Brown, MD, PhD Associate Professor of Medicine and Epidemiology Division of Endocrinology, Diabetes, & Metabolism Johns Hopkins University Baltimore, Maryland, USA

2 Slide 2 Disclosures Dr Brown has served as a consultant to Gilead, ViiV Healthcare, Merck, Abbvie, EMD-Serono, and Theratechnologies.

3 Endocrine and Metabolic Conditions are Prevalent Among HIV-infected Persons Slide 3 HIV Osteoporosis Diabetes Mellitus Dyslipidemia Hypogonadism

4 Endocrine and Metabolic Conditions are Prevalent Among HIV-infected Persons Slide 4 HIV Osteoporosis Diabetes Mellitus Dyslipidemia Hypogonadism Aging

5 Endocrine and Metabolic Conditions are Prevalent Among HIV-infected Persons Slide 5 HIV Inflammation Osteoporosis Diabetes Mellitus Dyslipidemia Hypogonadism Aging

6 Endocrine and Metabolic Conditions are Prevalent Among HIV-infected Persons Slide 6 HIV Osteoporosis Diabetes Mellitus Dyslipidemia Hypogonadism Fracture CVD Frailty Aging

7 Slide 7 Objective To know the optimal evaluation and treatment of endocrine and metabolic problems in HIV-infected patients, focusing on osteoporosis and diabetes mellitus

8 Bones Slide 8

9 Fragility Fractures in Women Slide 9 and Men over 50 years Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72 Images from the National Osteoporosis Foundation

10 Fracture Prevalence/100 Persons Fracture Prevalence/100 Persons Fracture Prevalence in HIV-infected and non-hiv-infected Persons in MGH/Partners Healthcare System: Slide P=0.002 (overall comparison) P< (overall comparison) HIV Women Non-HIV HIV Men Non-HIV 8,525 HIV-infected 2,208,792 non HIV-infected patients Triant, JCEM,

11 Prevalence of Osteoporosis in HIVinfected Patients vs HIV-uninfected Controls: A Meta-analysis Overall prevalence of osteoporosis in HIV-infected patients 15% Study Odds ratio (95% CI) Slide 11 Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002) Knobel (2001) Loiseau-Peres (2002) Madeddu (2004) Tebas (2000) Teichman (2003) Yin (2005) Overall (95% CI) 5.03 (1.47,17.27) 4.26 (0.22,82.64) 4.51 (0.26,79.27) 2.11 (0.54,8.28) 3.52 (0.15,81.92) 5.13 (1.80,14.60) 4.28 (0.46,39.81) (1.80,494.92) 3.40 (0.19,61.67) (0.97,313.73) 2.37 (1.09,5.16) 3.68 (2.31,5.84) Brown, AIDS, Odds ratio 11

12 Pathophysiology and Risk Factors Slide 12 HIV Disease Factors Inflammation and Viral Proteins bone resorption bone formation Medication Factors Tenofovir (TDF) Certain PIs ART initiation ( 2-6% over 96 weeks) 12

13 Pathophysiology and Risk Factors Patient-Related Factors Low Body Weight Smoking Alcohol Use Opiate Use Hepatitis C Co-infection Physical Inactivity Hypogonadism Low Vitamin D Slide 13 13

14 Slide 14 To Screen or Not to Screen. DXA DXA 14

15 Slide 15 Case Presentation: AD 62 year old white male referred to LD clinic for body fat changes HIV diagosed in 1987, nadir CD4 22, from 1997 to 2002 on d4t/3tc/idv, currently TDF/FTC/EFV Hypogonadism on transdermal testosterone COPD (60 pack-year tobacco history), multiple steroid courses No history of fracture, no height loss 15

16 Slide 16 US National Osteoporosis Foundation (NOF) Guidelines for DXA Screening Those with a fragility fracture after age 50 Women 65 yrs, Men 70 yrs Younger postmenopausal women and men years with clinical risk factors for fracture Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose 5 mg prednisone or equivalent for three months) associated with low bone mass or bone loss 16

17 Recommendations for DXA Slide 17 Screening in Brazil

18 Slide 18

19 Slide

20 Slide 20 Case Presentation: AD Dual X-ray Absorptiometry T-score L1-L4-2.2 Femoral Neck -2.2 Total Hip

21 Slide 21 Definitions Functional Definition (DXA)- WHO Definition Osteoporosis: T-score < -2.5 Osteopenia: T-score= -1.0 to -2.5 Normal: T-score > -1.0 Risk of fracture by x for each SD decrease Caveats: Z-score ( <-2.0) used in men < 50 years and premenopausal women BMD explains only about 50% of fracture risk 21

22 Slide 22 Secondary Causes of Low BMD Vitamin D deficiency 25 OH Vit D Hyperparathyroidism PTH, Ca++ Subclinical Hyperthyroidism TSH Hypogonadism Males: Free Testosterone Phosphate wasting Fractional Excretion of Phosphate Idiopathic Hypercalciuria 24 hr Urinary Calcium Celiac Sprue Tissue Transglutaminase Multiple Myeloma Serum Protein Electrophoresis Mastocytosis Serum Tryptase Cushing s Syndrome 24 hr Urinary Free Cortisol

23 Secondary Causes of Low BMD Vitamin D deficiency 25 OH Vit D Phosphate wasting Fractional Excretion of Phosphate Slide 23 23

24 Slide 24 Osteomalacia Impaired bone mineralization Accompanied by weakness, fracture, pain, anorexia, and weight loss Treated with Vitamin D, Ca++, +/- phosphate, not bisphosphonates Most important differential diagnosis for low BMD 24

25 US NOF Guidelines: Who to Treat* Slide 25 Those with hip or vertebral fractures Those with BMD T-scores -2.5 at the femoral neck, total hip, or spine by DXA Those with T-score b/t -1 and -2.5 (osteopenia) at above sites AND 10- year hip fracture probability 3% or 10- year all major osteoporosis-related fracture 20% based on FRAX model *applies to post-menopausal women and men 50 years 25

26 Slide

27 Slide 27 27

28 Management Options Slide 28 General recommendations Calcium/vitamin D supplementation Smoking cessation, Alcohol reduction Weight-bearing exercise Assess fall risk (Are you worried about falling?) Strength/Balance Training Rx options Bisphosphonates Selective estrogen receptor modulator Estrogen PTH analogue

29 Considerations When Choosing Between Bisphosphonates Slide 29 Alendronate Risedronate Ibandronate Zoledronate Efficacy Cost (1 year) $350 $350 $1200 $1100 Compliance (oral)/ + (IV) + GI Side Effects Yes (20%) Yes (20%) Yes (oral)/no(iv) Osteonecrosis of the Jaw Acute Phase Reaction No Yes Yes Yes Yes No No No (oral)/yes(iv) Yes (~10%) Atrial Fibrillation???? Esophageal Cancer Atypical Femoral Fracture??? No Yes Yes Yes Yes 29

30 Would you switch him off of Slide 30 TDF? 1. Yes 2. No

31 ART Management Slide 31

32 OsteoTDF Study Switch from TDF to ABC in Osteopenia/Osteoporosis Changes in Spine and Hip BMD at Week 48 Two-centered, randomized pilot study in virologically suppressed subjects receiving TDF with osteopenia/osteoporosis. Twenty six subjects switched to ABC and 28 continued TDF. Slide 32 In this small cohort, switching from TDF to ABC resulted in increases in hip and decreases in spine BMD at week 48. Negredo E, et al. J of Antimicrob Chemother. E-published August 13, doi: /jac/dku300.

33 Mean % Change from BL at Week 48 TROP Study (Switch): TDF to RAL Switch from TDF to ABC in Osteopenia/Osteoporosis Changes in Spine and Hip BMD at Week 48 Slide 33 Open-label, non-randomized study comparing BMD changes at week 48 in patients with osteopenia/osteoporosis at baseline on TDF, switching to RAL with boosted PI (N=37). Changes in Spine and Hip BMD at Week % 2.5% P <0.001 P <0.001 * Left total hip In this small switch cohort, there are increases in spine and hip BMD at week 48. Bloch M, et al. HIV Medicine 2014;15:

34 Median % Change (Q1,Q3) From Baseline Change in Spine and Hip Bone Mineral Density BMD Changes From Baseline to W e ek 48 Spine Hip 6 E/C/F/TAF % p <0.001* 2 0.9% p <0.001* Weeks E/C/F/TAF n= Weeks Median percentage changes (Q1, Q3) in hip and spine BMD from baseline to Week 48 were 0.9% (-0.3, 2.7) and 1.9% (-0.3, 4.3), respectively *Two-sided Wilcoxon signed-rank test. Posniak, CROI,

35 Diabetes Slide 35

36 Slide 36 Why Care about Diabetes? Very common with rapidly increasing prevalence One of leading causes of cardiovascular disease, blindness, ESRD, amputations, hospitalizations Common in HIV-infected Populations Diabetes can be controlled, but management is complicated and requires individualization

37 Slide 37 Diabetes Prevalence in Brazil Almeida-Pititto, Diabetes, Met Syn, Obesity, 2015

38 Slide 38 Pathogenesis of Diabetes in HIV-infected Patients Antiretroviral Medication Factors Thymidine analogues, older PIs HIV Factors Residual immune activation/inflammation Host Factors Adiposity HCV Genetic Factors: Family History, Race Concomitant Medications: Corticosteroids/Aytpical Antipsychotics

39 Slide 39 Case 53 year-old African American Male, HIV+ for 20 years, on ART since 2000 HIV RNA< 50 FTC/TDF/ EFV Mild/moderate lipoatrophy of face/buttocks/thighs Mild HTN, Normal lipids, no smoking Strong family history of DM BMI 27 kg/m 2

40 Slide 40 Diabetes Screening Who? IDSA: Prior to ART, within 4-6 weeks after ART initiation, every 6-12 months thereafter

41 Slide 41 Caveats for the use of HgbA1c for diagnosis For conditions with abnormal red cell turnover.., the diagnosis of diabetes must employ glucose criteria exclusively ADA Clinical Practice Recommendations, 2016

42 Glucose (mg/dl) Slide 42 HbA1c Underestimates Glycemia in HIV-infected Persons HIV (n=100) Control (n=200) mmol/l Kim, Diabetes Care, 2009 HBA1C (%)

43 Slide 43 How? Fasting Glucose Diabetes Screening in HIVinfected Persons If mmol/l ( mg/dl), consider 75 g OGTT Avoid A1c for screening (particularly in those on ABC, low CD4, PIs, high MCV)

44 Case 53 year-old African American Male, HIV+ for 20 years, on ART since 2000 VL< 50 FTC/TDF/ EFV Mild/moderate lipoatrophy of face/buttocks/thighs Mild HTN, Normal lipids, no smoking Strong family history of DM BMI 27 kg/m 2 Fasting Glucose 8.05 mmol/l (145 mg/dl) (confirmed) A1c 6.8% Slide 44

45 Slide 45 After DM is diagnosed, what should be the next steps? Lifestyle Modification First-line Drug Combination Therapy

46 Cumulative Incidence of Diabetes (%) Lifestyle Modifications for Slide 46 Prediabetes Diabetes Prevention Program: 150 minutes/week of exercise and caloric restriction goal: 7% weight loss 58% diabetes incidence Lifestyle Placebo Year 4.5 Knowler WC, et al. N Engl J Med. 2002;346:

47 Slide 47 Effect of Cutting 500 cal/day over 8 weeks in Obese Persons Effect on Weight Effect on Inflammation Hermana, Endocrine, 2009

48 Slide 48 After DM is diagnosed, what should be the next steps? Lifestyle Modification First-line Drug Combination Therapy

49 Slide 49 Metformin: THE First Line Drug

50 Slide 50 Metformin: Pros and Cons Pros A1c ~1% Long Track Record No Hypoglycemia No Weight Gain? CVD benefit Cons GI side effects Lactic Acidosis (rare) Contraindications: CKD (Scr>1.4 in women, 1.5 men) Hypoxia Decompensated Liver Disease Severe CHF Alcohol Abuse Past H/O Lactic Acidosis? Worsening Lipoatrophy

51 Slide 51 After DM is diagnosed, what should be the next steps? Lifestyle Modification First-line Drug Combination Therapy

52 Slide 52 What drug to add next? Sulfonylureas Glitazones (Pioglitazone) Insulin GLP-1 Analogues DPP-IV Inhibitors SGLT-2 Inhibitors Incretins

53 Slide 53 Sulfonylureas: Pros and Cons Pros A1c ~1% Long Track Record Microvascular Events Cost* ($7/month) Cons Weight Gain Hypoglycemia High Failure Rate *lowest price for average dose 30 day fill at goodrx.com

54 Slide 54 Pioglitazone: Pros and Cons Pros A1c ~1% No Hypoglycemia? CVD benefit HDL, TGs Liver Fat? Inflammation Low Failure Rate Modest effect on lipoatrophy Cons Weight Gain Fluid Retention/CHF Macular Edema Osteoporosis/Fracture Bladder Cancer (~ g)

55 Slide 55 Insulin: Pros and Cons Pros A1c: Unlimited Microvascular events Cons Hypoglycemia Weight Gain? Mitogenic effects Injectable

56 Slide 56 Starting Insulin in Type 2 DM Start with bedtime glargine, detemir, or NPH (10-15 units, increase by 2-3 units q 3 days until fasting is < 6.6 mmol/l (120 mg/dl)) Add prandial insulin if not at goal. Recommended as first line if A1c >9%, severe liver disease/kidney disease, hypertriglyceridemia

57 Slide 57 GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins GLP-1 secreted upon the ingestion food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucosedependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

58 Slide 58 Incretins GLP-1 Analogues exenetide (Byetta) liraglutide (Victoza) Exenetide LAR (Bydureon) dulagltide (Trulicity) albiglutide (Tanzeum) Lixisenatide (Lyxumia) DPP-IV Inhibitors sitagliptin (Januvia) saxagliptin (Onglyza) vildagliptin (Galvus) linagliptin (Trajenta) alogliptin

59 Slide 59 GLP-1 Analogues: Pros and Cons Pros A1c ~1% No Hypoglycemia Weight Loss? Inflammation? CVD benefit Cons GI Side Effects? Pancreatitis/ Pancreatic Cancer Risk

60 DPP-IV Inhibitors: Pros and Slide 60 Cons Pros No hypoglycemia Weight Neutral? Inflammation Cons A1c ~0.5% GI Side Effects? Pancreatitis/ Pancreatic Cancer Risk Hypersensitivity reaction No CVD benefit Heart Failure

61 Slide 61 Sodium Glucose Co-transporter 2 Inhibition: The gliflozins Insulin-independent reduction in glucose dapaglifozin canagliflozin empagliflozin 0.5-1% A1c reductions Weight loss (~2kg) Lowers BP No hypoglycemia urinary tract infections/candidiasis Polyuria/dehydration DKA risk? CVD benefit (empagliflozin, NEJM, 2015)

62 Slide 62 What drug to add next? Sulfonylureas Glitazones (Pioglitazone) Insulin GLP-1 Analogues Incretins DPP-IV Inhibitors SGLT-2 Inhibitors

63 Questions How should I diagnose diabetes in the HIVinfected patient? After the diagnosis is made, what should be the next steps? What should be the glycemic target? What else should I be doing to prevent complications? Slide 63

64 Slide 64 What should be the glycemic target? < 7%

65 UKPDS: MI and Microvascular Endpoints Associated With Increasing HbA 1c Slide 65

66 Meta-Analysis of Glycemic Slide 66 Control and CVD in Diabetes 10% Risk Reduction for CVD No Benefit on CVD Mortality 2-fold Increase Risk of Severe Hypoglycemia with Intensive Control Kelly, Annals of Int Med, 2009

67 Slide 67 Previous Tight DM Control and CVD: The Legacy Effect 10 Year Follow-Up: UKPDS Study Blood Sugar Control in Follow-up Risk of MI over 10 years of Follow-up Holman, NEJM, 2008

68 Slide 68 A1c Goal < 7% Individualization is Key: Tighter Control (A1c %): Younger, Healthier Looser Control (A1c %+): Older, Hypoglycemia Prone, Co-morbidities

69 What else should I be doing to prevent Slide 69 complications?: Microvascular Retinopathy: Yearly ophthalmologic exams Nephropathy: BP Control Spot Urine Microalbumin every 6-12 months ACE-I/ARB with microalbuminuria or HTN Lipid Control Neuropathy: Foot exams every 6-12 months Instruction in foot care Podiatry if evidence of neuropathy

70 What else should I be doing to prevent Slide 70 complications?: Macrovascular Attention to all CV risk factors A: Anti-platelet therapy B: Blood pressure C: Cholesterol D: Diabetes/Glucose Management S: Smoking Cessation Steno-2 Trial (Gaede, NEJM, 2003): CV Events by 50% with intensive control of all CV Risk Factors

71 Slide 71 Conclusions Osteoporosis DXA screening in HIVinfected patients in men > 50 yrs and postmenopausal women Treatment guidelines should follow those established for the general population Remember secondary causes Consider switches of TDF in those at higher risk Diabetes Regular DM screening Avoid A1c for diagnosis Lifestyle changes are critical Metformin first Individualize 2 nd and 3 rd line-drugs Goal < 7% in most, but should be individualized Multiprong approach to prevent complications