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Metabolic Complications in HIV: Do they still matter?

Metabolic Complications in HIV: Do they still matter?. David Alain Wohl, MD The University of North Carolina Chapel Hill. Ascent of Metabolic Complications. Osteopenia/Osteoporosis. Aging/Obesity. Mitochondrial Toxicity. Body Fat Redistribution. Inflammation/CVD.

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Metabolic Complications in HIV: Do they still matter?

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  1. Metabolic Complications in HIV:Do they still matter? David Alain Wohl, MD The University of North Carolina Chapel Hill

  2. Ascent of Metabolic Complications Osteopenia/Osteoporosis Aging/Obesity Mitochondrial Toxicity Body Fat Redistribution Inflammation/CVD

  3. Ascent of Metabolic Complications Osteopenia/Osteoporosis Aging/Obesity Mitochondrial Toxicity Body Fat Redistribution Inflammation/CVD

  4. 1. The Practical2. The Nearly Impossible

  5. 1. The Practical2. The Nearly Impossible

  6. SPIRIT: Study Design • Primary Endpoint: • Non-inferiority (12% margin) to PI + RTV + 2 NRTIs by FDA snapshot analysis HIV-1 RNA <50 c/mL at 24 weeks FTC/RPV/TDF FTC/RPV/TDF n=317 HIV-1 RNA <50 copies/mL Stable PI + RTV + 2 NRTIs ≥6 months On 1st or 2nd regimen No prior NNRTIs No known genotypic resistance to study ARVs 2:1 PI + RTV +2 NRTIs FTC/RPV/TDF n=159 24 weeks 48 weeks Primary Endpoint Secondary Endpoint Palella F, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.

  7. SPIRIT: Outcomes at Week 24 (FDA Snapshot Analysis – ITT Population) Change in CD4 count (cells/mm3) : FTC/RPV/TDF +20 vs. PI+RTV +32 (P=0.28) Palella F, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.

  8. 192 194 121124 163173 5350 SPIRIT: Changes from Baseline to Week 24 in Fasting Lipids P<0.001* Mean Baseline Values 3.864.08 Conclusion: Switching to FTC/RPV/TDF resulted in a greater improvement in 10-year Framingham Risk Score at Week 24 compared to PI + RTV + 2 NRTIs (P=0.001) Palella F, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.

  9. SPIRIT:Adverse Events Gastrointestinal Symptoms Switch to RPV: Significantly less fatigue, memory loss, headache, depression, and increased treatment satisfaction (all P<0.03) P<0.001 P<0.001 Palella F, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.

  10. ASSURE Study Design • Open-label, multicenter, non-inferiority study of subjects with confirmed HIV RNA <75 c/mL • All subjects had ≥6 months’ treatment with TDF/FTC + ATV/r as last regimen • Primary endpoint: proportion of subjects with HIV RNA <50 c/mL at Week 24 by the time to loss of virologic response (TLOVR) algorithm 2:1 Randomization ABC/3TC + ATV n=199 TDF/FTC + ATV/r N=296 Protocol-specified HAARTa TDF/FTC + ATV/r n=97 ART naive ≥6 months 0 24 48 Weeks a First or second regimen switch allowed for any reason EXCEPT virologic failure. Wohl D, et al ICAAC 2012

  11. Primary Analysis:Proportion with HIV-1 RNA <50 c/mL by TLOVR • ABC/3TC + ATV is non-inferior to TDF/FTC + ATV/r based on a 12% margin • Adjusted treatment difference: 0.33% 95% CI: (-7.97%, 8.64%) Wohl D, et al ICAAC 2012

  12. Inflammatory Biomarkers • No significant change from BL to Week 24 (all P>0.05) was seen within treatment groups • No significant difference in change from BL to Week 24 (all P>0.05) between treatment groups hsCRP IL-6 D-Dimer Wohl D, et al ICAAC 2012

  13. Urine β2 Microglobulin/Creatinine Ratio • The ratio declined significantly (P<0.001) from BL for the ABC/3TC + ATV arm, with no significant change (P=0.871) in the TDF/FTC + ATV/r arm • There was also a significant difference (P<0.001) between groups Geometric mean urine β2 microglobulin/creatine ratio, μg/g Wohl D, et al ICAAC 2012

  14. Bone Alkaline Phosphatase (BAP) Bone Biomarkers • The bone biomarkers all declined significantly (P<0.001) from BL for the ABC/3TC + ATV arm, with no significant change for the TDF/FTC + ATV/r arm • There was also a significant difference (P<0.001) between groups Parathyroid Hormone (PTH) C-Telopeptide Osteocalcin Wohl D, et al ICAAC 2012

  15. Emergent/Worsening Lab Toxicities (≥5% in Any Treatment Group) Wohl D, et al ICAAC 2012

  16. Atazanavir and Gall Stones • 14 cases of cholelithiasis developing in patients receiving ATV (median duration of ATV = 41 months (range 1-90), 12 on ritonavir, 7 were HCV co-infected). • 11 had stones analyzed • 8 were ATV on spectrometry Rakotondravelo S, et al. Clinical Infectious Diseases 2012;55(9):1270–72

  17. GS 114: Cobicistat vs. Ritonavir as ATV Pharmacoenhancers Randomized, Double-blind, Double Dummy, Active-controlled, International Study ATV + COBI + FTC/TDF (n=350) Placebo: RTV Treatment Naïve HIV-1 RNA ≥5,000 c/mLAny CD4 cell counteGFR ≥70 mL/min ATV + RTV + FTC/TDF (n=350) Placebo: COBI 48 Weeks 192 Weeks Primary EndpointSnapshot analysis (HIV-1 RNA <50 c/mL)Non-inferiority margin: 12% Gallant J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0103.

  18. GS 114: Primary Endpoint of HIV-1 RNA <50 c/mL by FDA Snapshot at Week 48 (ITT) ATV + COBI + FTC/TDF was non-inferior to ATV + RTV + FTC/TDF at Week 48 • Genotypic resistance at VF: Cobi/ATV 2/12 M184V/I vs. RTV/ATV 0/12 Gallant J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0103.

  19. Study 114:Changes in Fasting Lipids at 48 Weeks P=0.081 P=0.32 P=0.69 P=0.063 Gallant J, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0103.

  20. GS 114: Adverse Events Gallant J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0103.

  21. STARTMRK:Lipid Changes at 5 Years Fasting Lipid Levels at Baseline and Week 240 as Compared with NCEP Goals (≤200 mg/dL) (≤150 mg/dL) (≤100 mg/dL) (≥40 mg/dL) Rockstroh J, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.

  22. Fat Redistribution inAfrican Americans on RAL/TDF/FTC • Single arm 104 week study of RAL/TDF/FTC in 30 African Americans • Age 38, 85% male, BMI 38, CD4 323, VL 30k at BL • VAT, SAT, single slice CT at L4-5, DEXA, BMD, lipids, HOMA-IR • Results • Significant rise in VAT, SAT, trunk fat, limb fat and overall fat from BL • BMD fell slightly but significantly from BL  • 1.3 to 1.28  • No changes from BL in non-HDL-C, fasting triglycerides or HOMA-IR • Limb, trunk, and abd fat increases with RAL/TDF/FTC in AAs P=0.004 P=0.002 for 104 wks vs BL P=0.002 P=0.003 for 104 wks vs BL Wohl D, Young L, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEPE0103.

  23. Inflammatory Marker Changes with NRTI Switches • Patients suppressed on ABC/3TC based regimen (majority with PI/r) randomized to stay (n=13) vs. switch to TDF/FTC (n=14) • Conclusion: switching from ABC/3TC to TDF/FTC-based ART insuppressed patients may significantly reduce inflammation Alozie O, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. THPE093.

  24. 1. The Practical2. The Nearly Impossible

  25. PLWHA live with greater number of co-morbid conditions • ALIVE Cohort (Current and former IDU in Baltimore) • HIV+ more likely to have co-morbid condition (Odds Ratio 1.50; 95% CI 1.13–1.99) • Accounting for age, HIV associated with liver disease, anemia, obesity, and kidneydysfunction but not diabetes, COPD, or HTN. • Many under-diagnosed Salter M et al , CID 2011

  26. The role of obesity • US Military Natural History Study (1985-2004) • 1682 newly diagnosed with HIV • 37% overweight; 9% obese Crum-Cianflone N, et al , Plos 1, 2010

  27. Central Obesity and Frailty • Study of 40 HIV+ men and women, age 50+ • Median CD4 569, mean BMI 29 • 60% considered frail • Frail had a greater BMI, fat mass, and truncal fat with lipodystrophy (DXA) Krupa S, et al. J Am Geriatr Soc, 2012.

  28. Abdominal Visceral Fat Is Associated with Clustering Of Athero-Inflammatory-Thrombotic Risk Factors Atherogenic dyslipidemia  Triglycerides  HDL-cholesterol  Cholesterol/HDL-cholesterol ratio "Normal" LDL-cholesterol but apo B Small, dense LDL and HDL Postprandial hyperlipidemia Inflammation Insulin resistance Insulin resistance Hyperinsulinemia Hyperglycemia Type 2 diabetes Lipid core Thin fibrous cap Thrombotic state  PAI-1  Fibrinogen CORONARY ATHEROSCLEROSIS UNSTABLE PLAQUE Inflammatory state  CRP  Cytokines  risk of acute coronary syndrome Abdominal obesity Metabolic risk factors Despres JP. Ann Med 2006.

  29. Obesity and Inflammation Sun Cohort - N=750 HIV+ with CD4 100-500 if ART naïve or >100 if on ART Conley L, et al. 19th IAC; Washington, DC; July 22-27, 2012

  30. Obesity and Inflammation In univariate analysis, characteristics associated with increased BMI category include: Female gender; black race; total cholesterol; ApoE; insulin; leptin; interleukin-6; hsCRP; TNF-alpha; D-dimer; HOMA-IR; and cIMT Conley L, et al. 19th IAC; Washington, DC; July 22-27, 2012

  31. The role of obesity • Smaller increases in CD4 cells with ART in obese vs. normal weight (Crum-Cianflore N et al. AIDS 2010) • Central obesity associated with neurocognitive decline in HIV+ participants of CHARTER Cohort (McCuthen JA, et al. Neurology 2012) • Increased BMI associated with less partner rejection and condom use among MSM placing personal ads for same-sex partners. (Moskowitz D and Seal D. Arch Sex Behav 2009)

  32. Plate Method www.choosemyplate.gov

  33. Aortic Inflammation • Cross sectional study of fluorodeoxyglucose positron emission tomography (FDG-PET) to detect metabolic active cells, particularly macrophages, in the arterial wall as a measure of arterial inflammation. • 27 HIV-positive patients without known cardiovascular disease (CVD), on stable ART • 27 HIV-negative individuals without known CVD and matched to the HIV+ group for age, gender and Framingham Risk Score (FRS) for 10-year risk of CVD • 27 HIV-negative controls with known atherosclerotic disease, matched to HIV+ group by gender S Subramanian, et al. JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698

  34. Participants • The HIV+ patients had a mean CD4 of 592/mm3 and almost all had either undetectable (74%) or low level plasma HIV RNA levels. • Average age of the participants was 52 years for the HIV+ group, 54 years for the controls without CVD, and 69 years for the controls with CVD. • Coronary calcium scores were high in the controls with CVD, practically zero among the controls without CVD and in between for the HIV+ group. S Subramanian, et al. JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698

  35. From: Arterial Inflammation in Patients With HIV JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698 Figure Legend: 18F-FDG-PET indicates 18fluorine-2-deoxy-D-glucose positron emission tomography; CT, computed tomography; SUV, standardized uptake value. The FDG uptake was measured from a point distal to the origin of coronary vessels to avoid myocardial spillover. 18F-FDG-PET/CT imaging of the ascending thoracic aorta was performed according to validated, reproducible methods. A, To determine the TBR of the aorta, regions of interest are drawn around the aorta in the axial position. This is repeated along the length of the aorta (every 5 mm along the long axis of the vessel). A mean arterial SUV is derived from the average of the maximum SUV values in serial axial measurements (1.71 in this example). The venous background SUV is derived from 10 measurements obtained in the superior vena cava. B, TBR is calculated by dividing the mean arterial SUV by the mean venous SUV (TBR = 3.42 in this example). The SUV is the decay-corrected tissue concentration of FDG (in kBq/mL) divided by the injected dose per body weight (kBq/g). Date of download: 10/23/2012

  36. From: Arterial Inflammation in Patients With HIV JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698 Figure Legend: 18F-FDG-PET indicates 18fluorine-2-deoxy-D-glucose positron emission tomography; CT, computed tomography; FRS, Framingham risk score; HIV, human immunodeficiency virus; SVC, superior vena cava; TBR, target-to-background ratio. There is increased aortic PET-FDG uptake (red coloration) in a participant infected with HIV compared with a non-HIV FRS-matched control participant. Neither participant had known heart disease. For each participant, the FRS was low with a score of 2 and calcium was not present on the cardiac CT scan. Neither participant was receiving a statin. A indicates anterior-posterior orientation and F, foot-head orientation.

  37. S Subramanian, et al. JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698

  38. Low Dose ASA Reduces Platelet Activity and Immune Activation • Platelet aggregation (PA) study in 25 HIV+ pts on ART and 29 HIV- controls • Response to stimuli w/ ADP, AA, and w/o stimuli • Repeat after 1 week low dose ASA • HLADR+CD38+CD8 cells measured • Results • Greater PA in HIV+ vs. HIV- (P<0.05 for each) • Significant reduction after low dose ASA (P<0.01 for each) • Sig decline in HIV+ pts in CD38+ cells, not in HIV- T Cell Activation O’Brien M, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THAB0202.

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