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Metabolic Complications of HAART

Metabolic Complications of HAART. Asilomar Faculty Development Conference 15 September 2009 Ronald Wilcox MD FAAP Program Developed by the Delta AETC. Principal Investigator/Program Director: Ronald D. Wilcox MD FAAP. ROUND ONE. “Sugar”. DM Part Deux. Brittle Bones.

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Metabolic Complications of HAART

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  1. Metabolic Complications of HAART Asilomar Faculty Development Conference 15 September 2009 Ronald Wilcox MD FAAP

  2. Program Developed by the Delta AETC Principal Investigator/Program Director: Ronald D. Wilcox MD FAAP

  3. ROUND ONE “Sugar” DM Part Deux Brittle Bones Too Much, Too Little Da’ Lipid Dilemma $100 $100 $100 $100 $100 $200 $200 $200 $200 $200 $300 $300 $300 $300 $300 $400 $400 $400 $400 $400 $500 $500 $500 $500 $500

  4. 100 Class of anti-retrovirals most commonly associated with causing insulin resistance

  5. Insulin Resistance in HIV Most common thought: protease inhibitors Best way to measure insulin resistance is hyper-insulinemic euglycemic clamp Ex: 1 dose of indinavir  30% decrease in insulin sensitivity in HIV- subjects Mechanisms: 1. Reduction of glucose uptake in adipocytes by altering adipogenic proteins 2. Halving of GLUT4 translocation by noncompetitive reversible binding 100

  6. 200 Pneumocystis jiroveci treatment that is a pancreatic beta cell toxin

  7. 200 Pentamidine Second line therapy for severe PcP Dosed at 4 mg/kg IV daily Shown to initially stimulate beta cells of the pancreas  cell death possibly Should obtain accuchecks q6 hours while on this therapy to monitor for hypoglycemia and hyperglycemia with ketoacidosis

  8. 300 In a rat model, Zhang et al (2009) demonstrated an increased incidence of apoptosis in this type of cells triggered by exposure to protease inhibitors

  9. 1. fa/fa rats - exposed to PIs for 7 weeks  found increased apoptosis of the beta cells of the pancreas. 2. Exposed insulinoma cells and human pancreatic cells in vitro to 48-96 hours of RTV, LPV, ATV, or TPV  Greater cell death and reduced insulin-secretory capability. Exposure to the PIs led to activation of mitochondria-associated caspase-9, promoting release of cytochrome c leading to cell death. 300

  10. 400 Initial results of WIHS study in regards to effects of PIs on DM incidence AND Two races identified as having highest risk for DM development by the Swiss HIV Cohort Study

  11. 400 DM in HIV+ Women (WIHS) and Swiss HIV Co-hort Study • WIHS: • Initial cohort study: • 2.8% incidence in PI-receiving women • 1.2% those who had not received cART • 1.4% in controls - higher overweight incidence in HIV- women 33 vs 23% • Later review: • No difference between the HIV+ and HIV- women • NRTI Exposure > 3 years risk to 2.6 fold • Swiss HIV cohort study: • Asian ethnicity: 4.9 fold risk • Black ethnicity: 2.2 fold risk

  12. 500 When comparing cART-receiving HIV+ persons to HIV-uninfected persons, Brown et al in Arch Int Med in 2005 reported this amount increase in relative risk of development of DM (expressed as fold change)

  13. 500 Incidence of DM • Pre-HAART: Rare in HIV+ persons • As HIV+ patients’ BMIs have increased, so has the incidence of DM • One study reported diabetes incidence in PI recipients with lipodystrophy of 2% that rose to 7% after 14 months (0.5% in HIV- controls) • Brown et al • Prospective study over 4 years • 10% of HIV+ cART recipients developed DM whereas only 3% of HIV- men did. • After adjusting for age and BMI, there was a 4-fold increase in relative risk

  14. 100 Co-infection common in those with HIV that increases the likelihood of DM development

  15. 100 Risk Factors for DM in HIV • Butt A et al. AIDS 2009; 23(10): 1227-34 • 3227 HIV+ and 3240 HIV- VA patients • HIV+ persons: more likely to be younger, HCV Ab +, black males, with a lower BMI • Increasing age or BMI and minority race greatest risk factors among all veterans • HCV co-infection and use of nRTIs and NNRTIs (but not PIs) were associated with a higher risk of DM in HIV+ • Increasing alcohol use and hx of drug use negative predictors of DM • Compared to non-drinkers, HIV+ persons who drank 31-60 drinks per month had an OR of 0.40

  16. 200 nRTI associated with increased insulin resistance

  17. 200 IR and nRTIs • Stavudine • Increased truncal fat • Reduced peripheral fat • Increased plasma insulin levels • Effects only partially reversible • Lipoatrophy  decreased secretion of 2 important adipokines: leptin and adiponectin (which are both involved in glucose metabolism)

  18. 300 Recommended first line therapy for insulin resistance in HIV

  19. 300 Therapeutic options for IR in HIV • Metformin first choice therapy • Significantly decreases plasma insulin, BMI, and diastolic BP • No increased incidence in lactic acidosis • Use cautiously in those with lipoatrophy • Cannot use in those with impaired renal function (Cr > 1.4) • Glitazone sisters (Pio and Rosi) effectiveness in HIV+ << HIV- although have been shown to increase subQ fat in HIV- • Sulfonylureas – low dose when given with ritonavir due to increased levels • Therapy overall is same; insulin use lower in those diagnosed with DM after their HIV diagnosis

  20. 400 As evaluated at the CORE Center, the discrepancies seen in meeting ADA goals between HIV+ men and women for each of the following parameters: HbA1C Lipid levels Aspirin use

  21. 400 Meeting of ADA Goals in HIV • Adeyami et al. CID 2009; 49: 799-802 • 216 HIV+ patients of CORE Center evaluated • ADA Goals: • HbA1C < 7.0% • BP < 130/80 • Total cholesterol < 200 • LDL < 100 • TG < 150 • HDL > 40 in men, > 50 in women • Aspirin use in all

  22. 400 Meeting of ADA Goals in HIV • DM diagnosed a mean of 3 years after HIV diagnosis • Women at 47, men at 52 (p=.001) • Women had higher BMI (30.9 vs 27.3,p<.001) • Patients with undetectable VL more likely to meet HDL goal but less likely to meet TC or LDL goals • BP goals met in 56% of clients but less likely if on HAART

  23. 100 nRTI most commonly associated with osteopenia in studies

  24. 100 Tenofovir and Bone Loss • Inhibits mineralization of new bone, demonstrated in assays of the hip and spine • Associated with renal phosphate wasting • Appears to be worsened if vitamin 25(OH) D levels are low  increased PTH  bone resorption • Some authors have proposed that all patients on tenofovir should receive calcium and vitamin D supplementation

  25. 200 Effects of the Protease Inhibitor class and Zidovudine on bone mineral density

  26. 200 Zidovudine and PIs • Protease inhibitors as a class = increased incidence of osteopenia and osteoporosis • Zidovudine shown to induce osteoclastogenesis  increased bone resorption • Some studies suggest any HAART therapy may increase bone loss (next slide) although most suggest less NNRTI involvement • Duvivier et al (AIDS 2009, 23:817-24): lumbar spine BMD over 48 weeks decreased 4.9% in patients on LPV/r or IND/r versus 1.5% loss in those on NNRTI-based regimen BUT was equal loss in hip assay

  27. 200 NNRTIs vs PIs and Bone Loss • Brown Todd et al. JAIDS 2009 Aug 15; 51(5): 554-560 • 155tx-naïve patients randomized 1:2 to receive EFV or LPV/r with ZDV/3TC for 96 weeks • LPV/r arm – if had VL < 50 three times in weeks 24-48, ZDV/3TC was discontinued (89% by week 32) • Lower baseline total BMD assoc with lower weight, non-black race, and lower baseline HIV RNA levels • At week 24: LPV/r arm 0.7% decrease in BMD versus 0.6% in EFV arm. • At week 96: LPV/r arm (~90% monotherapy for average of 68 weeks) 2.5% decrease versus 2.3% decrease in EFV/ZDV/3TC arm • Authors’ conclusion: No difference in tx type

  28. 300 Proportion of treatment-naïve HIV-infected persons with osteoporosis or osteopenia

  29. 300 Tx-Naïve Patients • Many studies 1/3 of treatment-naïve HIV+ persons have osteopenia or osteoporosis • Thought to be due to chronic inflammation from HIV infection which may have direct effects on osteoclast activity • Control of viral load has shown a reversal of this effect in some studies

  30. 400 Component of the HIV virus associated with increasing osteoclast activity

  31. 400 gp120 • Given to HIV- persons at levels similar to someone with untreated HIV infection (Modarresi et al, Amer J Path 2009) • Induced expression of the osteoclast differentiation factor RANKL in CD4+ t-cells  increased bone resorption • Some studies have shown a decrease in HIV viral loads lead to an increase in bone density • Viral Protein Vpr also reported to have this association

  32. 500 Once yearly injectable treatment for osteoporosis recently shown by Huang et al to be safe and effective in HIV+ patients (AIDS 2009)

  33. 500 Zoledronate • 27 HIV + men, 3 HIV+ women • Excluded people with recent dental problems • Median T-scores of lumbar spine -1.7 and hip -1.4 • Median CD4 count 461 and 93% with VL <400 • Bone density measured absolutely and as sex-adjusted T-scores significantly improved in tx group • Increase of 3.7 + 4.1% in lumbar spine • Increase of 3.2 + 2.2% in hips • Bone resorption markers decreased over study • C-terminal telopeptides and cross-linked N-telopeptides of type I collagen • One patient developed uveitis

  34. 100 Two nRTIs most strongly associated with lipoatrophy

  35. 100 Lipoatrophy • Most commonly involves: • Face • Appendices • Buttocks • Strongest association with d4T > AZT use (thymidine analogues) • Thought to be due to inhibition of mitochondrial gamma-DNA polymerase  reduction of mitochondrial DNA

  36. 200 Highest non-medication related risk factor for development of lipo-atrophy as shown by the HOPS co-hort

  37. 200 Risk factors for Lipoatrophy • HOPS Study • Evaluated patients at two time points 21 months apart • Advanced immunodeficiency • CD4 < 100 at Survey 2 time (OR 4.2) • Higher HIV viral load • Older age • White race (OR 5.2) • Low BMI < 24 (OR 2.4) • Longer duration of HIV

  38. 300 Effects of obesity on CD3, CD4, and CD8 counts in HIV-infected patients as demonstrated by Adeyemi et al at the CORE Center (Metab Clin Exp 2009; 58: 1285-7)

  39. 300 Obesity and Inflammation CD3 CD4 • Current estimates: ~ 20-30% of HIV+ persons in US obese • Obesity increases via adipocytes substances with pro-inflammatory or immune-modulating functions • Leptin, adiponectin, CRP, IL-6, TNF-alpha • In non-HIV-infected obese persons: higher CD3, CD4, and CD8 levels  improved levels after gastric bypass surgery • Looked at 216 patients on HAART with VL < 50 for at least 6 months • As BMI increased, so did CD3, CD8, and total lymphocyte counts but CD4 not significantly increased CD8 TLC

  40. 400 Growth hormone releasing hormone that has been shown by Falutz et al to decrease visceral fat deposition (NEJM 2007)

  41. 400 Treatment of Lipodystrophy • Thiazolidinediones and metformin inconsisent effects on visceral fat • Metformin  lipoatrophy • Testosterone: dec total & subQ fat but not visceral • rhGH  fat-oxidizing and lipolytic properties  • non-sustaining loss visceral fat and decrease in BP and TG but increases lipoatrophy • Tesamorelin (GHRH) – • decreased visceral fat by 15% with increased subQ fat, decreased TG, and increased HDL • Expensive and requires parenteral administration • Liposuction or surgery • Lifestyle changes

  42. 500 Gold standard test for the study of fat composition and distribution in children (per Alves et al in the Brazilian J of ID 2008)

  43. 500 Evaluation of Lipodystrophy in Pediatric Populations • Pre-pubertal children have milder lipodystrophy than pubertal • Lipohypertrophy most common manifestation (12-20%) followed by mixed (5-9%) followed by lipoatrophy (4-8%) • DEXA scan best way to study fat composition and distribution in children • CT and MRI used to evaluate visceral fat • Clinical evaluation most common though to avoid use of sedating agents

  44. 100 HIV-infected patients on HAART respond (better, the same, or worse) to anti-lipid therapy compared to HIV-negative people

  45. 100 Response to Lipid Therapy • Protease inhibitors, efavirenz, and stavudine have been shown to increase levels of cholesterol and triglycerides • Elevated cholesterol levels in at least 25% of people on HAART • ACTG A5087 – 12 week study – • Fenofibrate – 9% LDL, 66% HDL, 48% TG NCEP goals met • Pravastatin – 36% LDL, 49% HDL, 18% TG

  46. Response to Lipid Therapy • French Agence Nationale de Recherche sur le SIDA (ANRS 126) • rosuvastatin 10 mg/d vs. pravastatin 40 mg/day (n=42 each arm) • Results: • LDL changes – 37% R vs 19% P (p<0.001) • HDL changes – no difference between arms • Overall it has been found that responses to anti-lipid therapy in HIV-infected persons is suboptimal compared to HIV-negative groups

  47. 200 HIV medication shown to decrease levels of statins

  48. 200 Lowered statin levels • Broken down by the CYP3A4 system • Efavirenz acts as an inducer of CYP3A4 so expect lower levels of statins • Elvitegravir also causes some induction of this enzyme

  49. 300 Co-infection associated with lower cholesterol levels than HIV+ mono-infected patients

  50. 300 HCV and Hyperlipidemia • Liver is involved with cholesterol metabolism – a severely diseased liver may be associated with low cholesterol levels • Brazilian study by Almeida of 110 HIV+ patients • Baseline total cholesterol: • HCV+: 141.7 + 33.2 • HCV-: 156.6 + 37.4 • Follow-up 14 months: • HCV+: 157.3 + 31.8 • HCV-: 183.0 + 38.5 • No effect seen on triglyceride levels by HCV

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