Metabolic Complications of HAART

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

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

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ROUND ONE "Sugar" DM Part Deux Brittle Bones Too Much, Too Little Da' Lipid Dilemma $100 $200 $300 $400 $500

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100 Class of against retrovirals most normally connected with bringing about insulin resistance

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Insulin Resistance in HIV Most regular thought: protease inhibitors Best approach to quantify insulin resistance is hyper-insulinemic euglycemic cinch Ex: 1 measurement of indinavir ��  30% lessening in insulin affectability in HIV-subjects Mechanisms: 1. Diminishment of glucose take-up in adipocytes by adjusting adipogenic proteins 2. Dividing of GLUT4 translocation by noncompetitive reversible restricting 100

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200 Pneumocystis jiroveci treatment that is a pancreatic beta cell poison

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200 Pentamidine Second line treatment for extreme PcP Dosed at 4 mg/kg IV every day Shown to at first invigorate beta cells of the pancreas ��  cell demise perhaps Should acquire accuchecks q6 hours while on this treatment to screen for hypoglycemia and hyperglycemia with ketoacidosis

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300 In a rodent display, Zhang et al (2009) exhibited an expanded frequency of apoptosis in this kind of cells activated by presentation to protease inhibitors

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1. fa/fa rats - presented to PIs for 7 weeks ��  discovered expanded apoptosis of the beta cells of the pancreas. 2. Uncovered insulinoma cells and human pancreatic cells in vitro to 48-96 hours of RTV, LPV, ATV, or TPV ��  Greater cell demise and lessened insulin-secretory ability. Presentation to the PIs prompted to enactment of mitochondria-related caspase-9, advancing arrival of cytochrome c prompting to cell demise. 300

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400 Initial aftereffects of WIHS study as to impacts of PIs on DM rate AND Two races recognized as having most noteworthy hazard for DM improvement by the Swiss HIV Cohort Study

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400 DM in HIV+ Women (WIHS) and Swiss HIV Co-hort Study WIHS: Initial partner concentrate on: 2.8% rate in PI-getting ladies 1.2% the individuals who had not got cART 1.4% in controls - higher overweight frequency in HIV-ladies 33 versus 23% Later survey: No contrast between the HIV+ and HIV-ladies NRTI Exposure > 3 years hazard to 2.6 overlay Swiss HIV companion contemplate: Asian ethnicity: 4.9 crease chance Black ethnicity: 2.2 overlap chance

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500 When contrasting cART-accepting HIV+ people with HIV-uninfected people, Brown et al in Arch Int Med in 2005 reported this sum increment in relative danger of advancement of DM (communicated as overlap change)

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500 Incidence of DM Pre-HAART: Rare in HIV+ people As HIV+ patients' BMIs have expanded, so has the rate of DM One study reported diabetes occurrence in PI beneficiaries with lipodystrophy of 2% that rose to 7% following 14 months (0.5% in HIV-controls) Brown et al Prospective study more than 4 years 10% of HIV+ cART beneficiaries created DM though just 3% of HIV-men did. In the wake of modifying for age and BMI , there was a 4-overlay increment in relative hazard

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100 Co-disease basic in those with HIV that improves the probability of DM advancement

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100 Risk Factors for DM in HIV Butt An et al. Helps 2009; 23(10): 1227-34 3227 HIV+ and 3240 HIV-VA patients HIV+ people: more inclined to be more youthful, HCV Ab +, dark guys, with a lower BMI Increasing age or BMI and minority race most serious hazard variables among all veterans HCV co-contamination and utilization of nRTIs and NNRTIs (however not PIs) were connected with a higher danger of DM in HIV+ Increasing liquor utilize and hx of medication utilize adverse indicators of DM Compared to non-consumers, HIV+ people who drank 31-60 drinks for each month had an OR of 0.40

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200 nRTI connected with expanded insulin resistance

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200 IR and nRTIs Stavudine Increased truncal fat Reduced fringe fat Increased plasma insulin levels Effects just somewhat reversible Lipoatrophy ��  diminished emission of 2 critical adipokines: leptin and adiponectin (which are both required in glucose digestion system)

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300 Recommended first line treatment for insulin resistance in HIV

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300 Therapeutic choices for IR in HIV Metformin first decision treatment Significantly diminishes plasma insulin, BMI, and diastolic BP No expanded frequency in lactic acidosis Use warily in those with lipoatrophy Cannot use in those with impeded renal capacity (Cr > 1.4) Glitazone sisters (Pio and Rosi) viability in HIV+ << HIV-in spite of the fact that have been appeared to build subQ fat in HIV-Sulfonylureas – low measurements when given with ritonavir because of expanded levels Therapy generally is same; insulin utilize bring down in those determined to have DM after their HIV determination

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400 As assessed at the CORE Center, the disparities found in meeting ADA objectives between HIV+ men and ladies for each of the accompanying parameters: HbA1C Lipid levels Aspirin utilize

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

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400 Meeting of ADA Goals in HIV DM analyzed a mean of 3 years after HIV conclusion Women at 47, men at 52 (p=.001) Women had higher BMI (30.9 versus 27.3,p<.001) Patients with imperceptible VL more prone to meet HDL objective however less inclined to meet TC or LDL objectives BP objectives met in 56% of customers yet more outlandish if on HAART

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100 nRTI most usually connected with osteopenia in studies

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100 Tenofovir and Bone Loss Inhibits mineralization of new bone, exhibited in measures of the hip and spine Associated with renal phosphate squandering Appears to be declined if vitamin 25(OH) D levels are low ��  expanded PTH ��  bone resorption Some creators have recommended that all patients on tenofovir ought to get calcium and vitamin D supplementation

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200 Effects of the Protease Inhibitor class and Zidovudine on bone mineral thickness

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200 Zidovudine and PIs Protease inhibitors as a class = expanded occurrence of osteopenia and osteoporosis Zidovudine appeared to incite osteoclastogenesis ��  expanded bone resorption Some studies propose any HAART treatment may build bone misfortune (next slide) albeit most recommend less NNRTI inclusion Duvivier et al (AIDS 2009, 23:817-24): lumbar spine BMD more than 48 weeks diminished 4.9% in patients on LPV/r or IND/r versus 1.5% misfortune in those on NNRTI-based regimen BUT was equivalent misfortune in hip examine

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200 NNRTIs versus PIs and Bone Loss Brown Todd et al. JAIDS 2009 Aug 15; 51(5): 554-560 155tx-gullible patients randomized 1:2 to get 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 ended (89% by week 32) Lower standard aggregate BMD assoc with lower weight, non-dark race, and lower benchmark HIV RNA levels At week 24: LPV/r arm 0.7% reduction in BMD versus 0.6% in EFV arm. At week 96: LPV/r arm (~90% monotherapy for normal of 68 weeks) 2.5% abatement versus 2.3% decline in EFV/ZDV/3TC arm Authors' decision: No distinction in tx sort

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300 Proportion of treatment-gullible HIV-contaminated people with osteoporosis or osteopenia

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300 Tx-Naïve Patients Many studies ��  1/3 of treatment-guileless HIV+ people have osteopenia or osteoporosis Thought to be because of constant aggravation from HIV disease which may effectsly affect osteoclast action Control of viral load has demonstrated an inversion of this impact in a few studies

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400 Component of the HIV infection connected with expanding osteoclast action

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400 gp120 Given to HIV-people at levels like somebody with untreated HIV disease (Modarresi et al, Amer J Path 2009) Induced look of the osteoclast separation calculate RANKL CD4+ lymphocytes ��  expanded bone resorption Some studies have demonstrated a lessening in HIV viral burdens prompt to an expansion in bone thickness Viral Protein Vpr likewise answered to have this affiliation

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500 Once yearly injectable treatment for osteoporosis as of late appeared by Huang et al to be protected and successful in HIV+ patients ( AIDS 2009)

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500 Zoledronate 27 HIV + men, 3 HIV+ ladies Excluded individuals with late dental issues Median T-scores of lumbar spine - 1.7 and hip - 1.4 Median CD4 tally 461 and 93% with VL <400 Bone thickness measured completely and as sex-balanced T-scores altogether enhanced in tx gather Increase of 3.7 + 4.1% in lumbar spine Increase of 3.2 + 2.2% in hips Bone resorption markers diminished over study C-terminal telopeptides and cross-connected N-telopeptides of sort I collagen One patient created uveitis

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100 Two nRTIs most emphatically connected with lipoatrophy

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100 Lipoatrophy Most regularly includes: Face Appendices Buttocks Strongest relationship with d4T > AZT utilize (thymidine analogs) Thought to be because of restraint of mitochondrial gamma-DNA polymerase ��  decrease of mitochondrial DNA

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200 Highest non-pharmaceutical related hazard figure for improvement of lipo-decay as appeared by the HOPS co-hort

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200 Risk variables for Lipoatrophy HOPS Study Evaluated patients at two time focuses 21 months separated 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 length of HIV

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300 Effects of corpulence on CD3, CD4, and CD8 tallies in HIV-tainted patients as exhibited by Adeyemi et al at the CORE Center ( Metab Clin Exp 2009; 58: 1285-7) .:ts