Presentation on theme: "Cardiovascular Risk and dyslipidemia"— Presentation transcript:
1 Cardiovascular Risk and dyslipidemia Dr Stéphane De WitSt Pierre Hospital - Brussels
2 Cardiac Risk Factors What are cardiac risk factors? Increased age Sex (men are at higher risk)SmokingElevated LDL cholesterol (LDL)Low HDL cholesterol (HDL)HypertensionPresence of diabetes (or risk equivalent)How to define cardiac risk and need for interventionPersons with 2 or more risk factors are at increased risk of coronary heart disease (CHD)Risk assessment tools can be used to calculate percent of CHD riskSlide #11: Cardiac Risk FactorsThe overall risk of acute coronary events depends on a combination of several risk factors that contribute to an individual’s overall global CV risk.2Wilson PW et al. Circulation. 1998;97:
3 Multiple Risk Factors: INTERHEART Multiple Traditional Risk Factors Confer Synergistic Increasein Risk of MI in General Population2.9 ( )2.4 ( )1.9 ( )3.3 ( )13.0 ( )42.3 ( )68.5 ( )182.9 ( )333.7 ( )1248163264128256512Odds Ratio (99% CI)Check Y Axis scaleSmoke (1)DM (2)ApoB/A1 (4)1+2+3All 4+ObesityAll Risk FactorsHTN (3)Risk Factor (adjusted for all others)+Psycho- social3Yusuf S et al. Lancet. 2004;364:
4 LDL Cholesterol (mg/dL) Lipids and CVD RiskIncreasing plasma LDL increases relative risk of CHDA 30 mg/dL ↑ in LDL is associated with ~30% ↑ CHD risk3.7LDL Cholesterol (mg/dL)40701001301601902.92.21.71.31.0Relative Risk of CHD(log scale)44Grundy SM et al. Circulation. 2004;110:
5 Higher HDL Reduces Cardiovascular Risk at All LDL Levels Framingham Heart Study – 10-Year Risk for CHD EventLDL (mg/dL)HDL (mg/dL)Relative Risk of CHD0.01.02.03.010016022085654525HDL-C is a modifier of CV risk at all levels of LDL-C.Data from the Framingham Study have demonstrated that increasing HDL-C plasma levels significantly reduce the risk of CHD at different levels of LDL-C. Even at high-risk levels of LDL-C (>200 mg/dL), elevated HDL-C levels significantly reduce the risk of CHD.For every 1 mg/dL increase in HDL-C, the CV risk is reduced by up to 3%. This protective effect of elevated HDL-C levels is especially important in therapy to modify CV risk, as interventions to increase HDL-C are often more successful than interventions to decrease LDL-C.1 mg/dL increase in HDL reduces CVD risk by 2% in men and 3% in women1Low HDL cutoffs: <40 mg/dL for men; <50 mg/dL for women251. Gordon T et al. Am J Med. 1977;62: ; 2. Gordon DJ et al. Circulation. 1989;79:8-15.
8 Studies of CVD risk associated with treatment in HIV Risk of CVDCohort studies of clinical outcome:CDC/HOPS: Holmberg et alJohn HopkinsMedicaid: Currier et alFrench HIV Hospital Database: Mary-Krause et alKaiser Permanente: Klein et alData collection of Adverse event of anti-HIV drugs (D:A:D)VA database: Bozzette et al( )( )
9 Causes of death in D:A:D 2000-2004 percentage / year Total # deaths: 1248CVD%Weber et al, CROI, 2005
10 The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Prospective, multinational, observational study initiated in 1999Formed by collaboration of 11 previously established HIV cohorts> 33,000 HIV-infected patients followed at 188 clinics in 20 countries in Europe, US, and AustraliaPurpose of the D:A:D studyTo determine the prevalence of risk factors for CVD among HIV-infected personsTo investigate any association between risk factors, stage of HIV disease, and use of ART
11 CV risk factors in an HIV-infected population: the DAD study Prevalence (%)102030405060Smoking52%TGs ≥203 mg/dL (2.3 mmol/L)34%HDL-C ≤35 mg/dL (0.9 mmol/L)26%Lipodystrophy25%Age (>45 y male; >55 y female)25%TC ≥239 mg/dL (6.2 mmol/L)22%Family history of CHD11%Hypertension8.5%UnmodifiableBMI >30 kg/m23.5%Potentially modifiableDiabetes2.5%Lipid & Adipose Tissueabnormalitiespotentially modifiablePrevious CHD1%CHD: coronary heart disease; BMI: body mass index; DAD: Data Collection of Adverse EventsFriis-Moller N et al. AIDS 2003; 17: 1179–1193
12 Relative rate per additional year Incidence of myocardial infarction and duration of exposure to cART (D:A:D cohort)Relative rate per additional yearof exposure to cART*: 1.17(95% CI: )Incidence / 1000 PY/ 95% CIcART Exposure (yrs)None < >6# MIPYFU10, , , , , , , , ,577*: Adjusted for conventional risk factors not influenced by cARTEl-Sadr et al, CROI 2005 (#N-186)
14 Antiretrovirals Uses and Risks Is there a hierarchy of treatment-associated risks for hyperlipidemia and cardiovascular diseaseamong NRTIs?among NNRTIs?among PIs?
15 2NN: Lipid Effects of EFV vs NVP at Week 48 Mean Change in Lipids From 48-week, multicenter, open-label, randomized trial in treatment-naive patients (N = 1216)NVP 400 mg QD (n = 220)NVP 200 mg BID (n = 387)EFV 600 mg QD (n = 400)NVP 400 mg + EFV 800 mg QD (n = 209)All plus d4T + 3TCSimilar efficacy with NVP BID and EFV but NVP did not meet equivalence criteriaGreater lipid changes with EFV (combination NVP + EFV arm excluded from lipid analysis)EFV + 3TC/d4TPooled NVP + 3TC/d4T49†50434040*3534313027Mean Change in Lipids FromBaseline to Week 48 (%)2020EFV, efavirenz; NVP, nevirapine.105.9†-4.1-10TCLDLHDLTGTC:HDL*P < .05 vs NVP.†P < .001 vs NVP.van Leth F, et al. PLoS Med. 2004;1:e19.1515
16 GS 934 and GS 903 Lipid Effects of Tenofovir vs Thymidine Analogues Prospective, randomized, double-blind studies in treatment-naive patientsTDF associated with more benign lipid changes and less lipoatrophyMean Δ From BL to Week 144, mg/dLGS 934GS 903TDF + FTC + EFV (n = 255)ZDV/3TC + EFV (n = 254)P ValueTDF + 3TC + EFV (n = 299)d4T + 3TC + EFV (n = 303)TCmmol/L240.62360.94.005300.79581.50.001LDL cholesterol100.26160.41NS140.36260.67HDL cholesterol130.34120.3190.2360.15.003TG40.04.04710.011341.511. Arribas J, et al. J Acquir Immune Defic Syndr. 2008;47:74-78.2. Gallant JE, et al. JAMA. 2004;292:16
17 Median Change From BL to Week 24 or 48 (%) GEMINI Study Lipids Effects of SQV/RTV vs LPV/RTV (On-Treatment Analysis)100SQV/RTV + TDF/FTCLPV/RTV + TDF/FTC80Week:2448244824482448P = .002260Median Change From BL to Week 24 or 48 (%)P = .00074739402629262120201820161712121279n =10610981100105108809910510880991061098199TCLDLHDLTGMore patients in the LPV/RTV group exceeded the NCEP threshold (39%) for total cholesterol vs the SQV/RTV arm (31%)Significant difference in fasting TC:HDL ratio between arms at Week 24 lost at Week 48Walmsley SL, et al. EACS Abstract PS1.4.
18 KLEAN Study Lipid Effects of FPV/RTV vs LPV/RTV at Week 48 100FPV/RTV 700/100 mg BID + ABC/3TC (n = 434)LPV/RTV SGC 400/100 mg BID + ABC/3TC (n = 444)80666060Median Change From BL (%)4139394033292320For more information about this study, see the capsule summary at:TCHDLLDLTGLipid effects comparable between armsEron JJ, et al. Lancet. 2006;368:18
19 ALERT Study Lipid Effects of FPV/RTV vs ATV/RTV at Week 48 FPV/RTV 1400/100 mg QD + TDF/FTC (n = 53)ATV/RTV 300/100 mg QD + TDF/FTC (n = 53)BaselineWeek 48LDLHDL250TCTG125991012009597171180100160153150Median Lipid Levels (mg/dL)15013112475116Median Lipid Levels (mg/dL)10050384348375025FPV/RTVATV/RTVFPV/RTVATV/RTVFPV/RTVATV/RTVFPV/RTVATV/RTVLipid effects comparable between armsSmith K, et al. IAS Abstract WEPEB023.
20 CASTLE Study Lipid Effects of ATV/RTV vs LPV/RTV at Week 48 ATV/RTV + TDF/FTC (n = 440)LPV/RTV + TDF/FTC (n = 443)60Median Change From BL (%)*5040*P < .000130**2010TCLDLHDLNon-HDLTGDifference estimates (%)-9.5-2.9-3.8-11.6-25.22% of ATV/RTV vs 7% of LPV/RTV subjects initiated lipid-lowering therapy during studyMolina JM, et al. CROI Abstract 37.202020
21 Mean TC:HDL Ratio (± SE) ARTEMIS Study Mean Fasting Lipid Levels Over Time for DRV/RTV vs LPV/RTVDRV/RTV + TDF/FTCLPV/RTV + TDF/FTCTGTC:HDL Rationg/mLmM2502.95.04.52002.3Mean TG Level ( ± SE)Mean TC:HDL Ratio (± SE)4.0NCEP cutoff1501.73.5DRV, darunavir; FTC, emtricitabine; HDL, high density lipoprotein; LPV, lopinavir; RTV, ritonavir; SE, standard error; TC, total cholesterol; TDF, tenofovir1001.13.024812162436482481216243648Time (Wks)Time (Wks)DRV/RTV n = LPV/RTV n =De Jesus E, et al. ICAAC Abstract 718b.
22 Boosted vs Unboosted PIs Low-dose RTV boosting associated withIncreased efficacy, less frequent dosing, reduced resistance on failureIncreased incidence of AEs and metabolic eventsPIs Administered UnboostedPIs Boosted With RTV 100 mg/dayPIs Boosted With RTV ≥ 200 mg/day*ATVATV/RTVLPV/RTVFPVFPV/RTV (naive pts only)FPV/RTVNFVDRV/RTV (naive pts only)DRV/RTVIDVSQV/RTVTPV/RTV*IDV/RTV*All RTV 200 mg/day except TPV requires RTV 400 mg/day,22
23 BMS-034 & BMS-089 Lipid Effects of Boosted and Unboosted ATV at Wk 48 ATV + ZDV/3TC (n = 404)ATV + d4T + 3TC (n = 105)Median Change From BL (%)Median Change From BL (%)50EFV + ZDV/3TC (n = 401)50ATV/RTV + d4T + 3TC (n = 95)4040***302430242425211820201316161010721TCLDLHDLTCLDLHDL*P < .00011. Squires K, et al. J Acquir Immune Defic Syndr. 2004;36:2. Malan DR, et al. J Acquir Immune Defic Syndr. 2008;47:
24 BMS-089: Week 96 Results of Boosted vs Unboosted ATV in ART-Naive Pts AI : randomized, open-label, multicenter trialATV 400 mg QD (n = 105)ATV/RTV 300/100 mg (n = 95)Both with d4T XR 100 mg QD + 3TC mg QDTrend for more virologic failure in ATV arm at Week 96*Greater effects on lipids with ATV/RTV vs ATVMedian lipid levels did not meet intervention levels at Week 96Change in Median Lipid LevelsFrom Baseline to Week 96ATV/RTV 300/100ATV 400403335P < .0530P < .012723Change From BaselineMedian Lipid Levels (%)20192014For more information about this study, see the capsule summary at:107TCHDLFastingLDLFastingTG*Not powered to determine if ATV noninferior to ATV/RTV.Malan DR, et al. J Acquir Immune Defic Syndr. 2008;47:2424
25 Mean Change From Baseline to Week 48 (%) SWAN: Change in Lipids After Switch From Comparator PI to ATV (Week 48)Switch to ATV* (n = 278)Continue PI (n = 141)TCLDLHDLNon-HDLTG159105-3P = NS-1-5P < .0001-3-15-3P = NS-5-12Mean Change From Baseline to Week 48 (%)-10-15-20-18-25Figure 11ATV, atazanavir; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; NS, not significant; RTV, ritonavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides.-30P < .0001-35-33-40P < .0001*Unboosted ATV, except ATV/RTV used in patients also receiving TDF.Gatell JM, et al. EACS Abstract PS1/1.25
26 ATAZIP: Switch From LPV/RTV to ATV/RTV Randomized trial of patients on LPV/RTV > 6 months randomized to continue LPV/RTV 400/100 mg BID (n = 127) or switch to ATV/RTV 300/100 mg QD (n = 121)20TGTCLDLHDLChange at Week 48 (mg/dL)-20P < .0001Switch to ATV-40Continue LPV/RTVP < .0001-60Mallolas J, et al. IAS Abstract WEPEB117LB.26
27 Percentage of change in lipid parameters (baseline-Month 12) NEFA study: Metabolic Changes in Patients Switching from PI to ABC, EFV or NVP Changes in Lipid Profile and insulin by Treatment GroupTC/HDLLDL-cHDL-cTriglyceridesInsulin*Percentage of change in lipid parameters (baseline-Month 12)*p <0.005Fisac C et al. Poster presented at: WAC Abstract ThPe7354
28 Meta-analysis of Impact of NRTI Backbone + PI/r on Lipids Multivariate analysis of percentage change in lipids from baseline toweek 48: Effects of NRTI versus PI used102030405060% changeDRV/r,SQV/rATV/rLPV/rFPV/rTDF/FTCABC/3TC or d4T/3TCTotal cholesterolTriglyceridesLDLHDLHill A, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THPE0167.28
29 Median Change From Baseline (mg/dL) MERIT Substudy: Fewer Lipid Effects With Maraviroc vs Efavirenz at Week 48 in naïve patientsEFVTCHDLLDLTGMVCP < .0001125Median Change From Baseline (mg/dL)P < .0001100(0.93)400P = .000275P < .0001(0.53)(0.05)50200(-0.23)25(0.35)(0.18)-25-50-200-75-100-400The boxes represent the interquartile range (IQR) from 25th to 75th percentile, while the horizontal black line in the box represents the median value. The whiskers extend to the most extreme data point within 1.5x the IQR from the box.P-values are for comparisons of medians (Wilcoxon Rank-Sum test)n = Median =(mmol/L)(0.23)(-0.10)MVC + ZDV/3TC associated with greater decrease in TC-to-HDL ratio vs EFV + ZDV/3TC: (-0.014) vs (-0.011) (P = .005)DeJesus E, et al. CROI Abstract 929.292929
30 MRK004: Serum Lipids at Week 96 Mean change from baseline (mg/dL) at week 96RAL* + TDF/FTC (N=160)EFV + TDF /FTC (N=38)Baseline MeanMean ChangeRAL vs EFVCholesterol166.2+1.1168.9+24.0P=0.002LDL-C103.9-5.8108.5+4.4P=0.045HDL-C38.0+7.437.9+13.0P=0.017Triglycerides134.7-10.8126.1+13.4P=0.145Total: HDL ratio4.6-0.7P=0.689* All RAL dose groups combinedMarkowitz M, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. TUAA0302.
31 SMART: Schematic of Study Design Mean follow-up:16 monthsViral Suppression ArmHAART continuously administered(n = 2752)HIV-infected patients with CD4+ cell count > 350 cells/mm3(N = 5472)Treatment Interruption ArmTreatment stopped when CD4+ cell count> 350 cells/mm3; restarted whenCD4+ cell count < 250 cells/mm3(n = 2720)
32 SMART: HIV Progression With Continuous HAART vs Interruption CD4-guided drug conservation strategy associated with significantly greater disease progression or death compared with continuous viral suppression: RR: 2.5 (95% CI: ; P < .001)ParameterNo. of Patients With EventsRR (95% CI)1.5Severe complications1141.4CVD, liver, or renal deaths311.5Risk of ComplicationsNonfatal CVD events631.4Nonfatal hepatic events142.5Nonfatal renal events70.1Favors TI1.0Favors CT10.0El-Sadr W, et al. N Engl J Med. 2006;355:32
33 Adjusted Relative Rate (95% CI) D:A:D Study Recent Use of ABC, ddI Associated With Increased Risk of MITAs not associated with increased risk of MICurrent or recent (within 6 months) use of ABC or ddI associated with increased relative risk of MI90% increase of risk of MI with recent ABC49% increase of risk of MI with recent ddIRisk most prominent in individuals with underlying CVD risk factorsIncreased risk no longer observed in patients who had discontinued ABC or ddI for > 6 monthsCHD (n = 639)Stroke (n = 195)ZDVRR: 1.40 (P = .005)ddId4T3TCRR: 1.63 (P = .0001)ABCTA, thymidine analogue.CHD (MI, CV deaths, invasive procedures)Stroke (possible/definitive)Increased risk restricted to MI and other CHD outcomes, but not strokeRelationship between abacavir, ddI and MI risk unexpected. Potential mechanism unknown.0.500.751.001.251.501.752.002.25Adjusted Relative Rate (95% CI)D:A:D study group, Lancet 200833
34 Inflammatory markers and HIV replication:increased mortality risk. Le Meilleur de … CROI F. Raffi, J. Reynes, B. Hoen, G. Peytavin, B. Masquelier153Inflammatory markers and HIV replication:increased mortality risk.SMART trialInterruption of ARV associated with a significant increase of IL- 6and D-dimersHigh levels of D-dimers and IL-6 associated with high risk of death(of any cause) (RR 26,5 & 11,8 respectively)High levels of IL-6 and D-dimers could explain part of the increased risk of CVD and death in the DC arm.STACCATO trialViral replication rebound after tratment interruption associated with:- increase of markers of endothelial activation (s-VCAM-1 = soluble vascular cell adhesion molecule) and inflammation (MCP-1 = monocyte chemotactic protein).- these changes were partially reversible 12 weeks after treatmentre-initiation.- decrease of IL-10 and adiponectinLes D-dimères sont des marqueurs de thrombogénèse. Le RR de décès en cas de D-dimères élevés observé dans l’étude SMART est très supérieur à celui jamais observé dans aucune étude du risque cardio-vasculaire. Ce RR concerne l’ensemble des décès survenus dans SMART. Les décès de cause CV sont significativement associés à une élévation des taux d’IL-6 et d’amyloïde P.Dans l’étude STACCATO, aucune corrélation n’était possible avec les marqueurs cliniques, du fait de la quasi-absence d’événements cardio-vasculaires.Le difficulté dans l’interprétation et l’extrapolation de ce type d’étude est qu’il n’est pas possible d’établir un lien causal direct entre les anomalies biologiques (marqueurs d’activation endothéliale) et les événements cliniques (risque CV, décès). En effet, l’augmentation de ces marqueurs biologiques d’activation endothéliale pourrait refléter un autre phénomène intercurrent et ne pas être strictement en rapport avec une dysfonction endothéliale.Kuller L, CROI 2008, Abs. 139 ; Calmy A CROI 2008, Abs. 14034
35 Hazard ratio (95% CI) of CVD Hazard Ratios for Four Groupings of CVD: ”ABC (no ddI)” vs. ”Other NRTIs”UnadjustedAdjusted for CV risk factorsHazard ratio (95% CI) of CVDCVD, expanded def. (n=112)CVD, minor (n=58)Myocardial infarction (n=19)CVD, major (n=70)184.108.40.206.912.613.0Favors “Other” ◄ Favors ABCLundgren J, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THAB0305.35
36 Hazard ratio* (95% CI) of CVD (expanded definition) Hazards Ratios* for ”ABC (no ddI)” vs. ”Other NRTIs” by CV Risk Status at Study EntryFavors “Other” ◄ Favors ABC> 5 CV risk factorsIschemic abnormalitieson ECGYesP>0.4No3.1At study entry:Hazard ratio* (95% CI) of CVD (expanded definition)P=0.1* Adjusted for CV risk factorsLundgren J, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THAB0305.36
37 % adjusted difference from “Other NRTIs” Biomarker Levels* at Study Entry: ”ABC (no ddI)” and ”ddI (+/- ABC)” vs. ”Other NRTIs”% adjusted difference from “Other NRTIs”If not shown, p>0.1(n=791)Median (IQR)levels in”Others NRTIs”(nmol/L)(µg/mL)(µg/L)(mg/mL)(pg/mL)0.4 ( )0.3 ( )65 (51-86)3.6 ( )2.2 ( )2.3 ( )p=0.07p=0.07p=0.02*Adjusted Mean DifferencesLundgren J, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THAB0305.
38 Potential clinical implications of HIV as activator of atherogenic process? rereplicationplicationActivationActivationofofvascularvascularendothendotheeliumliumInflammationInflammationStimulationStimulationCoagulationCoagulationcascadecascadeCRPhsCRPhsSS--VCAMVCAM--11DD--dimdimersersILIL--66PP--sseelectinlectinMCPMCP--11SericSericaamyloidmyloidAAAAntinti--athatheerogrogeniceniceffecteffectSericSericaamyloidemyloidePPAthAtheerogrogenesisenesisAdipoectinAdipoectinILIL--1010ARVARVtreatmenttreatmentSStatinstatins??
39 Emerging factors: Lp (a), CRP, IMT, and endothelial function Integrate CVD prevention & management in the long term follow up of HIV patients taking into account all contributing factorsFamily historyInactivity, dietAbdominal obesity*SexCigarette smokingAgeCHD riskLipids*Hypertension*HIV infection†HyperglycemiaHAART†Insulin resistance*Emerging factors: Lp (a), CRP, IMT, and endothelial functionDiabetes*Metabolic syndrome.†Precise contribution unclear.39
40 Contribution of Dyslipidemia to MI Risk HDL cholesterol(per mmol/L)Triglycerides(per log2 mmol/L higher)Total cholesterol(per mmol/L)PI exposure (per additional year)NNRTI exposure(per additional year)1100.1Relative Rate of MI* (95% CI)*Adjusted for conventional risk factors (sex, cohort, HIV transmission group, ethnicity, age, BMI, family history of CVD, smoking, previous CVD events, lipids, diabetes, and hypertension).†Unadjusted model.40Friis-Moller N et al. N Engl J Med. 2007;356:
41 Lipid Goals For HIV-Infected Patients NCEP lipid goals intended for general population likely appropriate for HIV-infected patientsLipid goals established to reduce cardiovascular riskData from D:A:D cohort suggest Framingham risk equation overestimates risk of cardiovascular events in HIV-infected patientsD:A:D equation more accurately predicted CHD outcomes in HIV-infected populationIncorporates PI exposure as well as conventional CHD risk parametersFriis-Moller N, et al. CROI Abstract 808.
42 Lipid-Lowering Therapy Overview FibratesLDL , TG , HDL Side effects: dyspepsia,gallstones, myopathyStatinsLDL , TG , HDLSide effects: myopathy, liver enzymesEzetimibeLDL , TG , HDL Side effects: liver enzymes,diarrheaOmega-3 Fatty AcidsLDL , TG , HDL Side effects: GI, tasteNicotinic AcidLDL , TG , HDL Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicityBile Acid SequestrantsLDL , TG , HDL Side effects: GI distress/ constipation, absorption of other drugsSeveral pharmacologic classes of lipid lowering agents (LLAs) are available, with varying effects on LDL, TG, and HDL. Side effects also vary among the classes.Niacin and bile acid sequestrants were among the first agents to become available for lowering serum lipids. However, these agents are not often used in HIV infected patients primarily due to side effects and dosing frequency.The cornerstones of modern lipid management are fibric acids and HMG CoA reductase inhibitors or statins.More recently adjunctive therapies including ezetimibe and omega 3 fatty acids derived from fish oils have been added to the statins to enhance their lipid lowering properties.42
43 Utility of Lipid-lowering Agents for Dyslipidemia in HIV Infection? There is a role for fibrates, statins and niacinBUTTarget lipid levels infrequently achieved in clinical trialsInteractions between statins and PIs can complicate useIncreased costIncreased pill burdenPotential for glucose intolerance with niacin
44 Lipids ManagementWhat are the preferred management approaches for patients with HAART-associated hyperlipidemia?Specifically, what factors should be considered in deciding whether to switch antiretroviral agents, use lipid-lowering therapy, or both?
45 Lipid-Lowering Therapy vs Switching PI 12-month, open-label study of 130 patients; 60% male; mean age: 39 yearsStable on first HAART regimen randomized toPI EFV (n = 34)PI NVP (n = 29)Add bezafibrate (n = 31)Add pravastatin (n = 36)Pravastatin or bezafibrate significantly more effective in management of hyperlipidemia than switching ART to an NNRTI350300250Mean Plasma TGs(mg/dL)2001501005036912Months350300250Mean Cholesterol(mg/dL)200For more information about this study, see the capsule summary at:1501005036912MonthsCalza L, et al. AIDS. 2005;19:45
46 Lipid Lowering Agents and ARVs: Drug Interactions SQV/RTV1Atorvastatin 347% AUCSimvastatin 3059% AUCPravastatin 50% AUCNFV2,3Atorvastatin 74% AUCSimvastatin 505% AUCPravastatin 47% AUCLPV/r4Atorvastatin 588% AUCPravastatin 30% AUCfosAPV5Atorvastatin 130% AUCEFV6Atorvastatin 43% AUCSimvastatin 58% AUCFibratesFluvastatinPravastatinStatin-FibratesAtorvastatinLovastatinSimvastatinLow interactionpotentialUse cautiouslyContraindicatedwith PIs1Fitchenbaum CJ, et al. AIDS. 2002;16:2Hsyu PH, et al. AAC. 2001;45:3Gerber J et al 2nd IAS 2003, #8704Carr RA, et al. 40th ICAAC, Toronto, Abstract 1644.5Telzir Package Insert 2003.6Gerber JG, et al. 11th CROI Abstr# 603.
47 Incidence of Smoking Is Increased Among HIV-Infected vs General Population APROCO Cohort (HIV+)MONICA Sample (HIV–)BloodGlucose≥126 mg/dLNSP<0.0001SmokingP<0.01Hypertension10203040506070Percent PatientsHDL<40 mg/dLLDL>160 mg/dLThere are few studies comparing risk factors for CV disease in HIV+ cohorts and in the general population.The distribution of risk factors for CV disease were compared between patients (35–44 years old) being treated for HIV infection with a PI-based regimen (APROCO Cohort; n=223) and a cohort of HIV negative men (MONIC cohort; n=527).The HIV+ population were characterized by a significantly higher prevalence of smoking, a lower prevalence of hypertension. There was no significant difference between the two populations in terms of the prevalence of diabetes (measured by elevated glucose >12.6 mg/dL).The estimated attributable risk due to smoking was 65% in HIV+ men and 29% in HIV+ women. The predicted risk of coronary heart disease was greater in HIV+ men (RR=1.2) and women (RR=1.6), p<0.001.The results suggest that smoking makes a significant contribution to the risk of CHD in HIV+ patients, particularly men, and that this is independent of other risk factors.N=223 HIV+ men and women on PI-based regimens vs 527 HIV– male subjects:HIV+ patients have lower HDL and higher TGPredicted risk of CHD > in HIV+ men (RR=1.2) and women (RR = 1.6), P<0.000147Savès M et al. Clin Infect Dis. 2003;37:292–298.
48 Summary CVD risk is increasing in the aging HIV population CVD risk is associated with HAART and lipid elevationPrevalence of dyslipidemia is substantial especially with some PI-based regimensConsider smoking, diet and exercise interventions standardWatch for insulin resistance and the metabolic syndromeUse lipid lowering therapies along NCEP guidelinesSwitching ART to less dyslipidemic agents may avoid the need for additional interventionsNew agents appear to have few short term impact on lipid profile
49 Emerging factors: Lp (a), CRP, IMT, and endothelial function Integrate CVD prevention & management in the long term follow up of HIV patients taking into account all contributing factorsFamily historyInactivity, dietAbdominal obesity*SexCigarette smokingAgeCHD riskLipids*Hypertension*HIV infection†HyperglycemiaHAART†Insulin resistance*Emerging factors: Lp (a), CRP, IMT, and endothelial functionDiabetes*Metabolic syndrome.†Precise contribution unclear.49
51 Background HIV infection and ART influences risk Pharmaceutical “push” Metabolic diseases in HIV-infected personsAssociated with agingprevalence will increase in years to comeCauses are multifactorialUnderlying risk (genetic and environmental influences)Untreated HIVART – directly and indirectlyManagementHIV-specific issuesHIV infection and ART influences riskPharmaceutical “push”Polypharmacy (drug-drug interactions, pill burden, etc)Guidelines used in general populationCompliance ? – next slide
52 The use of lipid-lowering drugs in high-risk populations: D:A:D Initiation of lipid-lowering drugs in six months following a first CV event if not already taking thisInitiation of lipid-lowering drugs in six months following a diagnosis of diabetes mellitus if not already taking this8020p = 0.007p = 0.007p = 0.2760% of patients40% of patients20MIOverallStroke2001200220032004Invasive1999/20002005/2006Overall20012002200320041999/20002005/2006Type of EventYear of EventYear of Event(n=384)(n=626)Sabin C. et al., CROI, 2007.
53 Scope When to seek consultation with metabolic specialists Diseases coveredPrevention of CV diseasePrevention and management of lipodystrophyTreatment of type II diabetesPrevention and management of hyperlactataemiaManagement of hypertensionDiseases not (yet) coveredRenal diseaseBone diseaseSexual dysfunction
54 Dynamic documentNo previous comprehensive HIV-specific metabolic disease management guidelines existDirect evidence guiding prevention and management of metabolic diseases in HIV are limitedSeveral extrapolations from guidelines in general population are madeCompeting risks since untreated HIV is life-threateningConservative approachVersion on web-site will be updated regularly based on:Input from users – pleaseNew information emerges