Presentation on theme: "HIV complications and morbidity"— Presentation transcript:
1 HIV complications and morbidity Manuel Battegay Div. Infectious Diseases & Hospital EpidemiologyHIV complicationsand morbidity
2 Content Introduction Selected specific adverse events ART and body shape changesART, HIV and metabolismCardiovascular risk general remarksART and LipidsART, Insulin resistance and diabetesHIV and cardiovascular riskTherapeutic approaches, GuidelinesImmune reconstitution inflammatary syndrome
3 cART dramatically improves life expectancy Type of study Decrease Mortality %1996 Delta RCT AZT vs dual ART1996 ACTG 175 RCT AZT vs dual ART1997 ACTG 320 RCT Dual vs HAART1997 SHCS OS No HAART vs HAART1998 HOPS OS No HAART vs HAART2003 EUROSIDA OS /97 HAART vs HAARTSHCS OS No HAART vs HAART2007 Danish Coh. OS HIV versus non HIV305086year old: another 43 years years life prolongation with cARTNormal life expectancy (?), The ART-Cohort Collaboration, The Lancet 2008Hammer et al NEJM 1996; NEJM 1997; Gulick et al, NEJM 1998, Lancet 1996; Lancet 1997, Egger & Battegay et al, The SHCS, BMJ 1997; Palella et al, NEJM 1998; Jaggy et al, Lancet 2003; Mocroft et al, EuroSIDA, Lancet 2003; Sterne et al, The SHCS, Lancet, 2005, Lohse N et al, Ann Med, 2007
4 Battegay et al, Antiviral Ther 2007 HIV Complications1. HIVdiarrhea, dementia, wasting2. Defined HIV related complicationopportunistic diseases3. Drug - related complicationARTOI treatmentInteraction4. IRIS5. Concurrent unrelated complicationCatheter related infectionUrinary tract infection6. Unrelated diseasesTumorsCardiovascularBattegay et al, Antiviral Ther 2007
5 cART switch Swiss HIV Cohort Study 2000-2005 Vo et al., JID, Juni 2008
7 Trends for specific side effects Vo et al., JID, Juni 2008
8 Content Introduction Selected specific adverse events ART and body shape changesART, HIV and metabolismCardiovascular risk general remarksART and LipidsART, Insulin resistance and diabetesHIV and cardiovascular riskTherapeutic approaches, GuidelinesImmune reconstitution inflammatary syndrome
9 Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen Hammer, S. M. et al. IAS Guidelines JAMA 2008;300:
10 Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen Hammer, S. M. et al. IAS Guidelines JAMA 2008;300:
11 Time to Onset of Abacavir HSR in Clinical Trials (n=206) Median time to onset 9 days89% of cases occurred within6 weeks of ABC initiationSerious and sometimes fatal hypersensitivitySymptoms worsen during continued therapy with abacavir and usually resolve upon discontinuationData on file, GlaxoSmithKline.
12 Hypersensitivity to Abacavir multi‑organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups:feverrashgastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)constitutional (including generalized malaise, fatigue, or achiness)respiratory (including dyspnea, cough, or pharyngitis).
13 PREDICT-1: Clinically Suspected or Skin Patch–Defined HSR with abacavir treatment 109Control arm7.88Prospective HLA-B*5701 screening arm76OR: 0.03P < .0001Incidence (%)543.4Use of HLA screening reduced clinically diagnosed HSRs by more than half, but 3.4% still had clinically diagnosed HSRs. Only 2.7% of clinically diagnosed HSR in the control group had a positive SPT (all were B5701 positive retrospectively) and no one in the screening groups had a SPT positive HSR. 46% of all HLA-B5701 positive patients in the control group had an HSR.2.7Immunologically Confirmed HSRNo Immunologically Confirmed HSRTotalHLA-B*5701 Positive232548HLA-B*5701 Negative794819842320%1(66/847)(27/803)(23/842)(0/802)Clinically Suspected HSRSkin Patch-Defined HSRMallal S, et al. NEJM 2008Specificity: 794/819 = 96.9%Sensitivity: /23 = 100%PPV: /48 = 47.9%NPV: 794/794 = 100%13
14 Content Introduction Selected specific adverse events ART and body shape changesART, HIV and metabolismCardiovascular risk general remarksART and LipidsART, Insulin resistance and diabetesHIV and cardiovascular riskTherapeutic approaches, GuidelinesImmune reconstitution inflammatary syndrome
15 Lipoatrophy vs Wasting Syndrome Lipoatrophy: loss of subcutaneous fat in face, buttocks, abdomen, and limbsLean tissue: (muscle) not lostWasting syndrome: both fat, lean tissue, and weight diminishHIV lipoatrophy is characterized by substantial loss of subcutaneous fat from the face (up to 50% volume loss), as well as fat loss in the peripheral limbs and buttocks1-3Peripheral fat loss may be most immediately evident in prominent veins in the arms and legs, along with increased muscle definition1Because lean body mass is usually not affected, the condition differs from the AIDS wasting seen before the ubiquity of HAART1Fichtenbaum CJ, et al. IAPAC Mon. 2005;11:39-46.Grinspoon S, et al. New Engl J Med. 2005;352:48-62.Yang Y, et al. Antivir Ther. 2005;10:Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.
16 Progression of Lipoatrophy Clinical AssessmentProgression of LipoatrophyFacial lipoatrophy gradingGrade 1: Mild/localized. Appearance almost normalGrade 2: Deeper, longer central cheek atrophy. Facial muscles (especially zygomaticus major) beginning to show throughGrade 3: Deeper, wider atrophic area. Muscles clearly showingGrade 4: Widespread atrophy. Facial skin lies directly on muscles over wide area, extending toward orbital regionFacial Lipoatrophy GradingGrade 1: Mild/localized. Appearance almost normalGrade 2: Deeper, longer central cheek atrophy. Facial muscles (especially zygomaticus major) beginning to show throughGrade 3: Deeper, wider atrophic area. Muscles clearly showingGrade 4: Widespread atrophy. Facial skin lies directly on muscles over wide area, extending toward orbital regionGrinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.
17 Lipoatrophy: Risk Factors Almost certainly interrelatedAntiretroviral therapyThymidine analogue exposure (d4T >ZDV)Combinations of ART (eg, EFV + NRTIs, NFV + NRTIs)Host factorsAgeHIV disease factorsDuration of illnessSeverity of illness: AIDS, low CD4+ cell countGrinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.
18 Lipohypertrophyincrease in fat depots — typically visceral, dorsocervical, and breast tissue fatSubcutaneous fat (pinch an inch fat) does not increaseDifficult to distinguish from general “lipohypertrophy” associated with modern livingHIV lipoatrophy is characterized by substantial loss of subcutaneous fat from the face (up to 50% volume loss), as well as fat loss in the peripheral limbs and buttocks1-3Peripheral fat loss may be most immediately evident in prominent veins in the arms and legs, along with increased muscle definition1Because lean body mass is usually not affected, the condition differs from the AIDS wasting seen before the ubiquity of HAART1Fichtenbaum CJ, et al. IAPAC Mon. 2005;11:39-46.Grinspoon S, et al. New Engl J Med. 2005;352:48-62.Yang Y, et al. Antivir Ther. 2005;10:
19 Visceral Fat (dark shaded areas) CT Scans of Two HIV+ PatientsSubcutaneous Fat(pinch an inch fat)Visceral Fat (dark shaded areas)HIV+ patient with visceral adiposity. Subcutaneous fat is scant and fat in the abdomen is thick.HIV+ patient with obesity. Subcutaneous fat is thick and fat in the abdomen is scant.Images courtesy of D.A. Wohl.
20 Lipoatrophy Prevalence Distribution in HIV+ vs HIV– Controls 70MenHIVControl60Percentage Reporting Fat Loss5040P <0.001P <0.001P <0.001P <0.00130P <0.001P =0.025P =0.05320P =0.22P =0.00410P =0.058CheeksFaceArmsButtocksLegsNeckChestWaistAbdominalFatUpperBack70Women60In the FRAM Study, among both men and women, self-reported fat loss (over a preceding 5-year period) among HIV-positive patients occurred more often than self-reported fat loss in HIV-negative controls at all sites measured1,2In men, the difference between the HIV-infected and uninfected control subjects was significant at the following sites: cheeks, face, arms, buttocks, legs, chest and waist1In women, the difference between the HIV-infected and uninfected control subjects was significant at the following sites: cheeks, face, arms, buttocks, and legs2Some HIV-infected men reported gain in fat. However, the prevalence of fat gain was significantly lower in HIV-infected men than controls in most central and peripheral sites.11. FRAM Study Group. J Acquir Immune Defic Syndr. 2005;40:2. FRAM Study Group. J Acquir Immune Defic Syndr 2006;42:50Percentage Reporting Fat LossP <0.00140P <0.001P <0.00130P <0.001P <0.001P =0.05520P =0.090P =0.3110P =0.055P =0.47CheeksFaceArmsButtocksLegsNeckChestWaistAbdominalfatUpperbackFRAM Study Group. JAIDS. 2005;40: FRAM Study Group. JAIDS. 2006;42:
21 Lipohypertrophy Prevalence Distribution in HIV+ vs HIV– Controls 70MenHIVControlP =0.00360P =0.3450Percentage Reporting Fat Gain40P <0.00130P =0.011P <0.001P =0.001P =0.04820P =0.003P =0.32P =0.4010CheeksFaceArmsButtocksLegsNeckChestWaistAbdominalfatUpperback70WomenP =0.13P =0.1760P <0.001P <0.001Regarding weight gain in the FRAM Study, more control patients of both genders reported weight gain over a 5-year period than HIV-positive patients with the single exception that more HIV-positive men reported fat gain at the upper back (not significant, P =.40). The pattern of differences in reported weight gain was similar for both men and women.1,2References1. FRAM Study Group. J Acquir Immune Defic Syndr. 2005;40:2. FRAM Study Group. J Acquir Immune Defic Syndr 2006;42:50P <0.001Percentage Reporting Fat GainP <0.04440P <0.009P =0.039P =0.543020P =0.4310CheeksFaceArmsButtocksLegsNeckChestWaistAbdominalfatUpperbackFRAM Study Group. J AIDS. 2005;40: FRAM Study Group. J AIDS. 2006;42:
22 Effect of NRTIs on Limb Fat Study 903Study 934*P<0.001TDF + 3TC + EFVd4T + 3TC + EFVMean Limb Fat (kg)8.6*4.51234567891048961445.07.9*8.1†‡*P=0.034P<0.001§P=0.001TDF + FTC + EFVZDV/3TC + EFVTotal Limb Fat (kg)126.0*5.57.4*‡P=0.01WeekWeek51 4949 44Gallant JE et al. JAMA. 2004;292: ; Pozniak AL et al. JAIDS. 2006;43:
23 Lipoatrophy at Weeks 48 and 96 (NRTI Arms Only) P Values at Week 96ZDV vs TDF: <0.001d4T vs TDF: <0.001d4T vs ZDV:50d4TZDV4042%TDF(% with >20% loss)Lipoatrophy3027%26%2016%N=337 (2 nuc-containing arms)Data available in the final CROI abstract109%8%4896Weeks on Studyd4TTDFZDVHaubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.
24 Lipoatrophy (>20% loss of extremity fat) at Weeks 48 and 96 P Values at Week 96LPV/r + EFV vs LPV/r:LPV/r + EFV vs EFV: <0.001LPV/r vs EFV:40EFVLPV/r3032%LPV/r + EFV(% with >20% loss)Lipoatrophy2021%17%10N=510Data available in the final CROI abstractThere was a significant difference between EFV and LPV/r in change in extremity fat at 96 weeks.A significantly higher proportion of subjects met the criteria for lipoatrophy (>20% loss of extremity fat) in the EFV arm as compared to the LPV/r arm. This result was consistent regardless of NRTI chosen.There was no significant difference between EFV and LPV/r in the increase in trunk fat at 96 weeks (like what was observed in Study 613).10%9%7%4896Weeks on StudyEFVLPV/rLPV/r + EFVHaubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.
25 Rosiglitazone vs Metformin in HIV-Infected Patients 39 HIV-infected men with lipodystrophy randomized to rosiglitazone 8 mg/day or metformin 2 g/day for 26 weeksBoth drugs increased insulin sensitivityMetformin associated with fat loss, rosiglitazone with SAT gainWeek 26 ResultsRosiglitazone (n = 19)Metformin (n = 20)Insulin resistance↓SAT↑VAT―TGTCAdiponectinFlow mediated vasodilatationvan Wijk JP, et al. ICAAC Abstract H-339. van Wijk JP, et al. Ann Intern Med. 2005;143:
26 Psychosocial Impact of body shape changes Self-evaluated quality of relationships with friends, family, sexual partner is inversely associated with self-perception of peripheral fat loss in HIV/AIDS outpatients (N=457)1A survey of HIV/AIDS patients with body fat changes (N=33)2Social withdrawalAdversely affected sexual relationshipsForced disclosure of HIV status due to facial lipoatrophyDepressionPoor body imageART noncomplianceEconomic impact of surgical interventionsmore challenging than living with HIVSantos CP et al. AIDS. 2005;19(suppl 4):S14-S21.Collins E et al. AIDS Reader. 2000;10:
27 Conclusions Body shape changes are multifactorial Lipoatrophy and lipohypertrophy do not commonly occur togetherNewer NRTI have low- or non-existing potential for body shape changes (abacavir, tenofovir)Body shape changes are partly reversibleAbdominal fat increases are common to all ART regimens studied so farThe psychosocial impact is strong
28 Content Introduction Selected specific adverse events ART and body shape changesART, HIV and metabolismCardiovascular risk general remarksART and LipidsART, Insulin resistance and diabetesHIV and cardiovascular riskTherapeutic approaches, GuidelinesImmune reconstitution inflammatary syndrome
29 CHD risk ractors in HIV - infected population GenderAbdominalObesity*FamilyHistoryInactivity,DietAgeCigaretteSmokingCHDLipids*RiskHyper-tension*--Multiple factors can contribute to CVD in any patient population. These factors fall into two main categories:Non-modifiable factors, including age, gender and family historyModifiable factors that can be changed through lifestyle management, such as smoking, diet, and exercise, or through drug intervention, eg, dyslipidemia and hypertensionAdditionally, lifestyle changes such as smoking cessation and diet can positively impact on other modifiable factors such as abnormal lipid profiles and high blood pressure.HIVInfectionHyper-glycemiaInsulin Resistance*ARTOrange = ModifiableGreen = NonmodifiableDiabetes*Metabolic syndrome
30 Variation despite risk factors Huge geographical variation, not explained by risk factors (‘French paradox’)Increase in Eastern Europe, Asia, AfricaIncrease with age, lag of about 10 years in women, no independent effect of menopauseMultifactorial aetiology, diabetes more important in women, role of triglycerides controversialTunstall-Pedoe et al, Lancet 1998
31 Multiple Risk Factors: INTERHEART Multiple Traditional Risk Factors Confer Synergistic Increase in 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- socialYusuf S et al. Lancet. 2004;364:
32 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)Higher HDL reduces cardiovascular and hypertriglyceridemia is independently associated with CVDGrundy SM et al. Circulation. 2004;110:
33 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;292:33
34 Mean Change From Baseline (mg/dL) Study 934: ZDV/3TC vs TDF + FTCMean Change Lipid ProfileTriglycerides Fasting LDLTDF + FTC + EFVTDF + FTC + EFV50ZDV/3TC + EFVZDV/3TC + EFV4030P =0.067Mean Change From Baseline (mg/dL)2010Base line TG149 mg/dL in TDF + FTC141 mg/dL in ZDV/3TCP =0.12-1041624324860728496Study WeekPozniak AL et al. JAIDS. 2006;43:
35 HEAT: Lipid Effects of ABC/3TC vs TDF/FTC at Week 48 80ABC/3TC + LPV/RTV (n = 343)TDF/FTC + LPV/RTV (n = 345)6460384032Median Change From BL (%)232013118-1TCHDLLDLTG-20Lipid effects comparable between armsSmith K, et al. CROI Abstract 774.
36 A5142: LPV/r + EFV vs LPV/r + 2 NRTIs vs EFV + 2 NRTIs Median Changes in Lipids From Baseline – Week 96P =0.023EFVLPV/rLPV/r + EFV*70*625760P ≤0.01*504644NSMedian Change From Baseline (mg/dL)403332NS3026*2219Significantly greater increases in both HDL and non-HDL cholesterol in the NRTI-sparing (16 and 44 mg/dL) compared to the two NRTI-containing regimens (P <0.001)No difference (P >0.3) in increases in both HDL and Non-HDL cholesterol between the 2 NRTI-containing regimens+8 and +26 mg/dL in LPV/r arm, respectively+9 and +22 mg/dL in EFV arm, respectively2016NS9810TCHDLNon-HDLTG*Statistically significant difference with other 2 arms, P ≤0.01.By week 96, 10% and 12% of EFV and LPV subjects used a lipid-lowering agent.Haubrich R et al. 14th CROI Los Angeles, CA. Abstract 38.
37 CASTLE: Lipid Effects of ATV/RTV vs LPV/RTV at Week 48 ATV/RTV + TDF/FTC (n = 440)60LPV/RTV + TDF/FTC (n = 443)Median 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 37.373737
38 Median Change From BL (%) KLEAN: Lipid Effects of FPV/RTV vs LPV/RTV at Week 48100FPV/RTV 700/100 mg BID + ABC/3TC (n = 434)LPV/RTV SGC 400/100 mg BID + ABC/3TC (n = 444)80666060Median Change From BL (%)413939403329For more information about this study, see the capsule summary at:2320TCHDLLDLTGLipid effects comparable between armsEron JJ, et al. Lancet. 2006;368:38
39 GEMINI: 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.
40 ARTEMIS: Mean Fasting Lipid Levels Over Time for DRV/RTV vs LPV/RTV DRV/RTV + TDF/FTCLPV/RTV + TDF/FTCTGTC:HDL Rationg/mLmM2502.95.04.52002.3Mean TG Level ( ± SE)Mean TC:HDL Ratio (± SE)4.0NCEP cutoff1501.7DRV, darunavir; FTC, emtricitabine; HDL, high density lipoprotein; LPV, lopinavir; RTV, ritonavir; SE, standard error; TC, total cholesterol; TDF, tenofovir3.51001.13.024812162436482481216243648Time (Wks)Time (Wks)DRV/RTV n = LPV/RTV n =De Jesus E, et al. ICAAC Abstract 718b.
41 ALERT: Lipid Effects of FPV/RTV vs ATV/RTV at Week 48 FPV/RTV 1400/100 mg QD + ABC/3TC (n = 53)ATV/RTV 300/100 mg QD + ABC/3TC (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.
42 Mean Change in Lipids From 2NN: Lipid Effects of EFV vs NVP at Week 4848-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 EFVEFV + 3TC/d4TPooled NVP + 3TC/d4T49†50434040*3534313027EFV, efavirenz; NVP, nevirapine.Mean Change in Lipids FromBaseline to Week 48 (%)2020105.9†-4.1-10TCLDLHDLTGTC:HDL*P < .05 vs NVP.†P < .001 vs NVP.van Leth F, et al. PLoS Med. 2004;1:e19.4242
43 Insulin Resistance Failure of target organs to respond normally to the action of insulin Ability of insulin to store exogenous glucose (muscle/fat) Ability of insulin to suppress endogenous glucose production (liver)43
44 Diabetes and Insulin Resistance in HIV Infection Type 2 diabetes secondary to insulin resistanceUsually asymptomaticPrevalence of type 2 diabetesRandom glucose 1%–2%OGTT 6%–10%Impaired glucose tolerance extra 15%–30%AssociationsLipoatrophy and fat accumulation Age76 pts had GTTNormal, IGT and DM diagnoses as per consensus guidelinesfasting BSLs norm in 98%2 hr BSLs abnormal in 23%MISTAKE (40 should be 60)Overall prevalence 22%Grinspoon S et al. N Engl J Med. 2005;352:48-62.
45 Impact of Various PIs on Glucose and Glucose Disposal Rate 2-Hour OGTTIDVLPV/rATV/rd4T3TCReferencesNoor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001;15:F11-F18.Dubé MP, Edmondson-Melançon H, Qian D, Aqeel R, Johnson DJ, Buchanan TA. Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients. J Acquir Immune Defic Syndr. 2001;27:Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS. 1999;13:F63-F70.Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS. 1999;13:Walli RK, Michl GM, Bogner JR, Goebel FD. Improvement of HAART-associated insulin resistance and dyslipidemia after replacement of protease inhibitors with abacavir. Eur J Med Res. 2001;6:Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS. 2002;16:F1-F8.Dubé MP, Qian D, Edmondson-Melançon H, et al. Prospective, 48-week, intensive metabolic study of amprenavir-based therapy. Clin Infect Dis. 2002;35:Sension M, Thiry A, Giordano M. Absence of insulin resistance through week 24 with atazanavir once-daily and efavirenz once-daily each with fixed-dose zidovudine plus lamivudine. Antivir Ther. 2002;7:L26.Noor MA, Parker RA, O’Mara E, et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS. 2004;18:Lee GA, et al. Clinical Infectious Disease Sep 1;43(5): Epub 2006 Jul 26.1. Noor MA et al. AIDS. 2001;15:F11-F18; 2. Dubé MP et al. JAIDS. 2001;27: ; 3. Behrens G et al. AIDS. 1999;13:F63-F70; 4. Martinez E et al. AIDS. 1999;13: ; 5. Walli RK et al. Eur J Med Res. 2001;6: ; 6. Noor MA et al. AIDS. 2002;16:F1-F8; 7. Dubé MP et al. Clin Infect Dis. 2002;35: ; 8. Sension M et al. Antivir Ther. 2002;7:L26; 9. Noor MA et al. AIDS. 2004;18: ; 10. Lee GA et al. Clin Infect Dis. 2006;43:
46 OR (95% CI) for insulin > 15 μU/mL Insulin Resistance in HIV-Infected Pts According to Specific Antiretrovirals533 HIV-infected and 755 HIV-uninfected men in MACS prospectively evaluated at 6-month intervals between 1999 and 2003Cumulative exposure to NRTIs, but not PIs or NNRTIs, associated with significant increases in insulin resistanceBased on markers for insulin resistance and hyperinsulinemiaParameterOR (95% CI) for insulin > 15 μU/mLSQV1.02IDV1.14*RTV (boosting dose)0.95NFV1.10d4T1.22*3TC1.12*ZDV0.98ddI0.950.011.02.0*P < .05Brown T, et al. AIDS. 2005;19:46
47 Metabolic Syndrome in HIV-Infected vs HIV-Uninfected Patients Conflicting data on whether metabolic syndrome more prevalent in HIV-infected patients and whether associated with antiretroviral therapyMay also reflect background regional variations in riskStudy, %Prevalence of Metabolic SyndromeP ValueHIV-Infected PatientsHIV-Uninfected ControlsUS; 471 men and women2627.77US; 2394 women3322< .001Spain; 710 men and women17N/A--NCEP ATP III, ≥ 3 of the following: Abdominal obesity (waist circumference > 102 cm for men; >88 cm for women), TG ≥ 150 mg/dL (≥ 1.70 mmol/L), HDL < 40 mg/dL (< 1.04 mmol/L) for men, < 50 mg/dL (< 1.30 mmol/L) for women, Blood pressure ≥ 130/≥ 85 mm Hg, Fasting glucose ≥ 110 mg/dL (≥ 5.55 mmol/L)1. Mondy K, et al. Clin Infect Dis. 2007;44: Sobieszczyk ME, et al. IAS Abstract WEPE Jerico C, et al. Diabetes Care. 2005;28:47
48 Prevalence of Traditional Cardiac Risk Factors at Baseline in the D:A:D Study Large cohort of HIV-infected patients on HAART followed longitudinally (N = 23,468)18,962 (80.8%) with previous ART exposure; 4506 (19.2%) antiretroviral naive100806051.5Percentage of Cohort With Risk Factor at Baseline4033.822.22011.48.51.43.52.5Family History of CHDPrevious History of CHDCurrent SmokingBMI > 30HTNDiabetes↑ Total Cholesterol↑ TGFriis-Møller N, et al. AIDS. 2003;17:4848
49 D:A:D Study: Incidence of MI A Small Increase in Incident CVD Is Associated WithDuration of Combination Antiretroviral TherapyRR per Year of ARTOverall1.16Men1.13Women1.361086Incidence of MI per 1000 PY42None< 11-22-33-44-55-66-7>7Exposure to ART (y)Friis-Moller N et al. N Engl J Med. 2007;356:49
50 D:A:D: Traditional Risk Factors for CHD in an HIV-Infected Population WorseBetterAge per 5 yrs olderRR: 1.32 ( )Male sexRR: 2.13 ( )Previous CVDRR: 4.64 ( )SmokingRR: 2.92 ( )Family historyRR: 1.40 ( )Diabetes (yes vs no)RR: 1.86 ( )Hypertension (yes vs no)RR: 1.30 ( )0.10.51510Relative Rate of MI (95% CI)Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family history of CVD, smoking, previous CVD event, TC, HDL, hypertension, diabetes.Friis-Møller, et al. N Engl J Med. 2007;356:5050
51 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.Friis-Moller N et al. N Engl J Med. 2007;356:
52 D:A:D – study results and abacavir 1st Feb 2007, 33,347 patients, 157,912 person-years.517 MI (event rate 3.3 [95% CI ] per 1,000 person-years)Abacavir and ddI associated with increased relative risk of MI of 1.9# and 1.49 respectivelyAssociated with recent abacavir and ddI use (<6mths), not cumulative exposure. Reversible on cessation of drug therapyAssociation remained after adjustment for HIV-RNA levels, CD4 count, dyslipidaemia, blood pressure, diabetes, fat loss/gain or latest glucose, Most pronounced in patients with a high underlying cardiovascular riskInsufficient data to assess TDF and FTCD:A:D Study Group, The Lancet, 26 April, 2008
53 D:A:D – study results and abacavir Analysis of 54 clinical trials involving 9,639 subjects exposed to ABC (7845 pyrs) and 5,044 subjects treated with non-ABC-containing regimens (4653 pyrs)Incidence of myocardial ischaemic events and MI similar regardless of therapy.no increased risk of coronary or myocardial events in any of the ABC-treated groups.Analysis of spontaneous reports submitted to GSK and the FDA found no signal of an increased risk of MI associated with use of ABC.1 million patient years of abacavir experienceCutrell A et al, The Lancet, 26 April, 2008
54 SMART: Treatment Interruption Associated With Increased CV Risk 2 HIV treatment strategies assessed for overall clinical benefit: CT or CD4-guided TITI associated with significantly greater disease progression or death, compared with CT: RR: 2.5 (95% CI: ; P < .001)ParameterHR (95% CI)Death from any cause1.8Risk of ComplicationsDeath from major cardiovascular, renal and hepatic events1.70.1Favors TI1.0Favors CT5.0El-Sadr W, et al. N Engl J Med. 2006;355:54
55 MI Rates by Age Group in HIV-Infected and HIV-Uninfected Patients Acute MI rates determined in 3851 HIV-infected and 1,044,589 HIV-uninfected patients fromOverall rates per 1000 person-years higher in HIV-infected vs HIV-uninfected patients: vs 6.98120HIV infected90HIV uninfected77.68Rates per 1000 Person-Yrs6043.6336.4733.393024.4718.7414.7810.134.657.560.883.3418-3435-4445-5455-6465-7475-84Age Group (Yrs)Triant VA, et al. J Clin Endocrin Metab. 2007;92:55
56 Framingham Underpredicts MI Risk in HIV Age, Sex, TC, HDL, Smoking, SBP, Medication for HBPObserved and Predicted MI Rates According to ART Exposure(D:A:D Study)87Observedrates65Best estimate ofpredicted ratesRates per 1000 Person-Yrs4321For more information, see the capsule summary at:None< 11-22-33-4> 4Duration of cART Exposure (Yrs)Does not include HIV-specific factors; Immune status, Increased inflammatory markers, Insulin resistanceLaw MG, et al. HIV Med. 2006;7:Friis-Moller N, et al. CROI Abstract 808.5656
57 Conclusions Strong correlation between LDL-C and CVD risk HDL-C independent predictor of CVDcART associated with increased risk of CVD, but uncontrolled HIV infection also risk for CV eventsOther traditional risks for CVD prevalent, including those that can be modified (smoking)NRTIs, NNRTIs, and PIs have varying effects on lipids, insulin resistance, and fat distribution changesBoosted PIs associated with increased prevalence of dyslipidemia, although evidence suggests that RTV contributes substantially to lipid effects
58 Prevalence of Elevated Cardiovascular Risk in HIV-Infected Patients 17% and 12% of HIV-infected men and women, respectively, had high predicted 10-year CHD risk according to Framingham equation10086878481HIV infected80HIV uninfected60Predicted 10-Year Risk of Developing CHD (%)4017201112125221Low risk (< 15%)Moderate risk (15% to 25%)High risk (≥ 25%)Low risk (< 15%)Moderate risk (15% to 25%)High risk (≥ 25%)MalesFemalesKaplan RC, et al. Clin Infect Dis. 2007;45:58
59 Prevention of cardiovascular disease EACS guidelines 2007 Estimate risk of IHD(Ischaemic Heart Disease) in next 10 yrsIHD risk <10%IHD risk 10-20%IHD risk >20%, prior CVD,type II diabetes, type I diabeteswith microalbuminuriaEncourage lifestyle changes (diet, exercise, cessation of smoking),reduce visceral fat, reduce insulin resistance and treat hypertensionLDL-c cut off level:5mmol/L(~190mg/dL) (5-4mmol/L(~190- ~155mg/dL))LDL-c cut off level:4mmol/L(~155mg/dL) (4-3mmol/L(~155- ~115mg/dL))LDL-c cut off level:3mmol/L(~115mg/dL) (3-2mmol/L(~115- ~80mg/dL))Consider modifying ART if:LDL-c is above cut off, i ART thought tocontribute to ↑ LDL-c level, if possiblewithout compromising HIV suppressionConsider modifying ART if:LDL-c is above cut off, i ART thought tocontribute to ↑ LDL-c level, if possiblewithout compromising HIV suppressionConsider modifying ART if:LDL-c is above cut off, i ART thought tocontribute to ↑ LDL-c level, if possiblewithout compromising HIV suppressionIf lifestyle changes, with or without modification of ART, do not result in sufficient lowering of LDL-cto below target level, use of lipid-lowering medication should be consideredAccessed from
60 Dietary Prevention of Dyslipidemia Randomized trial of NCEP diet in adults initiating ART (N = 90)95% on ZDV/3TC75% on EFV15- to 30-minute session with a dietician every 3 monthsOther outcomesReduced fat, calorie intakeReduced BMIIncreased dietary fiber intake220Diet Control200180TC (mg/dL)160140120100240220200180160140TG (mg/dL)1201008060406Lazzaretti F, et al. IAS Abstract WEAB303.60
61 Smoking Cessation: Nonpharmacologic Therapy InterventionsIdentify reasons for quittingDiscuss optionsSet a quit date, chosen by the patientSet up a support systemIdentify rationalizationsIdentify alternatives for cravingsProvide reliable sources of informationRefer to local smoking cessation programs
62 Effective Smoking Cessation Strategies DHHS guidelines: pharmacotherapy for all patients attempting to quit smoking except those with medical contraindicationsApproved pharmacotherapies: sustained-release bupropion, varenicline, nicotine gum, inhaler, nasal spray, and patchMore intensive intervention strategies significantly more effective than less intensive onesCounseling sessions lasting > 3 minutes and > 10 minutes were 1.3-fold and 2.3-fold, respectively, more likely to result in abstinence vs < 3 minutes8 sessions were 2.3-fold more likely to result in abstinence vs 0-1 sessionsTreatment by various clinician types, individualized counseling, and multiple intervention strategies associated with successful outcomesElzi L et al, Antiviral Therapy 2006, Fiore MC. Respir Care. 2000;45:62
63 Nicotine Replacement Therapy DrugActionCostDosingOTCGumFast acting$56.99110Wk 1–61 q 1–2 hWk 7–91 q 2–4 hWk 10–121 q 4–8 hLozenge$29.9948 lozengesPatchSlow acting$52.992-wk kitStep 121 mg X 6 wkStep 214 mg X 2 wkStep 37 mg X 2 wkPrescriptionInhaler10 mg cartridge$18.931 inhalerWk 1–126–16 cart/day(max 40/day)Wk 13–24Gradual taperNasal spray1 dose=2 sprays$ bottle(100 doses)Wk 1–81–2 doses/h (min 8/d)Wk 9–14Nicotine Replacement Therapy (NRT)ContraindicationsConcomitant tobacco usePrecautionsPregnancy category D – (human fetal risk); benefits must outweigh risksCardiovascular disease - 2 wks post MI, serious arrhythmias, & worsening angina pectorisNRT is not an independent risk factorHx of nasal airway reactions - irritation with NS formHx of local skin irritation - may occur with patch formAvailable at:
64 Smoking Cessation: Pharmacologic Therapy DrugDosingBupropion SRDays 1–3150 mg QDDay 4–end of treatment150 mg BIDHepatic impairmentMax:Varenicline0.5 mg QDDays 4–70.5 mg BIDDay 8–end of treatment1 mg BIDBupropionMechanism of actionWeak inhibitor of neuronal DA, NE, & 5-HT re-uptakePharmacokineticsAbsorption: steady state in 5-8 daysDistribution: 84% protein bound, Vd = 1,950 LMetabolism: CYP2B6Elimination: T1/2 = 21 hoursQuit Date = 2 weeks after initiationTreatment duration = 7-12 weeksIf no significant progress by 7 weeks discontinueDose titration not requiredIf significant progress by 7-12 weeks consider ongoing therapyChantix - In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymesα4β2 neuronal nicotinic Ach receptor partial agonistAgonist activity reduces cravings & antagonist effects inhibit reward sensationsHigh selectivity and affinityAbsorption: steady state in 4 daysDistribution: ≤20% protein boundMetabolism: 92% excreted unchanged in the urineElimination: T1/2 = 24 hoursPhysician's Desk Reference. Available at
65 Interactions Between Antiretrovirals and Smoking Cessation Drugs VareniclineNo reported drug interactions with antiretroviral agentsminimal metabolism, 92% excreted unchanged in the urineBupropionMetabolized in liver by various CYP450 enzymes, predominantly CYP2B6LPV/RTV and bupropion coadministration resulted in significantly decreased concentrations of bupropion and hydroxybupropionAdministration of ritonavir alone—most potent CYP3A4 inhibitor—may slow buproprion metabolismPatients receiving boosted PIs should be monitored carefully for bupropion lack of efficacy and adverse effects1. Hogeland GW, et al. Clin Pharmacol Ther. 2007;81: Hesse LM, et al. Drug Metab Dispos. 2001;29:65
66 Lipid-Lowering Therapy Overview Inhibit production of cholesterolAugment lipoprotein lipase (VLDL)StatinsLDL , TG , HDLSide effects: myopathy, liver enzymesFibric AcidsLDL , TG , HDL Side effects: dyspepsia,gallstones, myopathyEzetimibeLDL , TG , HDL Side effects: liver enzymes,diarrheaOmega-3 Fatty AcidsLDL , TG , HDL Side effects: GI, tasteSeveral 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.Nicotinic AcidLDL , TG , HDL Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicityBile Acid SequestrantsLDL , TG , HDL Side effects: GI distress/ constipation, absorptionof other drugs
67 Ezetimibe for Lipid Management Open-label, 24-week study of 19 patients with LDL 130 mg/dL ( mmol/L) receiving ezetimibe 10 mg/day, pravastatin 20 mg/day, and current antiretroviralsSignificant ↓ in TC and LDL and significant ↑ in HDL at Week 24*No adverse events noted250P = .011200BaselineWeek 24P = .005150Lipid Levels (mg/dL)100P = .00450TCLDLHDLTG*Subsequent study found that ezetimibe decreased LDL levels by 12% but had no effect on HDL or TG.1. Negredo E, et al. AIDS. 2006;20: Wohl D, et al. CROI Abstract 39.
68 Balancing ART and Lipid-Lowering Agents Lipid Management With ART in HIV-Infected PatientsPotential Drug–Drug Interactions With PIsFibratesFluvastatinPravastatin*EzetimibeStatin-FibratesAtorvastatinRosuvastatinLovastatinSimvastatinLow InteractionPotentialUse CautiouslyContraindicated With PIs*Not recommended with darunavir/ritonavir.Dubé M et al. Clin Infect Dis. 2003;37: ; Van Der Lee M et al. 13th CROI Denver, CO. Abstract 588; Prezista [package insert]. Raritan, NJ: Tibotec Therapeutics; 2006.
69 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)2001501005036912Months350For more information about this study, see the capsule summary at:300250Mean Cholesterol(mg/dL)2001501005036912MonthsCalza L, et al. AIDS. 2005;19:69
70 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.70
71 Strategies for Managing Hypertriglyceridemia Initial intervention: dietary modificationsConsider antiretroviral switch optionsIf TG > mg/mL (> mmol/L) and antiretroviral switch not possible, consider fibratesGemfibrozil 600 mg BID or fenofibrate 200 mg QD associated with 20% to 50% decrease in TG in general populationIf hypertriglyceridemia remains uncontrolledFish oil (up to 6 g/day) or niacin (0.5 to 2g twice-dialy) can be addedNiacin associated with flushing and increased insulin resistanceNCEP ATP III final report. Circulation. 2002;106:71
72 Content Introduction Selected specific adverse events ART and body shape changesART, HIV and metabolismCardiovascular risk general remarksART and LipidsART, Insulin resistance and diabetesHIV and cardiovascular riskTherapeutic approaches, GuidelinesImmune reconstitution inflammatary syndrome
73 IRIS = Inflammatory Immune Reconstitution Syndrome Incidence 3-25% Before ARTAdvanced diseaseHigh pathogen endemicityAfter ART initiationART early initiationVL decrease, CD4 increaseInflammationThreshold clinical diseasePathogen +++Pathogen (+)Pathogen specificimmunity inflammationCD4 very lowCD4 function and increase +++Battegay et al, JAC, 2008, Hirsch et al, CID 2004, French et al, AIDS 2004; Shelbourne et al, Med 2002
74 A5164 Methods: Study Schema, n=282 Immediate vs. Deferred ART in the Setting of Acute AIDS-Related OIs: Final Results of a Randomized Strategy Trial ACTG A5164OI/BI TreatmentStartsImmediate ArmStart ARTn=14148wksDeferred ArmStart ARTN=14148wksRecommendedStart window-142284284224Study dayEnrollmentA5164 Methods: Study Schema, n=282Adapted from Andrew Zolopa. CROI 2008; abstract 142.
77 A5164: Time to AIDS progression or death 11694Probability of Surviving Without Death/New AIDS-Defining IllnessHR=0.5399%CI (0.25, 1.09)P = 0.023Time to Death/New AIDS-Defining Illness (Weeks)Better CD4 increase, non significantly different VL resultsLess clinical progressionAdapted from Andrew Zolopa. CROI 2008; abstract 142.
78 NEW NIH DHHS Guidelines „Some experts base the timing of initiation of antiretroviral therapy in treatment-naive patients with active TB disease on CD4 cell counts at the start of treatment, as shown belowCD4 <100 ART after 2 weeksCD4 =100–200 ART after 8 weeksCD4 = 200–350 ART after 8 weeks*CD4 >350 ART after 8-24 weeks or after end of TB treatment** On case by case basis in clinician’s judgment.A rifamycin should be included for pts receiving ART (dose adjustment) (AII). Rifabutin is the preferred rifamycin in HIV-infected pts with active TB disease due to its lower risk of substantial interactions with ART (AII).Compiled from Benson et al at 2008