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Cardiovascular Risk in HIV: What Is the Role of Antiretroviral Therapy?

Cardiovascular Risk in HIV: What Is the Role of Antiretroviral Therapy?. David A. Wohl, MD

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Cardiovascular Risk in HIV: What Is the Role of Antiretroviral Therapy?

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  1. Cardiovascular Risk in HIV: What Is the Role of Antiretroviral Therapy? David A. Wohl, MD Clinical Associate Professor, Division of Infectious DiseasesUniversity of North Carolina at Chapel Hill, School of MedicineCo-Principal InvestigatorUNC-CH AIDS Clinical Trials Unit (NIH/DAIDS)Co-Director of HIV ServicesNorth Carolina Department of CorrectionsChapel Hill, North Carolina

  2. Overview • HIV-related morbidity and mortality • CVD and risk factors • Similarities and differences compared with general population • Review of ongoing cohort studies:insights and limitations • HAART and CV risk: Are there any differences among ARV agents?

  3. HIV-related Morbidity and Mortality

  4. 100 100 80 60 10 40 20 1 0 EuroSIDA: Reduction in the Incidence of AIDS and Death Since the Introduction of HAART Morbidity and Mortality Across Europe, Israel, and Argentina ~10,000 Patients % patients on HAART Combined rate of AIDS and death Combined AIDS and death rates Patients (%) Sept 1994 March 1995 Sept 2001-onwards March 1995-Sept 1995 March 1997-Sept 1997 Sept 1997-March 1998 March 1998-Sept 1998 Sept 1998-March 1999 March 1999-Sept 1999 Sept 1999–March 2000 March 2000-Sept 2000 Sept 1995-March 1996 Sept 1996–March 1997 Sept 2000-March 2001 March 2001-Sept 2001 March 1996- Sept 1996 Mocroft A et al. Lancet. 2003;362:22-29.

  5. HIV Liver Malignancy Heart Immunosuppression Increases the Riskof Non–HIV-related Death (D:A:D Study) RR of Death According to Immune Function and Specific Cause 100 10 Relative risk of death 1.0 0.1 50–99 <50 100–199 200–349 350–499 >500 Latest CD4+ count (cells/mm3) • N=23,441 • Of these, 82% on ART • 1248 (5.3%) deaths 2000–2004 (1.6/100 person-years) • Incidence of CV-related mortality (9%) lower than other non–HIV-related deaths,liver-related mortality (14%), and HIV-related mortality (30%) Weber R et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 24, 2005;Boston, MA. Abstract 595.

  6. No. of Patients With Events Relative Risk 95% CI Subgroups 1.5 Severe complications 114 1.4 CVD, liver, renal deaths 31 1.5 Nonfatal CVD events 63 1.4 Nonfatal hepatic events 14 2.5 Nonfatal renal events 7 0.1 10 VS Better DC Worse SMART Study: Uncontrolled HIV Replication Increases the Risk of CVD • CD4+ guided drug conservation (DC) strategy was associated with significantly greater disease progression or death compared with continuous viral suppression (VS): RR 2.5 (95% CI: 1.8–3.6; P<.001) • Includes increased CVD-, liver-, and renal-related deaths and nonfatal CVD events Severe Complications End Point and Components SMART=Strategies for Management of Anti-Retroviral Therapy. El-Sadr W et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 8, 2006; Denver, CO. Abstract 106LB.

  7. HIV-related Morbidityand Mortality: Summary • HIV+ patients have an increased life expectancy since the introduction of HAART • The best prospective data show the relative rate of MI in HIV+ population is low and decreasing over time • From a public health standpoint, MI and other CVD events are a relatively smaller issue in HIV+ patients when compared with overall HIV-related morbidity and mortality • Most guidelines support maximal viral suppression and increased immune function • Increasing CD4+ T-cell count to levels approaching uninfected controls may reduce all-cause mortality, as well as HIV-related mortality1 1. Weber R et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 24, 2005; Boston, MA. Abstract 595.

  8. Cardiovascular Diseaseand Risk Factors Similarities and DifferencesCompared With the General Population

  9. ? HIV infection HAART Traditional Factors Are the Biggest Contributor to Coronary Heart Disease (CHD) in HIV Population Gender Abdominal obesity* Family history Inactivity, diet Cigarette smoking Age CHD Risk Lipids* Hyper-tension* Hyper-glycemia Emerging markers:Lp(a) CRP, IMT and endothelial function Insulin resistance* Diabetes * Metabolic syndrome. CRP=C-reactive protein; IMT=intima-media thickness; Lp(a)=lipoprotein(a).

  10. 512 2.9(2.6–3.2) 2.4(2.1–2.7) 1.9(1.7–2.1) 3.3(2.8–3.8) 13.0(10.7–15.8) 42.3(33.2–54.0) 68.5(53.0–88.6) 182.9(132.6–252.2) 333.7(230.2–483.9) 256 128 64 32 16 Odds ratio (99% CI) 8 4 2 1 Smk(1) DM(2) HTN(3) ApoB/A1(4) 1+2+3 All 4 +Obes +PS All RFs In the General Population, Multiple Traditional Risk Factors Confer Synergistic Increases in the Risk of MI: INTERHEART Study Evaluated Factors Associated With MI in 15,000 MI Patients vs 15,000 Case Controls Risk factor (adjusted for all others) >90% of total risk can be attributed to these factors.ApoB/A1=apolipoproteins B and A1; DM=diabetes mellitus; HTN=hypertension; Obes=abdominal obesity; PS=psychosocial; RF=risk factors; Smk=smoking. Yusuf S et al. Lancet. 2004;364:937-952.

  11. Overall Incidence of CV Events Is Low in an HIV-infected Population: HOPS Cohort • >8000 patients followed since 1993 in HIV Outpatient Study (HOPS) • 1807 selected patients from 3/1/96 to 9/30/05 with available baseline and ≥1 cholesterol, TG,and glucose value recorded (note possible selection bias) • Results: 84 CVD events in 57 patients • No association found for specific ARV/class, pre-HAART CD4+ cell count, time on HAART, BMI >30, peak VL, peak TC, peak LDL, or peak TG • Risk of CV events reduced with lipid-lowering agents MV Logistic Regression Analysis of Risk Factors for CVD(n=1807) 10 3.31 3.24 1.95 1.73 0.97 Adjusted odds ratio(95% CI) 1 Age >40 Diabetes Hyper- lipidemia HTN Nadir HDL* P<.001 P<.001 P=.024 P=.059 P=.004 0.1 * Continuous variable. MV=multivariate; VL=viral load. Lichtenstein K et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 6, 2006; Denver, CO. Abstract 735.

  12. Risk Factors for CHD inan HIV+ Population Better Worse Age per 5 years older Male gender Previous CVD Smoking Family history Diabetes mellitus (yes vs no) RR 2.29 (1.61-3.26) Hypertension (yes vs no) RR 1.67 (1.21-2.30) 0.1 1 5 10 0.5 Relative rate of myocardial infarction (95% CI)Multivariable Poisson model(adjusted for BMI, HIV risk, cohort, calendar year, and race) Copenhagen HIV program (D:A:D) Lundgren JD et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 23, 2005; Boston, MA. Abstract 62.

  13. APROCO Cohort (HIV+) P<.0001 MONICA sample (HIV–) P<.0001 P=NS P<.01 P=NS Incidence of Smoking Is Increased AmongHIV-infected Individuals vs the General Population • HIV+ men and women (n=223) on PI-based regimens vs 527 HIV- male subjects • HIV+ patients have lower HDL-C and higher TG • Predicted risk of CHD was greater in HIV+ men (RR=1.2) and women (RR=1.6), P<.0001 70 60 50 40 Patients (%) 30 20 10 0 HDL-C <40 mg/dL LDL-C 160 mg/dL Hypertension Smoking Blood glucose 126 mg/dL No difference in TC Savès M et al. Clin Infect Dis. 2003;37:292-298.

  14. NRTIs + PIs NRTIs + NNRTIs VA Database: No Evidence of Increased CV Events in 36,766 Veterans With HIV (1993-2001) • 8.5-year retrospective assessment of VA databases • Median exposure: • NRTI: 17 months • PI: 16 months • NNRTI: 9 months • CV disease and overall mortality • 1764 CV admissions • 521 CV deaths • 16,731 total deaths • Marked decline in overall mortality since HAART • No evidence of increase in CV hospital admissions or CV mortality with HAART CVD Admissions 2.5 2.0 1.5 Admissions per 100 pt-yrs 1.0 0.5 0 No ART 0 <2 2–4 >4 ART (years of use) Bozzette SA et al. N Engl J Med. 2003;348:702-710.

  15. 2 1 0.5 0.25 99/00 01 02 04/05 03 Overall RR Model adjusted for: sex, age, cohort, prior CVD, family CVD history, smoking, BMI, cART exposure Model adjusted for serum-lipids (total cholesterol, HDL-C, and triglycerides) D:A:D Study: Rates of MI in HIV-infected and HAART-treated Patients Over Time RR (95% CI) • Incidence of MIs is low: 345 over 94,469 pt-years follow-up (3.7/1000 pt-years) •  PI exposure associated with  risk of MI (RR: 1.17/year of exposure; 95% CI 1.12-1.23) • No evidence of  risk of MI with  NNRTI exposure, despite fewer years of experience(RR: 1.07/year of exposure; 95% CI 1.00-1.14) • PI exposure 72,846 pt-yrs; NNRTI exposure 52,457 pt-yrs D:A:D=Data Collection on Adverse Events of Anti-HIV Drugs. Friis-Møller N et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 8, 2006; Denver, CO. Abstract 144.

  16. Studies on CV Risk in HIV-infected and HAART-treated Patients Are Inconsistent • P=prospective; R=retrospective. • Bozzette SA et al. N Engl J Med. 2003;348:702-710. • Lichtenstein K et al. 13th CROI, Denver 2006. Abstract 735. • Friis-Møller N et al. 13th CROI, Denver 2006. Abstract 144. • Klein D et al. 13th CROI, Denver 2006. Abstract 737. • Currier JS et al. J Acquir Immune Def Syndr. 2003;33:506-512. • Mary-Krause M et al. AIDS. 2003;17:2479-2486. • Moore RD et al. 10th CROI, Boston 2003. Abstract 132. • Rickerts V et al. Eur J Med Res. 2000;5:329-333. • El-Sadr W et al. 13th CROI, Denver 2006. Abstract 106LB.

  17. Cardiovascular Disease and Risk Factors: Similarities and Differences Compared With the General Population • Traditional risk factors for CV disease, suchas age and smoking, increase CV risk in both HIV+ and HIV– individuals • HIV disease may confer its own increase in CVD risk • HAART may contribute to increased CV risk, but the absolute increase due to HAART is low

  18. NRTIs GI discomfort Headache Hypersensitivity reaction Neuropathy Pancreatitis Bone marrow suppression Lactic acidosis Lipoatrophy Dyslipidemia NNRTIs Rash CNS Hepatitis Dyslipidemia Teratogenicity Protease inhibitors GI discomfort Diarrhea Paresthesia Hyperbilirubinemia Dyslipidemia Lipodystrophy Nephrolithiasis Skin/nail changes Interaction with ARVs Food interactions Choosing an Initial Regimen: Tolerability and Toxicity Type and magnitude of lipid variation may vary between classes and agent

  19. Metabolic Effects of Low-dose Ritonavir RTV 100 mg bid or LPV/r (HIV–) 14 days * P≤.001; †P=.01; ‡P=.015.Shafran SD et al. HIV Med. 2005;6:421-425.

  20. KLEAN study: FPV/r vs LPV/r (+ ABC/3TC):No Differences in Lipid Levels Between Study Arms • Open-label, non-inferiority study: 878 ART-naïve, HIV+ patients randomized to FPV + RTV (n=436) 700 mg/100 mg bid or LPV/r (SGC) 400 mg/100 mg bid (n=443) • Primary end points: proportion of patients achieving HIV-1 RNA <400 c/mL at Week 48 and treatment discontinuations because of an adverse event Fasting Lipid Levels at Week 48 KLEAN=Kaletra versus Lexiva with Epivir and Abacavir in ART-Naïve patients; SGC=soft gel capsule. Eron R Jr et al. Lancet. 2006;368:476-482.

  21. TC LDL-C HDL-C TG ATV 300 + RTV 35 ATV 400 30 29 30 26 23 25 20 16 Mean change frombaseline (%) 15 15 10 6 5 0 -5 -3 P value <.01 0.21 0.69 <.01 Fasting Lipid Profiles forBoosted vs Unboosted Atazanavir 96-week randomized, open label, prospective study of ATV + RTV (300/100 mg) vs ATV (400 mg), both in combination with 3TC and extended-release d4T (N=200) Lipid Percent Changes From Baseline to Week 48 Malan N et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 7, 2006;Denver, CO. Abstract 107LB.

  22. Lipid Profiles: Once-daily BoostedFPV/r vs ATV/r + (TDF/FTC) Baseline Cholesterol Triglycerides Week 24 Mg/dL LDL HDL Mg/dL Smith K et al. Presented at: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, CA. Abstract H-1670a.

  23. Total Cholesterol <200 mg/dL ATV 400 Comparator PI LDL-C <130 mg/dL Patients (%) ATV 400 Comparator PI BL Wk 12 BL Wk 12 Patients (%) BL Wk 12 BL Wk 12 TG <150 mg/dL HDL ≥40 mg/dL ATV 400 Comparator PI ATV 400 Comparator PI Patients (%) Patients (%) BL Wk 12 BL Wk 12 BL Wk 12 BL Wk 12 Lipid Profiles:Atazanavir vs Comparator PI Sension M et al. 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, MA. Poster #858.

  24. ACTG 5142: LPV/r vs EFV vs LPV/r + EFV Stratified for VL ≤ or > 100,000, hepatitis coinfection, and selection of NRTI Week 96 LPV/r SGC400/100 mg twice daily + 2 NRTIs* (n=253) Antiretroviral-naïve patients*; VL >2000 copies/mL; any CD4+ cell count (N =753) EFV 600 mg once daily + 2 NRTIs* (n=250) LPV/r SGC533/133 mg twice daily +EFV 600 mg once daily (n=250) • Primary end points • Time to virologic failure • Regimen completion: virologic failure or toxicity-related discontinuation of any regimen component *Lamivudine plus either ZDV, d4T XR, or TDF, selected by investigator before randomization. Riddler SA et al. 16th International AIDS Conference. August 13-18, 2006. Toronto, Ontario. Abstract THLB204.

  25. ACTG 5142: 96-Week Tolerability Results ACT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Riddler SA et al. 16th International AIDS Conference. August 13-18, 2006. Toronto, Ontario. Abstract ThLB204.

  26. Lipid Effects of NNRTIs: EFV vs NVP Lipid Changes at Week 48 • 2NN study • Prospective analysisin treatment-naïve patients • Lipid profiles • Randomized treatments • Efavirenz (n=289) • Nevirapine (n=417) • All patients: 3TC + d4T * P<.05 and †P<.001 vs NVP arm. Adapted from van Leth F et al. PLoS Med. 2004;1:64-74.

  27. 40 36 P<.001 30 21 20 Mean change from baseline (mg/dL) 10 TDF + FTC + (EFV) Combivir + (EFV) 0 -10 0 4 16 24 32 48 Study week Lipid Changes Differ Among NRTIs Fasting Total Cholesterol d4T vs TDF (3TC + EFV) P<.001 P<.001 Mean change from baseline value (mmol/L) P<.001 P=.003 Arribas JR et al. Presented at: 18th International Conference on Antiviral Research; April 11-14, 2005; Barcelona, Spain;Gallant J et al. N Engl J Med. 2006;354:251-260; Podzamzscer D et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, MA. Abstract 587S.

  28. Summary • Dyslipidemia has been reported with PIs, NNRTIs,and NRTIs • Ritonavir boosting affects lipid profiles regardless of the PI chosen • NNRTIs are associated with increases in all lipid parameters • All NRTIs, when used in combination with other antiretrovirals, are associated with an increasein lipid parameters • HDL-C increases seen with antiretrovirals may favorably impact cardiovascular risk

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