Cardiovascular Side Effects of HIV Treatment

Jean-Guy Baril, MDMark Wainberg, Phd

The D:A:D Cohort• What is D:A:D?

– The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) – A prospective multi-cohort study of HIV-1 positive persons under active follow

up. • D:A:D 1 – 23,441 patients enrolled 1999-2001• D:A:D 2 – 12,900 patients enrolled through Spring 2004• D:A:D 3 – 16,000 patients enrolled in 2010

• 11 cohorts worldwide • More than 49,000 patients from 212 clinics in 33 countries in Europe, USA

and Australia. • Core Data:

– Incident cases of cardiovascular disease in HIV infected persons • Other Data:

– Risk factors for CVD including previous MI, stroke, family history, smoking status, diabetes, dyslipidemia, and hypertension

– Investigate associations between these risk factors, stage of HIV disease and use of antiretroviral therapies

– Non-AIDS defining malignancies– End-stage renal disease– Chronic liver disease– Death

Source: http://www.cphiv.dk/dad/about/tabid/106/default.aspx

MI incidence increases with longer exposure to combination antiretroviral

therapy

Source: Class of Antiretroviral Drugs and the Risk of Myocardial Infarction.Writing committee: N Friis-Moller et al. N Engl J Med. 2007 April 26;356:1723-35

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Adjusted relative rate, 1.16 per year of exposure; 95% confidence interval [CI],1.09 to 1.23

MI Risk and Drug Class

Source: Class of Antiretroviral Drugs and the Risk of Myocardial Infarction.Writing committee: N Friis-Moller et al. N Engl J Med. 2007 April 26;356:1723-35

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Increased risk of myocardial infarction after cumulative exposure to HIV medications

• Cumulative exposure (relative rate [RR] per additional year) – Indinavir 1.12 [95% CI, 1.07–1.18] – Lopinavir-ritonavir 1.13 [95% CI, 1.05–1.21]– Abacavir 1.07 [95% CI, 1.00–1.14]

• Recent Exposure to– abacavir 1.70 [95% CI, 1.17–2.47]– didanosine RR,1.41 [95% CI, 1.09–1.82]

Source: Risk of Myocardial Infarction in Patients with HIV Infection Exposed to SpecificIndividual Antiretroviral Drugs from the 3 Major Drug classes: The Data Collection onAdverse Events of Anti-HIV Drugs (D:A:D) Study.Worm SW et al. J Infect Dis. 2010 Feb 1;201(3):318-30.

FDA Meta-Analysis of CVD Risk from Abacavir Containing Regimens

Source: Ding X., et al. No Association of Myocardial Infarction with ABC Use:An FDA Meta-analysis . CROI 2011 Paper #808

D:A:D Risk for Current or Recent Exposure to Abacavir

• Relative Rate – 1.70 [95% CI, 1.17–2.47]

Source: Risk of Myocardial Infarction in Patients with HIV Infection Exposed to Specific IndividualAntiretroviral Drugs from the 3 Major Drug classes: The Data Collection on Adverse Events ofAnti-HIV Drugs (D:A:D) Study. Worm SW et al. J Infect Dis. 2010 Feb 1;201(3):318-30.

D:A:D Risk for Cumulative Exposure to Abacavir

• Relative Rate of MI per Additional year– 1.07 [95% CI, 1.00–1.14]

Source: Risk of Myocardial Infarction in Patients with HIV Infection Exposed to Specific IndividualAntiretroviral Drugs from the 3 Major Drug classes: The Data Collection on Adverse Events ofAnti-HIV Drugs (D:A:D) Study. Worm SW et al. J Infect Dis. 2010 Feb 1;201(3):318-30.

Abacavir Associated MI Risk in the Quebec Cohort

Source: Durand M et al. Association between HIV infection, antiretroviral therapy, and risk ofacute myocardial infarction: a cohort and nested case-control study using Québec's publichealth insurance database. J Acquir Immune Defic Syndr. 2011 Jul 1;57(3):245-53.

Lack of CVD Risk with Atazanavir

Source: Monforte A. d’A. et al. ATV-containing ART Is Not Associated with an Increased Risk ofCardio- or Cerebro-vascular Events in the D:A:D Study . CROI 2012 Paper #823

No Effect from Ritonavir Boosting

Source: Monforte A. d’A. et al. ATV-containing ART Is Not Associated with an Increased Risk ofCardio- or Cerebro-vascular Events in the D:A:D Study . CROI 2012 Paper #823

Effect of Lopinavir on Lipid Levels

Source: Montes ML, et al. Lipid disorders in antiretroviral-naive patients treated withlopinavir/ritonavir-based HAART: frequency, characterization and risk factors.J Antimicrob Chemother. 2005 May;55(5):800-4

MI Risk with Protease Inhibitor Use

• Unadjusted Relative Rate Per Year of Exposure– 1.16 (95% CI, 1.09 to 1.23)

• Adjusted for Lipid Levels– 1.10 (95% CI, 1.04 to 1.18)

Source: Class of Antiretroviral Drugs and the Risk of Myocardial Infarction.Writing committee: N Friis-Moller et al. N Engl J Med. 2007 April 26;356:1723-35

Incidence rate ratio per year of exposure to ARVs on risk of CKD

Univariate Multivariate

IRR(/year)

95% CI p IRR(/year)

95% CI p

Tenofovir 1.32 1.21-1.41 <0.0001 1.16 1.06-1.25 <0.0001

Indinavir 1.18 1.13-1.24 <0.0001 1.12 1.06-1.18 <0.0001

Atazanavir 1.48 1.35-1.62 <0.0001 1.21 1.09-1.34 0.0003

Lopinavir 1.15 1.07-1.23 <0.0001 1.08 1.01-1.16 0.030

CKD, confirmed (persisting for >3 months) decrease in eGFR <60 mL/min/1.73m2 if eGFR at baseline >60 mL/min/1.73m2 or confirmed 25% decrease in eGFR if baseline eGFR <80 mL/min/1.73m2. Adjusted for eGFR baseline, AIDS at baseline, AIDS during follow up, use of nephrotoxic drugs, current CD4, current age, current HIV viral load. Any CV event (stroke, acute MI, bypass, angioplasty or carotid endarterectomy), hypertension, diabetes, hepatitis C status, non-AIDS malignancy, and gender. Variable included as time-updated. No other ARVs or types of antiretroviral regimen were significantly associated with CDK.

Ole Kirk et al. 2010 Chronic Kidney Disease and Exposure to ART in a Large Cohort with Long-termFollow-up: The EuroSIDA Study Paper # 107LB