Clinical, behavioral and biomarker predictors of PCSK9 levels in HIV-infected patients naïve of statin therapy: A cross-sectional analysis from the Swiss HIV cohort


      • Better characterization of Proprotein Convertase Subtilisin Kexin 9 (PCSK9) profile is needed in HIV patients.
      • In HIV-infected individuals naïve of statin treatment, marijuana consumption and low CD4 values are associated with higher PCSK9 levels.
      • A future randomized controlled study assessing PCSK9 inhibitors in HIV patients should be considered in order to improve control of dyslipidaemia.


      Background and aims

      Better characterization of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) profile is currently needed to tailor appropriate lipid-lowering strategies in HIV patients.


      HIV-infected individuals aged ≥ 40 years and naive of statin therapy included in the Swiss HIV cohort study were screened for PCSK9 levels with a routine blood sample collection in 2014 at the Geneva University Hospitals. An exploratory linear regression model was built including clinical (age, sex, ethnicity, cardiovascular risk factors, body mass index, low CD4 defined as ≤200 cells/μl, leucocytes, lymphocytes, platelet, antiretroviral therapy), behavioral (tobacco and marijuana smoking, alcohol use and physical activity) and biomarker (CRP, TNF-α, IL-8, Il-10 and MCP-1) to investigate association with continuous PCSK9 levels.


      We studied 239 HIV-infected individuals who met inclusion criteria and available PCSK9 levels with a mean age of 49 years. 35 subjects (14.6%) reported marijuana consumption, of whom 20 (57.1%) reported daily consumption and 15 (6.3%) occasional use. PCSK9 levels were correlated with low-density lipoprotein-cholesterol (LDL-C). Our exploratory model identified marijuana consumption (p=0.023) and low CD4 values (p=0.020) as significantly associated factors with higher PCSK9 levels. No association was found with Framingham risk score. Patients with marijuana consumption had significantly higher levels of PCSK9 with a dose-response effect (p < 0.001); the association persisted after adjustment for the calculated Framingham risk score (p=0.003) and additional adjustment for clinical variables (p=0.027).


      In HIV-infected individuals naïve of statin treatment, marijuana consumption and low CD4 values are associated with higher PCSK9 levels independently of clinically relevant confounding factors.

      Graphical abstract

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        • Gencer B.
        • Mach F.
        Sweetless'n low LDL-C targets for PCSK9 treatment.
        Eur. Heart J. 2015; 36: 1146-1148
        • Navarese E.P.
        • Kolodziejczak M.
        • Schulze V.
        • et al.
        Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis.
        Ann. Intern. Med. 2015; 163: 40-51
        • Sabatine M.S.
        • Giugliano R.P.
        • Keech A.C.
        • et al.
        Evolocumab and clinical outcomes in patients with cardiovascular disease.
        N. Engl. J. Med. 2017; 376: 1713-1722
        • Nicholls S.J.
        • Puri R.
        • Anderson T.
        • et al.
        Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial.
        J. Am. Med. Assoc. 2016; 316: 2373-2384
        • Marcus J.L.
        • Neugebauer R.S.
        • Leyden W.A.
        • et al.
        Use of abacavir and risk of cardiovascular disease among HIV-infected individuals.
        J. Acquir. Immune Defic. Syndr. 2016; 71: 413-419
        • Hemkens L.G.
        • Bucher H.C.
        HIV infection and cardiovascular disease.
        Eur. Heart J. 2014; 35: 1373-1381
        • Calmy A.
        • Gayet-Ageron A.
        • Montecucco F.
        • et al.
        HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial.
        AIDS. 2009; 23: 929-939
        • Kohli P.
        • Ganz P.
        • Ma Y.
        • et al.
        HIV and hepatitis C-coinfected patients have lower low-density lipoprotein cholesterol despite higher proprotein convertase subtilisin kexin 9 (PCSK9): an apparent "PCSK9-lipid paradox".
        J. Am. Heart Assoc. 2016; 5
        • Satta N.
        • Pagano S.
        • Montecucco F.
        • et al.
        Anti-apolipoprotein A-1 autoantibodies are associated with immunodeficiency and systemic inflammation in HIV patients.
        J. Infect. 2018; 76: 186-195
        • Catapano A.L.
        • Graham I.
        • De Backer G.
        • et al.
        2016 ESC/EAS guidelines for the management of dyslipidaemias.
        Eur. Heart J. 2016; 37: 2999-3058
        • Swiss H.I.V.C.S.
        • Schoeni-Affolter F.
        • Ledergerber B.
        • et al.
        Cohort profile: the Swiss HIV Cohort study.
        Int. J. Epidemiol. 2010; 39: 1179-1189
        • Sauter R.
        • Huang R.
        • Ledergerber B.
        • et al.
        CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART.
        Medicine (Baltim.). 2016; 95 (e5094)
        • Gencer B.
        • Montecucco F.
        • Nanchen D.
        • et al.
        Prognostic value of PCSK9 levels in patients with acute coronary syndromes.
        Eur. Heart J. 2016; 37: 546-553
        • Auer R.
        • Vittinghoff E.
        • Yaffe K.
        • et al.
        Association between lifetime marijuana use and cognitive function in middle age: the coronary artery risk development in young adults (CARDIA) study.
        JAMA Intern. Med. 2016; 176: 352-361
        • Wandeler G.
        • Kraus D.
        • Fehr J.
        • et al.
        The J-curve in HIV: low and moderate alcohol intake predicts mortality but not the occurrence of major cardiovascular events.
        J. Acquir. Immune Defic. Syndr. 2016; 71: 302-309
        • Benedini S.
        • Luzi L.
        Lipodystrophy HIV-related and FGF21: a new marker to follow the progression of lipodystrophy?.
        J. Transl. Int. Med. 2016; 4: 150-154
        • D'Agostino R.B.
        • Russell M.W.
        • Huse D.M.
        • et al.
        Primary and subsequent coronary risk appraisal: new results from the Framingham study.
        Am. Heart J. 2000; 139: 272-281
        • Tarr P.E.
        • Ledergerber B.
        • Calmy A.
        • et al.
        Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons.
        Eur. Heart J. 2018; 39: 2147-2154
        • Group D.A.D.S.
        • Sabin C.A.
        • Worm S.W.
        • et al.
        Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.
        Lancet. 2008; 371: 1417-1426
        • Ryom L.
        • Lundgren J.D.
        • El-Sadr W.
        • et al.
        Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study.
        Lancet HIV. 2018; 5: e291-e300
        • Ruscica M.
        • Ferri N.
        • Fogacci F.
        • et al.
        Circulating levels of proprotein convertase subtilisin/kexin type 9 and arterial stiffness in a large population sample: data from the Brisighella heart study.
        J. Am. Heart Assoc. 2017; 6
        • Alonso R.
        • Mata P.
        • Muniz O.
        • et al.
        PCSK9 and lipoprotein (a) levels are two predictors of coronary artery calcification in asymptomatic patients with familial hypercholesterolemia.
        Atherosclerosis. 2016; 254: 249-253
        • Hsue P.Y.
        • Waters D.D.
        Time to recognize HIV infection as a major cardiovascular risk factor.
        Circulation. 2018; 138: 1113-1115
        • Feinstein M.J.
        • Bahiru E.
        • Achenbach C.
        • et al.
        Patterns of cardiovascular mortality for HIV-infected adults in the United States: 1999 to 2013.
        Am. J. Cardiol. 2016; 117: 214-220
        • Feinstein M.J.
        • Mitter S.S.
        • Yadlapati A.
        • et al.
        HIV-related myocardial vulnerability to infarction and coronary artery disease.
        J. Am. Coll. Cardiol. 2016; 68: 2026-2027
        • Stein J.H.
        • Hsue P.Y.
        Inflammation, immune activation, and CVD risk in individuals with HIV infection.
        J. Am. Med. Assoc. 2012; 308: 405-406
        • Lichtenstein K.A.
        • Armon C.
        • Buchacz K.
        • et al.
        Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study.
        Clin. Infect. Dis. 2010; 51: 435-447
        • Zanni M.V.
        • Toribio M.
        • Robbins G.K.
        • et al.
        Effects of antiretroviral therapy on immune function and arterial inflammation in treatment-naive patients with human immunodeficiency virus infection.
        JAMA Cardiol. 2016; 1: 474-480
        • Stein J.H.
        • Hsue P.Y.
        Inflammation and arterial injury in individuals with human immunodeficiency virus infection.
        JAMA Cardiol. 2016; 1: 481-482
        • Nan C.
        • Shaefer M.
        • Urbaityte R.
        • et al.
        Abacavir use and risk for myocardial infarction and cardiovascular events: pooled analysis of data from clinical trials.
        Open Forum Infect. Dis. 2018; 5 (ofy086)
        • O'Halloran J.A.
        • Dunne E.
        • Tinago W.
        • Denieffe S.
        • Kenny D.
        • Mallon P.W.G.
        Switching from abacavir to tenofovir disoproxil fumarate is associated with rises in soluble glycoprotein VI, suggesting changes in platelet-collagen interactions.
        AIDS. 2018; 32: 861-866
        • Ridker P.M.
        • Rifai N.
        • Bradwin G.
        • Rose L.
        Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events.
        Eur. Heart J. 2016; 37: 554-560
        • Vlachopoulos C.
        • Terentes-Printzios D.
        • Georgiopoulos G.
        • et al.
        Prediction of cardiovascular events with levels of proprotein convertase subtilisin/kexin type 9: a systematic review and meta-analysis.
        Atherosclerosis. 2016; 252: 50-60
        • Macchi C.
        • Ferri N.
        • Favero C.
        • et al.
        Long-term exposure to air pollution raises circulating levels of proprotein convertase subtilisin/kexin type 9 in obese individuals.
        Eur. J. Prev. Cardiol. 2018; 2047487318815320
        • Ricci C.
        • Ruscica M.
        • Camera M.
        • et al.
        PCSK9 induces a pro-inflammatory response in macrophages.
        Sci. Rep. 2018; 8: 2267
        • Rodondi N.
        • Pletcher M.J.
        • Liu K.
        • Hulley S.B.
        • Sidney S.
        Marijuana use, diet, body mass index, and cardiovascular risk factors (from the CARDIA study).
        Am. J. Cardiol. 2006; 98: 478-484
        • Steffens S.
        • Veillard N.R.
        • Arnaud C.
        • et al.
        Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.
        Nature. 2005; 434: 782-786
        • Quercioli A.
        • Pataky Z.
        • Vincenti G.
        • et al.
        Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity.
        Eur. Heart J. 2011; 32: 1369-1378
        • Yankey B.A.
        • Rothenberg R.
        • Strasser S.
        • Ramsey-White K.
        • Okosun I.S.
        Effect of marijuana use on cardiovascular and cerebrovascular mortality: a study using the National Health and Nutrition Examination Survey linked mortality file.
        Eur. J. Prev. Cardiol. 2017; 24: 1833-1840
        • Auer R.
        • Sidney S.
        • Goff D.
        • et al.
        Lifetime marijuana use and subclinical atherosclerosis: the coronary artery risk development in young adults (CARDIA) study.
        Addiction. 2018; 113: 845-856
        • Nicholls S.J.
        • Miller C.
        Taking the lid off the pot on marijuana and cardiovascular disease.
        Eur. J. Prev. Cardiol. 2017; 24: 1831-1832
        • Kamani C.H.
        • Gencer B.
        • Montecucco F.
        • et al.
        Stairs instead of elevators at the workplace decreases PCSK9 levels in a healthy population.
        Eur. J. Clin. Investig. 2015; 45: 1017-1024
        • Navarese E.P.
        • Kolodziejczak M.
        • Winter M.P.
        • et al.
        Association of PCSK9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: the PCSK9-REACT study.
        Int. J. Cardiol. 2017; 227: 644-649
        • Camera M.
        • Rossetti L.
        • Barbieri S.S.
        • et al.
        PCSK9 as a positive modulator of platelet activation.
        J. Am. Coll. Cardiol. 2018; 71: 952-954
        • Ferri N.
        • Marchiano S.
        • Tibolla G.
        • et al.
        PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement.
        Atherosclerosis. 2016; 253: 214-224
        • Giunzioni I.
        • Tavori H.
        • Covarrubias R.
        • et al.
        Local effects of human PCSK9 on the atherosclerotic lesion.
        J. Pathol. 2016; 238: 52-62
        • Bucher H.C.
        • Richter W.
        • Glass T.R.
        • et al.
        Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: the Swiss HIV cohort study.
        J. Acquir. Immune Defic. Syndr. 2012; 60: 135-142
        • Ruscica M.
        • Ferri N.
        • Macchi C.
        • et al.
        Liver fat accumulation is associated with circulating PCSK9.
        Ann. Med. 2016; 48: 384-391

      Linked Article

      • PCSK9 in HIV infection: New opportunity or red herring?
        AtherosclerosisVol. 284
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          While modern drug therapy has improved survival of patients with immune deficiency virus (HIV) infection, the rate of myocardial infarction among affected individuals has increased by 50% [1]. This is not explicable by conventional cardiovascular (CV) risk factors and could relate to HIV infection itself or to specific drug treatments [2].
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