Statin therapy and low-density lipoprotein cholesterol reduction in HIV-infected individuals after acute coronary syndrome: Results from the PACS-HIV lipids substudy

    Statin therapy and LDLc reduction in HIV-infected individuals after acute coronary syndrome. Results from the PACS-HIV Lipids substudy Franck Boccara MD, PhD, Joe Miantezila Basilua MSc, Murielle MaryKrause PhD, Sylvie Lang PhD, Emmanuel Teiger MD, PhD, Philippe Gabriel Steg MD, Christian Funck-Brentano MD, PhD, Pierre-Marie Girard MD, PhD, Dominique Costagliola PhD, Ariel Cohen MD, PhD, Marguerite Guiguet PhD PII: DOI: Reference:

S0002-8703(16)30235-6 doi: 10.1016/j.ahj.2016.10.013 YMHJ 5308

To appear in:

American Heart Journal

Received date: Accepted date:

18 July 2016 17 October 2016

Please cite this article as: Boccara Franck, Miantezila Basilua Joe, Mary-Krause Murielle, Lang Sylvie, Teiger Emmanuel, Steg Philippe Gabriel, Funck-Brentano Christian, Girard Pierre-Marie, Costagliola Dominique, Cohen Ariel, Guiguet Marguerite, Statin therapy and LDLc reduction in HIV-infected individuals after acute coronary syndrome. Results from the PACS-HIV Lipids substudy, American Heart Journal (2016), doi: 10.1016/j.ahj.2016.10.013

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ACCEPTED MANUSCRIPT Statin therapy and LDLc reduction in HIV-infected individuals after acute coronary

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syndrome. Results from the PACS-HIV Lipids substudy.

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Running head: Lipids after ACS in HIV-infected patients

Franck BOCCARA, MD, PhD1,2, Joe MIANTEZILA BASILUA, MSc3,4, Murielle MARY-KRAUSE, PhD3,4

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Sylvie LANG, PhD1, Emmanuel TEIGER, MD, PhD5, Philippe Gabriel STEG, MD6,7,8,9, Christian FUNCKBRENTANO, MD, PhD10,11,12 13, Pierre-Marie GIRARD, MD, PhD14, Dominique COSTAGLIOLA, PhD3,4,

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Ariel COHEN, MD, PhD1, Marguerite GUIGUET, PhD3,4 on behalf the PACS-HIV investigators (Prognosis of Acute Coronary Syndrome in HIV-infected patients)

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AP-HP, Hôpitaux de l'Est Parisien, Hôpital Saint-Antoine, Service de Cardiologie, 75012, Paris, France;

Sorbonne Universities, UPMC University Paris 06, Faculty of Medicine. 2

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INSERM, UMR_S 938, UPMC, F-75012, Paris, France; emails: [email protected],

[email protected], [email protected] 3

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INSERM, UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, F-75013, Paris, France;

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Sorbonne Universities, UPMC University Paris 6, UMR_S 1136, Pierre Louis Institute of Epidemiology and

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Public Health, F-75013, Paris, France; email: [email protected], [email protected], [email protected]; [email protected] 5

Cardiology Department Hôpital Henri-Mondor, Assistance-Publique-Hôpitaux de Paris & INSERM-U955, 51

Avenue du Maréchal de Lattre de Tassigny, 94000 Creteil, France. Email : [email protected] 6

FACT (French Alliance for Cardiovascular clinical Trials), Département Hospitalo-Universitaire FIRE,

AP-HP, Hôpital Bichat, Paris, France; 7

Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;

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INSERM U-1148, F-75018 Paris, France;

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NHLI, Imperial College, Royal Brompton Hospital, London, UK; email: [email protected]

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Sorbonne Universities, UPMC University Paris 06, Faculty of Medicine, Department of Pharmacology and

UMR ICAN 1166, F-75013 Paris, France; 11

AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-1421, F-75013 Paris, France;

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INSERM, CIC-1421 and UMR ICAN 1166, F-75013 Paris, France;

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Institute of Cardiometabolism and Nutrition (ICAN) email; [email protected]

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Department of Infectious and Tropical Diseases, Hôpital Saint-Antoine, AP-HP, and INSERM, UMR_S 1136, F-75013, Paris, France. Email: pierre-

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Institut Pierre Louis d’Epidémiologie et de Santé Publique,

CORRESPONDENCE and REQUESTS FOR REPRINTS:

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[email protected]

rue du Faubourg St Antoine, 75012, Paris, France.

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Franck Boccara, MD, PhD, Department of Cardiology, Saint Antoine Hospital, University Paris 6, AP-HP, 184

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Tel: +3314928449, fax +33149282683, email: [email protected]

Manuscript word count: 3629. Tables: 3, Figures: 2

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Supplementary data: Tables: 2, Figure: 1

Abstract: 249 words

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Funding

This study was funded by the Agence Nationale de Recherches sur le Sida et les Hepatites Virales [French

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National Agency for Research on AIDS and Viral Hepatitis] and Sidaction-Ensemble contre le SIDA], Paris,

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France

Clinical Trials.gov identifier NCT00139958

Highlights Bullets HIV+ individuals exhibited worse lipid profiles in the first 6 months after first ACS than did controls. Less potent statins were more frequently prescribed to HIV+ individuals following ACS. High intensity statin therapy should be prescribed following first ACS in HIV+ individuals. Drug-drug interactions between statins and some protease inhibitors have to be recognized

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ACCEPTED MANUSCRIPT ABSTRACT BACKGROUND Knowledge about lipid interventions in secondary prevention in HIV-infected individuals is limited, studies are sparse.

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METHODS A prospective observational multicenter study enrolled 282 patients on statin 1 month after first ACS (95 HIV-infected individuals, 187 HIV-uninfected). Data on fasting lipids (total cholesterol [TC], low-

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density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non–HDL-C, triglycerides, TC:HDL-C ratio) were collected over 3 years. The evolution of lipid concentrations was analyzed

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using mixed-effects models. Achievement of NCEP-ATP III lipid goals and prescribed statin intensity was assessed.

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RESULTS Mean age of patients was 49.0 years, and 94% were men. Baseline lipids were similar in the two groups. Six months after first ACS, less LDL-C reduction was observed in the HIV-infected group (Adjusted mean change, -10.13; 95% Confidence Interval [CI], -20.63 to 0.37; p=0.06) than in the HIV-uninfected group (Adjusted mean change, -38.51; 95% CI, -46.00 to -31.04; p<0.0001) Similar trends were observed for TC and

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non–HDL-C. After ACS, initial statin prescription for HIV-infected compared to HIV-uninfected individuals was more frequently a moderate-intensity statin (66% vs 45%) and less frequently a high-intensity statin (15%

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versus 45%). Over 3 years of follow-up, the proportion of HIV-infected patients receiving high-intensity statin remained persistently lower than the proportion observed in the HIV-uninfected group.

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CONCLUSIONS In this observational study, HIV-infected individuals after first ACS exhibited worse lipid profiles than controls particularly during the first 6 months while receiving less potent statins. Appropriate statin

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intensity should be prescribed in HIV-infected individuals with awareness of potential drug-drug interactions.

KEY WORDS: Coronary heart disease, Dyslipidemia, Statin, HIV, Cardiovascular prevention, Residual cardiovascular risk

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ACCEPTED MANUSCRIPT ABBREVIATIONS AND ACRONYMS cART = combination antiretroviral therapy CI = confidence interval

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CVD = cardiovascular disease HDL-C = high-density lipoprotein cholesterol

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HIV = human immunodeficiency virus LDL-C = low-density lipoprotein cholesterol

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NRTI = nucleoside reverse transcriptase inhibitor

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TC = total cholesterol

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ACCEPTED MANUSCRIPT Cardiovascular disease (CVD) is an increasingly important cause of morbidity and mortality among people living with the human immunodeficiency virus (HIV), particularly for those on combination antiretroviral therapy (cART)

1, 2

. Today, CVD is the third leading cause of death among HIV-infected people on cART. The

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burden of AIDS-related diseases has decreased substantially in countries where people with HIV have access to cART and they are living longer. Consequently, these populations are now developing age-related complications.

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Cardiac complications have shifted from myocardial and pericardial diseases—linked to immunosuppression—to atherosclerotic CVD, including myocardial infarction (MI) and peripheral and cerebrovascular diseases

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.

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Compared with the general population, HIV-infected people on cART are now at higher risk of MI 5, 6. Numerous factors have been associated with this increased atherosclerotic cardiovascular risk, including a higher prevalence

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of traditional risk factors, particularly smoking but also illicit drug use, HIV-related chronic infection and inflammation resulting in persistent immune activation, and use of cART, directly or indirectly, via disturbances in lipid and glucose metabolisms. Several studies have demonstrated in vitro and in vivo the effect of cART on lipid and glucose metabolism through adipocyte dysfunction leading to a lipodystrophy syndrome

. Equally,

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the pathogenesis of HIV-related dyslipidemia has been extensively studied

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. Conversely, the management of

HIV-related dyslipidemia and the clinical benefits of statins have not yet been fully addressed. In primary

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prevention, studies have consistently demonstrated that HIV-infected people on statin therapy less frequently achieve their lipid goals when compared with HIV-uninfected individuals 13-20.

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Few data regarding secondary prevention are available among HIV-infected people

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. While the

prevention strategies recommended for the general population are frequently applied to the HIV population, gaps

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in knowledge persist concerning the achievement of lipid goals through the use of statins in HIV-infected individuals. Moreover, there’s a common belief that lipid-lowering therapy may not work as well among HIVinfected individuals. Prognosis of Acute Coronary Syndrome in HIV-infected patients (PACS-HIV) is a comparative observational study describing the prognosis at long term of patients with a first acute coronary syndrome (ACS). We found previously that HIV-infected people experienced recurrent acute coronary events more frequently than HIVuninfected controls (hazard ratio [HR]: 4.6; 95% confidence interval [CI]: 1.4 to 15.0)

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after one year.

Furthermore, this increased risk persisted over 3 years (HR: 3.4, 95% CI: 1.3 to 8.8) and was associated with persistent atherogenic dyslipidemia, including increased concentrations of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and HIV infection itself 22. Whether the biological response to statin therapy and its intensity after ACS differs between HIV-infected and HIV-uninfected individuals has yet to be investigated.

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ACCEPTED MANUSCRIPT We therefore conducted a substudy using data from the PACS-HIV cohort to quantify and compare the evolution of lipids and the attainment of lipid goals, taking into consideration statin therapy and intensity of treatment,

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between HIV-infected and HIV-uninfected individuals during the 3 years following a first ACS event.

Methods

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Study design and patient selection

This substudy was nested in the PACS-HIV study, which prospectively enrolled 103 HIV-infected

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participants and 195 HIV-uninfected participants matched for age (± 5 years), sex, and type of ACS event (STsegment elevation myocardial infarction [STEMI], non-ST-segment elevation myocardial infarction [NSTEMI],

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and unstable angina)) following their first ACS episode between September 2003 and March 2006. Participants were recruited from 23 French cardiac intensive care units. This substudy included all eligible participants in the PACS-HIV study who were prescribed statin therapy in the month following hospitalization after the index ACS. Follow-up duration was prespecified as 3 years and data were collected at 6, 12, 18, 24, and 36 months.

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The last patient was followed till January 2010. A detailed description of the PACS-HIV study is available

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The primary outcome was change in lipid parameters over the 3 years following initial ACS in the HIV-infected

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and HIV-uninfected groups. The secondary outcome was the proportion of individuals in each group who

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achieved the lipid goals recommended in the updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines

23, 24

. The 2013 US guidelines were not used as they were not available at

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the time of our study25. The goals were: LDL-C < 100 mg/dl; non–HDL-C ≤ 130 mg/dl; TC ≤ 200 mg/dl; HDLC ≥ 40 mg/dl; TC:HDL-C ≤ 5; and triglycerides < 150 mg/ml. Statin intensity was classified as low (Pravastatin <40 mg/day, Simvastatin <20 mg/day, Fluvastatin <80 mg/day), moderate (Pravastatin >40 mg/day, Simvastatin =>20 mg/day , Fluvastatin >80 mg/day, Atorvastatin <40 mg/day, Rosuvastatin <20 mg/day), or high (Atorvastatin >40 mg/day, Rosuvastatin >20 mg/day) 25. This study was funded by the Agence Nationale de Recherches sur le Sida et les Hepatites Virales [French National Agency for Research on AIDS and Viral Hepatitis] and Sidaction-Ensemble contre le SIDA], Paris, France. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. Statistical analysis Continuous variables are expressed as mean ± standard deviation (SD) and comparisons between groups were conducted using Student’s t-test. Categorical variables are expressed as counts and percentages, and the chi-

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ACCEPTED MANUSCRIPT square or Fisher’s exact tests were used, as appropriate, to compare groups. A mixed model for repeated measures was used to compare the evolution of lipid values over 3 years in the two groups. A random coefficient model using baseline lipid parameters as the dependent variables and an unstructured variance-covariance

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structure was fitted, to model within-individual errors accounting for longitudinal, repeated measurements correlated within an individual. As statin therapy was expected to produce a rapid decline in LDL-C

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concentration, a piece-wise linear model with a 6-month cut-point was used to model the evolution of lipid concentrations and to estimate differences in lipid variation between the two groups. The slopes of evolution of

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lipid values from the month 6 change-point through month 36 were compared between groups. A generalized linear model, taking repeated observations into account, was used to compare the probability of achieving lipid

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goals at months 6, 12, 18, 24, and 36. All models retained the matching variables of age, sex, and type of ACS. To take recurrence into account sensitivity analyses were conducted after censoring lipid measurements at the time of ACS recurrence. Statistical calculations were performed using SAS software (version 9.3, Cary, NC,

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USA).

Results

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The study population included 95 HIV-infected and 195 HIV-uninfected individuals who were on statin

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therapy at 1 month after the initial ACS episode. Mean ± SD follow-up was 36.3 ± 6.3 months. The mean ± SD age of the cohort was 49 ± 9.5 years and 94% were men. Baseline clinical and biological characteristics were

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similar between the two groups, except for a higher frequency of illicit drug use (p = 0.0001) and lower mean body mass index (p < 0.0001; Table 1) in the HIV-infected group. At hospital admission, the HIV-infected group had twice as many individuals with known hypertriglyceridemia as the HIV-uninfected group (p = 0.0002) and a higher mean triglyceride concentration (p = 0.001). None of the other lipid parameters differed between the two groups. The rates of chronic statin and fibrate use before the index ACS were similar in the two groups. Notably, fasting glucose was lower in the HIV-infected group (p = 0.01). At 1 month after index ACS, statin prescription patterns differed by HIV status, with higher proportions of HIV-infected individuals prescribed pravastatin (n = 67 [70%] vs. n = 46 [25%]), rosuvastatin (n = 6 [6%] vs. n = 6 [3%]), and fluvastatin (n = 2 [2%] vs. n = 0) and lower proportions for atorvastatin (n = 15 [16%] vs. n = 112 [60%]) and simvastatin (n = 5 [5%] vs. n = 23 [12%]). Taking into account both the statin therapy type and daily dose, HIV-infected patients were more frequently prescribed low-intensity (19% vs. 10%) or moderate intensity (66% vs. 45%) statin treatment, and less frequently prescribed high-intensity treatment (15% vs. 45%)

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ACCEPTED MANUSCRIPT (p<0.0001). One month after index ACS, ezetimibe was co-prescribed in three HIV-uninfected and no HIVuninfected individuals. Throughout the 3 year follow-up, the proportion of HIV-infected patients receiving high-intensity

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treatment persistently remained lower than that in the HIV-uninfected group (Figure 1) despite a shift in statin prescription patterns with increased use of rosuvastatin, particularly in the HIV-infected group (Supplementary

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Figure 1).

Evolution of lipid parameters over 3 years

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The change in LDL-C, TC, and non-HDL-C concentrations, and in TC:HDL-C ratio, differed between HIV-infected and HIV-uninfected individuals, particularly during the first 6 months (Figure 2). At month 6 after

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initial ACS, reduction of LDL-C was lower in the HIV-infected group (Adjusted mean change, -10.13; 95% CI, 20.63 to 0.37; p=0.06) than in the HIV-uninfected group (Adjusted mean change, -38.51; 95% CI, --46.00 to 31.04; p<0.0001) (Table 2). Conversely, the slope of variation indicated that a significant decrease in LDL-C was observed from months 6 through 36 in the HIV-infected group (p < 0.0001), but not in the HIV-uninfected

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group (p = 0.59). The same trend was observed for non-HDL-C, TC, and TC:HDL-C ratio. HDL-C concentration increased in both groups over the first 6 months, and from months 6 through 36 no significant

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change was detected in either group. While the HIV-infected group consistently maintained a higher

Statin intensity

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concentration of triglycerides, no significant change was observed over 3 years for either group.

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A comparison of the mean reductions in LDL-C concentration achieved at month 6 was conducted between the two groups, by statin intensity class. Irrespective of the statin intensity class, reduction of LDL-C was persistently lesser in the HIV-infected than the HIV-uninfected group. No variation in LDL-C concentration was observed in the HIV-infected participants on low-intensity statin therapy (adjusted mean variation of LDLC, +1.46; p=0.91) while a small effect was observed in the HIV-uninfected group (adjusted mean variation, 23.88; p=0.08). Among participants on moderate-intensity statin therapy (the most frequently prescribed intensity class, representing 65% of the HIV-infected and 45% of the HIV-uninfected groups), the decrease in LDL-C was less pronounced in the HIV-infected group (adjusted mean variation, –15 mg/dl, p = 0.04) as compared with the HIV-uninfected group (adjusted mean variation, –33 mg/dl, p < 0.0001; adjusted mean difference 18 mg/dl, p = 0.07). The same trend towards a lesser reduction of LDL-C concentrations in HIVinfected compared to HIV-uninfected participants was also observed among those on high-intensity statins (adjusted mean variation -20.14 mg/dl (p=0.36) and -53.05 mg/dl (p<0.0001), respectively). However, the lack

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ACCEPTED MANUSCRIPT of statistical difference between the two groups (adjusted mean difference 32.92 mg/dl, p =0.16) may reflect insufficient power to detect differences due to the small sample size as only 14 HIV-infected participants received high-intensity statin.

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Attainment of lipid goals

The HIV-infected group was less likely to attain their goals for all lipid parameters, other than HDL-C, at month

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6 (HIV status regression coefficients, p < 0.05) (Table 3). The HIV-infected group less frequently achieved the LDL-C goals in the first 6 months (42.6% vs. 67.7%, p = 0.0002). From month 6 to month 36, no further

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improvement in achievement of goals was observed in the HIV-uninfected group (time regression coefficient, p > 0.10). Concomitantly, the HIV status by time interactions were not significant, suggesting that attainment of

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all of the lipid goals did not improve over time in the HIV-infected group. In fact, less than half of the HIVinfected group had an LDL-C value < 100 mg/dl in the first 18 months. No significant difference was detected between groups for attainment of the HDL-C goal at month 6, nor was a difference observed in the 24 months thereafter.

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Effect of protease inhibitor regimen on lipid levels Before the index ACS, protease inhibitors were being taken by 64 (67.4%) HIV-infected individuals (Table 1).

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Protease inhibitor therapy was stopped in two of these patients and started in two others in the month after the

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ACS. Throughout the 3-year follow-up, very few changes were made to the protease inhibitor regimen for another antiretroviral therapy. Of the 64 HIV-infected individuals receiving a protease inhibitor at baseline, 53

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(83%) were still on this therapy at month 36. Eight (26%) of the 31 individuals not on a protease inhibitor at baseline started a protease inhibitor regimen during the 3 years of follow-up. Throughout the 3 years of followup, we observed no effect of protease inhibitor regimen on LDL concentrations or on attainment of LDL goals (Supplementary Data, Tables 1 and 2).

Sensitivity analyses Twenty-two patients (11 HIV-infected and 11 HIV-uninfected) developed recurrent ACS during the 3-year study period. The lower lipid reduction in HIV-infected patients compared to HIV-uninfected patients was confirmed in sensitivity analyses with censoring of lipid measurements after recurrence (data not shown).

Statin tolerability Toxicity requiring statin discontinuation was reported in four patients (2 HIV-infected and 2 HIV-uninfected). Overall, symptomatic and/or biological episodes of toxicity were reported 13 times in 11 (11%) HIV-infected individuals and 21 times in 21 (11%) HIV-uninfected individuals. The most frequently reported adverse events

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ACCEPTED MANUSCRIPT were myalgia (n = 25), elevation of liver enzymes (serum aspartate aminotransferase and/or alanine aminotransferase: n = 4), and skin symptoms (n = 3).

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Discussion

This PACS-HIV substudy showed, for the first time, that after a first episode of ACS, HIV-infected

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individuals experienced a slower decrease in concentrations of atherogenic lipoproteins compared with HIVuninfected individuals. After an ACS, atherogenic dyslipidemia persisted more frequently in HIV-infected

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versus HIV-uninfected individuals during the first 6 months on statin therapy. During this period, the decreases in lipid concentrations and the achievement of lipid goals (including LDL-C, non-HDL-C, TC, and TC:HDL-C)

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were lower and less frequent in the HIV-infected group. These detrimental results persisted throughout the 3year follow-up. However, HIV-infected individuals were less frequently prescribed high-intensity statins as compared to HIV-uninfected individuals. The majority of HIV-infected individuals were prescribed moderateintensity statin therapy. In this group, we observed a trend towards a lower LDL-C decrease during the first 6

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months after initial ACS as compared with the HIV-uninfected group. STUDIES OF LIPID GOALS ATTAINMENT IN HIV-INFECTED INDIVIDUALS

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To date, few studies have reported attainment of lipid goals in the context of primary or secondary prevention in

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an HIV-infected population 14, 16-20. These studies unanimously advanced the conclusion that current management of HIV-associated dyslipidemia is suboptimal. Few focused specifically on the post-ACS setting,

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and most were retrospective and conducted in both primary and secondary prevention settings. In a HIV-infected cohort in which 5% (n = 27) had a diagnosis of coronary heart disease, Oh et al. 16 found that less than half of these participants had a non–HDL-C < 130 mg/dl (equivalent to the LDL-C goal of < 100 mg/dl). This study did not, however, provide information on the lipid-lowering drugs prescribed. In another retrospective study, comparing 53 HIV-infected individuals who developed dyslipidemia and 53 age-matched controls, Townsend et al. 14 reported that 80% were prescribed statin therapy, and the HIV-uninfected group was more likely than the HIV-infected group to achieve the TC goal at months 3 and 6 (50% vs. 18%; odds ratio, 4.57; p = 0.003; and 60% vs. 28%; odds ratio, 3.25; p = 0.014; respectively). In this study, at months 3 and 6, less than 45% of the HIV-infected group met the NCEP-ATP III goals. The authors postulated that this result was likely due to treatment with inappropriately low dose of statins: pravastatin was the most frequently prescribed medication, with a mean dose of 14.2 mg and titration was not frequently conducted. In the HIV Outpatients Study cohort17, only one-third of the high-risk participants met the NCEP-ATP III goals for LDL-C and non-HDL-C. Although

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ACCEPTED MANUSCRIPT major gaps in knowledge exist concerning the biological response to statin therapy and behavioral– environmental mechanisms potentially contributing to a disproportionate burden of dyslipidemia in HIV-infected populations, the present PACS-HIV substudy findings are aligned with the evidence reported in the scientific

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literature concerning lipid parameters. The slower decrease of atherogenic lipoproteins, the lower rate of attainment of lipid goals, and the persistence of these detrimental results over a long follow-up observed among

management of HIV-associated dyslipidemia is suboptimal.

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the HIV-infected group as compared to the HIV-uninfected group, supports the assertion that current

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DOES STATIN “RESISTANCE” EXIST IN HIV-INFECTED INDIVIDUALS? Potential “resistance” to statin therapy has been proposed by several research teams 15, 26, 27, including our group . This phenomenon may, however, simply be an artifact of the use of inappropriately low-dose statins. Three

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key factors may contribute to a lower use of potent and high-dose statins in HIV-infected populations. First, a possible risk of drug-drug interactions exists between antiretroviral drugs and statins. Protease inhibitors could inhibit CYP3A4 and may lead to plasma accumulation of statins, especially simvastatin and lovastatin and, to a

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lesser extent, atorvastatin and rosuvastatin, increasing the risk of dose-related adverse events, while nonnucleoside reverse transcriptase inhibitors are inductors of CYP3A4 and may decrease plasma concentrations of

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those statins. This may have led to the under-prescription of high-intensity statins due to the apprehension of potential drug-drug interaction which is less well-known by cardiologists. In fact, all the initial and chronic

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prescriptions of statins were made by cardiologists and not HIV physicians in the PACS-HIV study. These reinforce the need to evaluate the use of high dose statin in this high cardiovascular risk specific population

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particularly in secondary prevention both in terms of tolerability, biological efficacy and clinical benefits. However, the data from the PACS-HIV substudy indicate that in the most frequently prescribed statin therapy group (i.e. moderate-intensity), HIV-infected individuals had a lesser, albeit non-statistically significant, decrease in LDL-C concentration at month 6 as compared to that in the HIV-uninfected group but again potential drug-drug interaction particularly with NNRTIs may have decreased the effects of the moderate-intensity statins used. Second, a high prevalence of myalgia in relation to use of nucleoside reverse transcriptase inhibitors, before the introduction of statin medication, has been reported among HIV-infected people. 29 This consideration may equally reinforce hesitation to prescribe potent and high-dose statins. Third, a suspected, yet unexplored, low adherence to statin therapy in this population may also be a powerful contributive factor to the aforementioned “resistance”. Altogether, our results are in line with data in secondary prevention in both HIVinfected individuals

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and in the general population (27%)30 suggesting the underutilization of high-intensity

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ACCEPTED MANUSCRIPT statin therapy in the real life in patients discharge for a CHD event and poor LDLc goal achievement (less than 50%) in the HIV population. However, the newest ACC/AHA guidelines25 recommend that all ACS patients between 21 and 75 years old are prescribed high-intensity statin therapy. Whether this recommendation will lead

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to a larger proportion of ACS HIV-infected patients being prescribed high-intensity statin remains to be to be

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investigated in this new era.

STUDY LIMITATIONS

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This substudy has several key methodological limitations. First, the observational design and small sample size limited the analysis of statin intensity. The balance produced by matching HIV-infected and HIV-

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uninfected participants on type of ACS event and period of enrolment, in addition to age and sex, was insufficient to enable subgroup analyses powered to detect differences. Adherence to prescribed statin therapy was neither questioned nor measured among participants during follow-up. Every 6 months over the 3-year follow-up participants were routinely asked if a statin therapy was being prescribed (type and dosage), was

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discontinued, and was well tolerated (biological and clinical tolerance). Non-adherence to statin therapy may have contributed to a smaller decrease in lipid parameters, which may in turn have led to an underestimation of

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the true effect of statins on lipid goals. The study’s observational and prospective design did not control for statins titration over the 3-year follow-up. Failure to titrate or shift to a more potent statin was based exclusively

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on participant or physician decisions. While the possible influence of lifestyle, diet, and exercise modifications were not assessed in the present analysis, they may have affected the lipid parameters. We did not, however,

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expect these factors to vary between the HIV-infected and HIV-uninfected groups. Another limitation was the standard of HIV care at the time of enrolment in the PACS-HIV study with protease inhibitor-based antiretroviral regimens predominately used. However, protease inhibitors remain on the list of recommended antiretroviral drugs and, in 2014, around 40% of HIV-infected patients on ART consulting in France received protease inhibitors (FHDH-ANRS CO4, personal communication). Whether widespread use of new antiretroviral drugs, such as integrase inhibitors, would lead to a higher proportion of ACS HIV-infected patients under high intensity statins remains debatable. Regarding the impact of protease inhibitor regimen on lipid concentration, very few changes of this regimen occurred during the entire follow up. Consequently, no conclusions could be drawn about the effect of changes in protease inhibitor therapy on lipids. Lastly, rosuvastatin, the most recent potent statin, was introduced in France in March 2004, which was 6 months after the first patient was enrolled. This may have affected the results, as a shift from pravastatin to

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ACCEPTED MANUSCRIPT rosuvastatin was reported throughout the entire 3-year follow-up in both groups, and was predominantly observed in the HIV-infected group. Despite these limitations, the PACS-HIV substudy is the first prospective multicenter study to quantify and compare lipid profiles between HIV-infected and HIV-uninfected populations

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in a post-ACS setting.

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CONCLUSIONS

People living with HIV, as compared to HIV-uninfected individuals, are less likely to have LDL-C reduction in

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the first 6 months after ACS. Concomitantly, we observed that less potent statins were more frequently used in HIV-infected individuals. The new 2013 US guidelines recommend the use of high intensity statin in all post

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ACS patients between 21 and 75 years old with or without HIV infection. Our results reinforces the need for a better collaboration between cardiologists and HIV physicians to prescribe the appropriate statin and its intensity in light of the risk of potential drug-drug interactions. Whether the advent of new potent LDL-C lowering drugs,

ACKNOWLEDGMENTS

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must be investigated in the future.

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such as PCKS9 inhibitors, could contribute to better LDL-C reduction in this high cardiovascular risk population

Sophie Rushton-Smith, PhD, provided editorial support on the final version of the manuscript and was funded by

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the authors. We thank Mabel Nuernberg, Msc, for critical reading of the manuscript. We are thankful to all the

Funding

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patients who participate in the study. We also thank all the investigators and contributors.

This study was funded by the Agence Nationale de Recherches sur le Sida et les Hepatites Virales [French National Agency for Research on AIDS and Viral Hepatitis] and Sidaction-Ensemble contre le SIDA], Paris, France

Conflict of interest F.B. reports research grant form Boehringer-Ingelheim, speaker fees from AstraZeneca, Merck-Sharpe Dohme; advisory board member for Amgen, Sanofi, Gilead, ViiV Healthcare. S.L. received travel grants from Bristol-Myers-Squibb. E.T. is proctor for Medtronic and St Jude and is receiving grants from Medtronic. P.G.S. reports research grants (to INSERM U1148) from Servier, Sanofi; speaker or consultant honoraria (including steering committee, DMC. and CEC memberships) from Amarin, 13

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AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo-Lilly GlaxoSmithKline, Medtronic, Merck-Sharpe Dohme, Novartis, Otsuka, Pfizer, Regado, Sanofi, Servier, The Medicines Company, Vivus and stockholder from Aterovax. P.M.G. received speaker fees from Bristol-Myers-Squibb, Janssen, ViiVHealthcare, consultant honoraria from Merck-Sharpe Dohme, Janssen, Bristol-Myers-Squibb, Gilead and research grants from Roche, Gilead. D.C. has received travel grants, consultancy fees, honoraria and study grants from various pharmaceutical companies including Gilead Sciences, Janssen-Cilag, Merck-Sharp & Dohme-Chibret, and ViiV Healthcare. A.C. reports research grant from RESICARD (research nurses); consultant and lecture fees from AstraZeneca, Bayer Pharma, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline and Sanofi-Aventis. J.M.B., M.M.K., C.F.B., M.G. report no conflicts of interest.

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Rosenson RS, Kent ST, Brown TM, Farkouh ME, Levitan EB, Yun H, Sharma P, Safford MM, Kilgore M, Muntner P, Bittner V. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. Journal of the American College of Cardiology. 2015;65:270-277

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ACCEPTED MANUSCRIPT Figure legends

FIGURE 1 Distribution of statin intensity prescribed over 3 years in HIV-infected and HIV-uninfected

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individuals low intensity : pravastatin <40 mg/day, simvastatin <20 mg/day, fluvastatin <80 mg/day

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moderate : pravastatin >40 mg/day, simvastatin >20 mg/day , fluvastatin >80 mg/day, atorvastatin <40 mg/day, rosuvastatin <20 mg/day

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high : atorvastatin >40 mg/day, rosuvastatin >20 mg/day

FIGURE 2 Lipids level among HIV-infected (continuous line) and HIV-uninfected (dotted line) individuals

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who were prescribed statin medication in the first month following an acute coronary syndrome. Values are

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mean ± SD

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ACCEPTED MANUSCRIPT Appendices

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CARDIOLOGIC CENTRES and INVESTIGATORS: Hôpital Bichat, Paris-Ph.G. Steg and O. Fondard; Hôpital Cochin, Paris – S. Weber and K. Wahbi; Hôpital Lariboisière, Paris – P. Beaufils. P. Henri and G. Sideris; Hôpital Pitié-Salpétrière, Paris – D. Thomas, G. Montalescot and F. Beygui; Hôpital Saint Antoine, Paris – A. Cohen, F. Boccara, S. Ederhy, C. Meuleman, S. Janower, F. Raoux, G. Dufaitre, N. Benyounes; Hôpital Tenon, Paris – P.L. Michel; B. Petillon, A. and N. Hammoudi; Hôpital H. Mondor, Créteil – P. Gueret, J.L Dubois-Randé, E. Teiger and P. Lim; Hôpital A. Béclère, Clamart – M. Slama, P Colin and C. Saudubray; Hôpital A. Paré, Boulogne – O. Dubourg and O. Milleron; Hôpital V. Dupuis, Argenteuil – B. Gallet and F. Duclos; Hôpital de Gonesse – S. Godard and L. Fuchs; Hôpital d’Eaubonne – V. Dormagen and P. Lewy; Hôpital intercommunal, Le Raincy - Monfermeil – S. Cattan and O. Nallet; Hôpital Côte de Nacre, Caen – G. Grollier and J. Shayne; Hôpital de Bocage, Dijon – J.E. Wolf and Y. Cottin; Hôpital A. Michallon, Grenoble – J. Machecourt and H. Bouvaist; Hôpital L. Pradel, Lyon – G. Finet and B. De Breyne; Hôpital Laennec, Nantes – J.N. Trochu; Hôpital Pasteur, Nice – M. Baudouy, E. Ferrari and M. Benhamou; Hôpital La Miletrie, Poitiers – J. Allal and D. Coisne; Hôpital Ponchaillou, Rennes – H. Le Breton and M. Bedossa; Hôpital de Rangueil, Toulouse – J. Puel and M. Elbaz; Centre Hospitalier, Pointe à Pitre, Guadeloupe – L. Larifla

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INFECTIOUS DISEASE CONTRIBUTORS: Hôpital Bichat, Paris – S. Matheron, R. Landman and G. Fremont; Hôpital Cochin, Paris –G. Spiridon, P. Blanche, J.P. Morini and D. Sicard; Hôpital de la Croix Saint Simon, Paris – V. Zeller; Hôpital Européen G. Pompidou, Paris – D. Batisse; Hôpital Lariboisière, Paris – P.Clevenbergh; Institut Pasteur, Paris – G. Cessot; Hôpital Pitié-Salpétrière, Paris – E. Dohin, M.A. Valantin and S. Khelifa; Hôpital Saint Antoine, Paris – P.M Girard, F. Lallemand, B. Lefebvre, J.P. Laporte, J.L. Meynard, H. Bideault, O. Picard, M.C. Meyohas, P. Campa, J. Tredup, L. Fonquernie and G. Raguin; Hôpital Saint Louis, Paris – J.M. Molina and A. Furco; Hôpital Tenon, Paris – S. Gharakanian, J.P. Vincensini, J.B. Guiard-Schmid, G. Pialoux and B. Cardon; Hôpital H. Mondor, Créteil –A.S. Lascaux, F. Chaix and P. Lesprit; Hôpital A. Béclère, Clamart – R. Fior and F. Boue; Hôpital A. Paré, Boulogne – C. Dupont; Hôpital Beaujon, Clichy – C. Bellier; Hôpital Bicêtre, Le KremlinBicêtre – A. Blanc and T. Lambert; Hôpital V. Dupuis, Argenteuil – T. Touahri and G. Force; Hôpital R. Poincaré, Garches – P. de Truchis; Bideault, O. Picard, M.C. Meyohas, P. Campa, J. Tredup, L. Fonquernie and G. Raguin; Hôtel Dieu, Paris – M.A Compagnucci-Seguenot; Hôpital L. Mourier, Colombes – I. Cahitte; Hôpital Necker, Paris – L. Roudière; Hôpital P. Brousse, Villejuif – M.E. Techer; Centre Médical, Forcilles – P. Thelpin; Hôpital de Gonesse – D. Troisvallets; Hôpital d’Eaubonne – A. Lepretre; Hôpital intercommunal, Le Raincy Monfermeil – M. Echard; Centre Hospitalier, Longjumeau – Y. Le Mercier; Centre Hospitalier, Alençon – D. Houlbert; Hôpital Côte de Nacre, Caen – S. Dargere, C. Bazin and R. Verdon; Centre Hospitalier, Chambéry – B. De Goer; Hôpital de Bocage, Dijon –M. Duong and P. Chavanet; Hôpital A. Michallon, Grenoble – E. Gozlan and P. Leclercq; Hôpital E. Herriot, Lyon – F; Brunel-Dal Mas; Hôpital Archet, Nice – J. Durant and P. Heudier; Hôtel Dieu, Nantes – C. Brunet-François; Hôpital La Miletrie, Poitiers – G. Le Moal; Hôpital Ponchaillou, Rennes – J.M. Chapplin and C. Arvieux; Centre Hospitalier, Roanne – G. Chaumentin; Centre Hospitalier, Rodez – B. Guerin; Hôpital de Purpan, Toulouse – E. Bonnet; Centre Hospitalier, Vannes – Y. Poinsignon; Centre Hopsitalier, Basse-Terre – F. Boulard; Centre Hospitalier Intercommunal, Créteil – I. De Lacroix; Centre Hospitalier, Pointe à Pitre –M.T. Goerger-Sow; Paris, M. Kirstetter, M. Volstein, F. Laylavoix, X. Copin and C. Ceppi.

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ACCEPTED MANUSCRIPT Appendix References 1.

National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on

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Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.

Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National

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2.

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Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39.

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Author Contribution Study concept and design: Boccara, Cohen, Mary-Krause, Costagliola, Guiguet Acquisition of data: Lang, Boccara, Girard, Teiger, Miantezila Basilua, Funck-Brentano, Guiguet Analysis and interpretation of data: Miantezila Basilua, Mary-Krause, Costagliola, Boccara, Cohen, Guiguet Drafting of the manuscript: Boccara, Cohen, Mary-Krause, Costagliola, Guiguet Critical revision of the manuscript for important intellectual content: Steg, Teiger, Funck-Brentano, Guiguet Statistical analysis: Miantezila Basilua, Guiguet Administrative, technical, and material support: Boccara, Lang Study supervision: Boccara, Cohen, Mary-Krause, Costagliola, Funck-Brentano, Girard, Teiger, Guiguet Role of the Sponsor: The funding organization did not participate in the design, analysis, preparation, review, or approval of this manuscript.

19

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FIGURE 1

20

ACCEPTED MANUSCRIPT FIGURE 2 Total cholesterol

MA NU

SC

RI P

T

LDLc

Total cholesterol/HDLc

HDLc

AC

CE

PT

ED

Non HDLc

Triglycerides

21

ACCEPTED MANUSCRIPT TABLE 1 Baseline clinical characteristics HIV-uninfected

(n = 95)

(n = 187)

47.9 ± 9.3 (95) 88 (92.6)

ST-segment elevation myocardial infarction

46 (48.4)

Non-ST-segment elevation myocardial

19 (20.0)

US

Men

MA N

infarction Unstable angina

p Value

49.6 ± 9.6 (187)

0.17

176 (94.1)

0.63

CR I

Age, yrs

HIV-infected

PT

Variable

107 (57.2) 40 (21.4)

0.17

30 (31.6)

40 (21.4)

20 (21.7)

11 (6.1)

0.0001

57 (60.6)

122 (65.2)

0.45

22.4 ± 3.0 (93)

26.9 ± 4.6 (184)

< 0.0001

44 (47.3)

70 (37.6)

0.12

Known hypertriglyceridemia

37 (40.2)

35 (19.3)

0.0002

Hypertension

16 (17.2)

49 (26.3)

0.09

6 (6.4)

23 (12.4)

0.12

Family history of premature CVD

21 (22.1)

51 (27.3)

0.35

Chronic use of statin at baseline

11 (11.6)

24 (12.8)

0.76

Chronic use of fibrate at baseline

4 (4.2)

7 (3.7)

0.85

LDL-cholesterol, mg/dl

123 ± 43.7 (76)

133.3 ± 43.8 (166)

0.11

HDL-cholesterol, mg/dl

40.2 ± 14.1 (78)

43.0 ± 12.3 (171)

0.11

Use of illicit drugs

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Current smoker

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Body mass index, kg/m2

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Known hypercholesterolemia

Diabetes mellitus

At initial admission

22

ACCEPTED MANUSCRIPT 160.2 ± 48.1 (78)

161.7 ± 46.6 (170)

0.81

Total cholesterol, mg/dl

205.4 ± 53.4 (85)

204.2 ± 47.6 (172)

0.85

5.5 ± 2.1 (78)

5.1 ± 1.8 (170)

0.14

Total-cholesterol/HDL-cholesterol ratio

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Non-HDL-cholesterol, mg/dl

238.9 ± 179.7 (84)

Fasting glucose, mg/dl

104.0 ± 33.7 (84)

119.2 ± 58.0 (159)

0.01

Serum creatinine, mg/dl

10.5 ± 8.7 (91)

10.1 ± 3.8 (182)

0.66

–

–

34 (35.8)

–

–

81 (85.3)

–

–

482 ± 292 (92)

–

–

HIV-RNA <200 copies/mL

64 (67.4)

–

–

Hepatitis B or hepatitis C coinfection*

25 (26.3)

–

–

Protease inhibitor

64 (67.4)

Lopinavir

31 (32.6)

ED

Atazanavir

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Indinavir

CE

Amprenavir

AC

NRTI

0.001

US MA N

Antiviral therapy

NNRTI

166.9 ± 125.1 (172)

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Triglycerides, mg/dl

CD4 cell count, mm3

11 (11.6) 6 (6.3) 5 (5.3)

Data are presented as n (%) or mean ± SD (n). *Hepatitis B (n=5), Hepatitis C (n=18), Hepatitis B and Hepatitis C (n=2) NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor.

23

ACCEPTED MANUSCRIPT

p Value

Adjusted mean

months (95% CI)

p Value

Adjusted monthly

p Value

CR I

Adjusted mean change at 6

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Table 2. Decrease in plasma lipid concentration compared with baseline by HIV infection status and period (acute and late phase) of statin therapy

difference (95% CI)

mean change from 6 to

Adjusted mean

p

difference (95% CI)

Value

LDL-C <0.0001

Reference

-10.13 (-20.63 to 0.37)

0.06

28.38 (15.49 to 41.27)

-41.70 (-50.56 to -32.84)

<0.0001

-10.24 (-22.24 to 1.76)

0.09

-38.33 (-47.16 to -29.50)

<0.0001

Reference

-9.14 (-20.42 to 2.13)

0.11

29.18 (14.86 to 43.50)

< 0.0001

-0.07 (-0.32 to 0.18)

0.59

Reference

-0.79 (-1.09 to -0.48)

< 0.0001

-0.72 (-1.12 to -0.32)

0.04 (-0.30 to 0.38)

0.82

Reference

-0.68 (-1.09 to -0.27)

0.0001

-0.27 (-1.26 to -0.18)

0.005 (-0.35 to 0.36)

0.97

Reference

-0.61 (-1.00 to -0.21)

0.002

-0.61 (-1.14 to -0.08)

0.0004

TE

D

HIV-infected

-38.51 (-46.00 to -31.04)

MA

HIV-uninfected

NU S

36 months (95% CI)*

HIV-infected

Total cholesterol HIV-uninfected

HIV-infected

Reference

31.46 (16.54 to 46.38)

0.0001

0.008

AC

HIV-uninfected

CE P

Non-HDL-C

0.0002

0.02

HDL-C

24

ACCEPTED MANUSCRIPT

2.86 (-0.03 to 5.76)

0.05

Reference

HIV-infected

7.29 (3.44 to 11.14)

0.0002

4.42 (-0.39 to 9.24)

HIV-uninfected

-1.30 (-1.66 to -0.94)

<0.0001

Reference

HIV-infected

-0.54 (-1.02 to -0.05)

0.03

0.76 (0.16 to 1.36)

HIV-uninfected

-23.34 (-54.84 to 8.16)

0.15

Reference

HIV-infected

-8.44 (-46.90 to 30.01)

0.66

14.89 (-34.81 to 64.60)

0.07

Reference

-0.12 (-0.27 to 0.03)

0.12

-0.09 (-0.28 to 0.11)

0.005 (-0.01 to 0.02)

0.52

Reference

NU S

MA

0.01

-0.02 (-0.04 to 0.00)

0.05

-0.02 (-0.05 to 0.00)

0.82 (-1.11 to 2.76)

0.40

Reference

-0.46 (-2.71 to 1.78)

0.68

-1.29 (-4.26 to 1.68)

0.37

0.06

0.56

0.39

CE P

TE

D

Triglycerides

0.65

CR I

Total cholesterol:HDL-C

-0.03 (-0.15 to 0.10)

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HIV-uninfected

Note: Mixed model for repeated measures adjusted for baseline lipid value, age, sex, and type of acute coronary syndrome.

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CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

25

ACCEPTED MANUSCRIPT Table 3. Achievement of lipid goals during the 36 months follow-up as recommended by the updated National Cholesterol Education Program Adult Treatment Panel III Guidelines1, 2.

HIV-infected

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p Values* HIVuninfected

% (n)

6 months

42.6 (54)

67.7 (87)

12 months

40.0 (55)

18 months

42.9 (56)

ED CE

Non HDL-C ≤ 130 mg/dl

0.05

< 0.0001

0.79

0.14

0.004

0.47

0.63

72.2 (72) 66.1 (65)

68.6 (51)

73.3 (75)

37.7 (53)

69.8 (86)

12 months

41.9 (62)

64.9 (94)

18 months

41.8 (55)

78.3 (69)

24 months

45.8 (59)

69.0 (58)

36 months

54.4 (57)

67.5 (77)

AC

6 months

0.11

55.6 (99)

61.1 (54)

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36 months

0.0002

MA N

LDL-C ≤ 100 mg/dl

24 months

Interaction

US

% (n)

Time

CR I

HIV status

Total cholesterol ≤ 200 mg/dl 6 months

62.5 (72)

80.9 (89)

12 months

54.2 (72)

78.1 (96)

26

18 months

69.7 (66)

84.9 (73)

24 months

63.2 (68)

85.2 (61)

36 months

68.2 (66)

83.3 (78)

HDL-C ≥ 40 mg/dl 56.6 (53)

55.2 (87)

12 months

59.7 (62)

71.9 (96)

18 months

64.3 (56)

70.0 (70)

24 months

53.3 (60)

36 months

54.4 (57)

66.0 (53)

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6 months

18 months

AC

24 months

CE

12 months

36 months

0.002

0.70

0.29

< 0.0001

0.58

0.89

MA N

ED

Total cholesterol:HDL-C ≤ 5

0.30

US

6 months

0.18

CR I

0.66

PT

ACCEPTED MANUSCRIPT

70.0 (60) 66.2 (77)

83.7 (86)

66.1 (62)

84.0 (94)

63.6 (55)

85.5 (69)

69.5 (59)

86.2 (58)

71.9 (57)

81.8 (77)

Triglycerides ≤ 150 mg/dl 6 months

34.3 (67)

67.4 (86)

12 months

30.6 (72)

65.6 (96)

18 months

41.5 (65)

75.4 (69)

24 months

36.8 (68)

67.2 (64)

36 months

39.1 (64)

71.4 (77)

27

ACCEPTED MANUSCRIPT Values are % (number of available data). *P values obtained by generalized linear model for repeated measures; difference of achievement of goals between the HIV-uninfected and the HIV-infected group (HIV status) ; improvement in achievement of goals from 6 to 36 months in the HIV-uninfected group (time) and in the HIV-

AC

CE

PT

ED

MA N

US

CR I

PT

infected group (HIV-status by time interaction)

28