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Cardiovascular risk and dyslipidemia among persons living with HIV: a review



Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles?


Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments.

Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted.

Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied.

Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered.

Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin.

Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice.


Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.

Peer Review reports


In the recent years we observed an improvement of survival and quality of life in people living with HIV (PLWHIV), due to the success of combined antiretroviral treatment (cART) [1].

The early treatment, the reduced toxicity of antiretroviral regimens and the fading of thymidine-analogues-based regimens and the high dosage of ritonavir represent less atherogenic antiretroviral agents for most PLWHIV. This is not enough since PLWHIV live longer, thus in addition to age they add up all degenerative diseases caused by HIV and the side effects of antiretroviral drugs.

This should encourage physicians and researchers in seeking the patient’s well-being, not only through HIV-RNA suppression, but thinking about other more ambitious goals, perhaps more distant from infectious diseases.

Aim of this review is to focus the attention on PLWHIV at risk of developing a cardiovascular event. What is the most suitable cART? Which statin or fibrate to use in order to reduce the risk? How to influence behavior and lifestyles? Everything in the coming years will be played in this field, so we must be prepared.

Prevention of cardiovascular events

An inappropriate lifestyle, in particular smoking, reduced exercise, unhealthy diet and psychosocial stress are responsible for an increased CVD risk. The “lifestyle” is generally based on established patterns of behaviour over time, which have been internalized from childhood and adolescence through the interaction of genetic and environmental factors and that are maintained or even encouraged by the social context in adulthood age.

The dietary habits and physical activity in particular are key factors for the reduction of CV diseases: risk factors such as alcohol use, high blood pressure, high body mass index, hypercholesterolemia, diabetes, low fruit and vegetable intake and physical inactivity, collectively account, with smoking, for more than 60% of cardiovascular deaths globally [2]. Energy intake should be limited to the amount of energy needed to maintain (or obtain) a healthy weight, that is a BMI >20.0 but <25.0 kg/m2.

The wide variety of foods of animal and vegetable origin is the basis for a healthy and balanced diet. Many published data show that the Mediterranean diet appears to be protective against cardiovascular disease and total mortality. The use of this type of diet can have beneficial effects not only on prevention of the main CVD risk factors but also on the course of the disease once it presented. The recommendations of the Mediterranean diet are reasumed in Table 1.

Table 1 Main recommendations of the Mediterranean diet [127131]

Smoking remains the main responsible for the majority of CVD [3]. The 10-year fatal CVD risk is approximately doubled in smokers. The RR in smokers <50 years of age is five-fold higher than in non-smokers [4].

Preventing PLWHIV from starting smoking is critical, because stop smoking remains a formidable challenge. Although the percentage of smokers is declining in Europe, it still remains high and is rising in women, including adolescents and people socially disadvantaged [5]. Widening education-related inequalities in smoking cessation rates have been observed in many European countries. The risks associated with smoking show a dose-response relationship with no lower limit for deleterious effects [4]. Duration also plays a role, and while cigarette smoking is the most common, all types of smoked tobacco, including low-tar (‘mild’ or ‘light’) cigarettes, filtered cigarettes, cigars and pipes, are harmful [6]. There is no age limit to the benefits of smoking cessation.

Some studies have investigated how much the increased mortality in PLWHIV was attributable to smoking. In 2013, a Danish study [7] observed that the cohort of PLWHIV who smoked had an increased risk of death from causes non-AIDS related at least four times higher. A more recent analysis of the same cohort [8] shows that among HIV people who have never smoked the risk of heart attack is similar to that of HIV-uninfected subjects; in contrast, among the HIV active smokers the risk was three times larger than that observed in HIV negative smokers. The Danish data can be reproduced in the HIV population of Western Europe who started an antiretroviral treatment. Researchers in the ART Cohort Collaboration [9] analyzed all living patients in antiretroviral therapy by at least one year, for whom data on smoking habits were available between January 1999 and December 2008. However, they excluded the intravenous drug users because in these subjects the habit of smoking is widespread and mortality rates are higher than the rest of the HIV population. The analysis took into account 17,995 individuals for a total follow-up of 79,760 person-years. Of these 60% were smokers. According to the results, the mortality rate due to all causes was 7.9 (CI 95%: 7.2 to 8.79) per 1000 person-years among smokers and 4.2 (CI 95%: 3.5 to 5.0) among non-smokers.

Finally, it as to be remembered that some ways in which people cope with stress such as drinking, smoking or overeating, are not healthy especially in PLWHIV.

Combination antiretroviral therapy (cART) switching

General principles

Switching from current cART to a more lipid-friendly regimen may represent an option to improve dyslipidemia and to reduce cardiovascular risk in PLWHIV. The principles of cART switching also in the setting of dyslipidemia are to maintain virologic suppression, improve adherence and tolerability [10, 11]. Regimen or single drug substitution may be done carefully and based on the review of different patterns: a) individual factors contributing to dyslipidemia; b) complete clinical and cART regimens history; c) virologic responses to previous cART regimens; d) historical genotypic resistance test; e) adherence history; f) previous cART associated toxicities. Besides, influence of current cART regimen on lipids profile could be evaluated. Clinical trial data on naïve patients demonstrated that differences antiretroviral classes influence lipid values, even if there is heterogeneity among agents within every class: ritonavir (RTV) has been shown to significantly increase plasma lipid levels, in particular lopinavir/ritonavir (LPV/r) and fosamprenavir/ritonavir (FPV/r), to lesser extent with atazanavir/ritonavir (ATV/r) [12, 13].

At the CROI 2017, much attention was centered on the D.A.D, findings on darunavir (DRV) in regards to the development of cardiovascular events. Their analysis had been based on 7 years of follow-up and linked the cumulative use of DRV/r to a gradually increasing risk of CVD [14]. CVD incidence with cumulative DRV was similar to that seen with old-times PIs indinavir and LPV/r. Authors did not show any clear explanation yet, after indicating that abnormal lipids did not modify the CVD risk with DRV/r, and did not provide any distinction between subjects treated with DRV/r BID versus QD.

In the class of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), dyslipidemia has been associated with exposure to stavudine, zidovudine and abacavir, whereas tenofovir disoproxil fumarate (TDF) has been noted to have a favourable lipid influence [15, 16]. In the NNRTIs class, efavirenz has been associated with increases in total cholesterol and triglycerides, whereas rilpivirine has been shown to have less effect on lipid parameters than efavirenz [17]. Data on etravirine (ETR) are limited [18]. The integrase inhibitors (INIs) have a little effect on lipid profile [1921], as well as C-C chemokine receptor type 5 (CCR5) inhibitor (maraviroc) [22]. Since each cART switching has a potential virologic failure risk, it is recommended to prefer regimens that are supported by clinical trials, switch studies or observational cohort studies. The potential options to appropriately switch cART agents are listed below:

Switching within NRTIs: there is evidence of improvement of total cholesterol (TC), LDL-C and TGL switching from abacavir (ABC)/lamivudine to TDF/emtricitabine (FTC) [23, 24].

Switching from protease inhibitor boosted (PI/r) to NNRTIs: Most data on effect of switching from PI/r to nevirapine or efavirenz derived from the early cART era [25, 26]. In the recent years, the randomized SPIRIT study, switching from PI/r to rilpivirine (RPV) has been associated with improved lipid parameters and 10-year Framingham score [27]. In the ETRASWITCH study the switch from PI/b to ETR showed a significant reduction in total cholesterol, TGL and glycemia [28].

Switching from PI unboosted to NNRTI: in a most recent observational trials switch from unboosted PI to RPV has been associated with significant improved of lipids parameters [29].

Switching from PI/r to an INSTI: Switching studies from PI/r to raltegravir (RAL) (SWITCHMRK and SPIRAL) demonstrated a significant lipid and cardiovascular biomarkers reduction in RAL arm. However, in the SWITCHMRK study it was noticed an increased risk of virologic failure that was probably linked to a bias in the patient’s selection [30, 31]. In the open-label STRATEGY study, including nearly 433 participants on first- or second-line treatment regimens with no previous virologic failure, were randomly assigned (2:1) to switch to elvitegravir/cobicistat (EVG/COBI)/FTC/TDF or continue stable PI/r regimens. At week 48, gastrointestinal symptoms improved in the group switched to EVG/COBI/FTC/TDF. Moreover, the INI based regimens led to significant decreases in total cholesterol, triglycerides and HDL-c in LPV/r switches, decrease in triglycerides in ATV/r switches and increase in HDL-c in darunavir switches [32].

Switch strategies in antiretroviral therapy in the management of dyslipidemia

Antiretroviral therapy suppresses viral replication and reduces the concentration of systemic immune activation markers [33, 34] and several studies reported the influence of therapy modification on biomarkers of CVD (Table 2). On the other hand, multiple evidences suggest that some antiretrovirals such as the class of PI and the NRTI abacavir can contribute to the increased cardiovascular risk observed among HIV infected subjects [35]. Protease inhibitors are associated to higher rates of dyslipidemia and increase of intima-media thickness [12]. ABC has been initially reported to increase the risk of myocardial infarction by data coming from the D:A:D in 2008 [36]. The supposed mechanism is that this drug can be associated to endothelial disfunction and/or increased platelets activation. Subsequent reports from the D:A:D study highlighted that abacavir might represent a risk factor especially for patients presenting other preexisting cardiovascular risk factors, but further analyses from the Food and Drugs Administration did not link ABC to increased frequencies of cardiovascular episodes, thus did not lead to restrictions in the prescription and use of ABC [37]. Several trials have shown a beneficial effect of switching to a NNRTI-containing antiretroviral regimen, as it is shown in Table 3.

Table 2 Switch studies reporting the influence of therapy modification on biomarkers of cardiovascular disease
Table 3 Trials on the therapeutic switch to a NNRTI-containing regimen

Monitoring after switching cART regimen

During the first 3 months after the switch, the patient should be closely monitored to assess tolerability and adherence to new cART regimen.

HIV-RNA test may be performed to check for rebound viremia 4 weeks after the switch and then every 3 months during the first year; fasting lipids (cholesterol and triglycerides) should be assessed within 3 months after the change and every 3 months during the first year. In absence of new complaints, subsequent monitoring should be performed on a regularly scheduled basis [10, 11].

New antiretroviral drugs and cardiovascular risk

Tenofovir Alefenamide

Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir disiproxil fumarate (TDF). In this new formulations TAF show higher levels of TDF-DP in periphereal blood mononuclear cells and lymphoid tissues than TDF. TAF showed safety advantages compared to TDF containing regimen regarding bone and renal toxicity [38], regarding the lipid profile, increase from baseline in fasting total cholesterol, LDL cholesterol, HDL and triglycerides were observed in TAF than with TDF. TAF has no “statin-like” phenomenon which characterized TDF. Long-term data are not know.


Cabotegravir is an investigational HIV INI drug, currently being studied in Phase IIb clinical trials. During preliminary studies conducted on healthy subjects both in monotherapy and in combination with RPV [39, 40] no consistent, clinically significant, or dose-related changes in haematology, clinical chemistry, vital signs, or ECG abnormalities or trends were observed. Lou et al. [41], in a study that assessed its effect on cardiac repolarization in healthy subjects, demonstrated that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization. In a fase IIa study, Spreen et al. [42] described two cases of laboratory abnormalities in HIV-1 infected patients in Cabotegravir monotherapy arm. A subject with type I diabetes had grade 2 hyperglycemia at baseline and at all time points other than day 7 (hypoglycemia) and the follow-up visit (grade 3 hyperglycemia). The other subject, on day 7, had grade 4 TGL elevation subsequent to a very high–fat meal the previous evening, and TGL were within normal limits at all other readings. Even the phase IIb studies, LATTE and LATTE-2 (still ongoing), underlined the good safety profile of cabotegravir with no cases of ECG abnormalities or metabolic disorders [43].


Doravirine is a NNRTI currently being studied in Phase III clinical trials as both a single-drug tablet and as part of a fixed-dose combination tablet. In a preliminary study with single and multiple doses of doravirine in healthy subjects, no serious adverse events were reported, and there were no consistent, clinically relevant, treatment-related effects of doravirine on vital signs or ECGs. Overall, no clinically significant trends or signals were observed in laboratory assessments, vital signs or ECGs [44]. In a randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine Shurmann et al. described no clinically significant abnormalities in vital signs, routine blood and urine chemistry panels, haematology, ECGs, or physical or neurological examinations in any participant [45]. Results of a phase IIb clinical trial, presented by Gatell et al. at the 12th International Congress on HIV Drug Therapy being held in Glasgow, showed that 6.8% of patients had an increase in total cholesterol and 6.3% an increase of LDL cholesterol [46].

Pharmacological treatment of dyslipidemia

Drugs for the treatment of hypercholesterolemia


Statins are the cornerstone of the treatment of hypercholesterolemia. They reduce the synthesis of cholesterol in the liver by competitively inhibiting the hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. The reduction in intracellular cholesterol concentrations induces LDL receptor expression on the hepatocyte cell surface, which results in increased extraction of LDL-cholesterol (LDL-C) from the blood and a decreased concentration of circulating LDL-C and other lipoproteins including triglycerides-rich particles.

A number of large-scale clinical trials have demonstrated that statins substantially reduce cardiovascular (CV) morbidity and mortality in both primary and secondary prevention [47, 48]. In the general population, each 1.0 mmol/L (39 mg/dl) reduction in LDL-C level has been significantly associated with a 10% reduction in all-cause mortality, largely reflecting significant reductions in deaths due to coronary heart disease [47].

Meta-analyses of randomized controlled trials that focused on primary prevention, demonstrated that in people without established CV disease but with CV risk factors, the use of statins was associated with significantly improved survival and large reductions in the risk of major CV events [48, 49]. Benefits of statin therapy were observed in nearly all subgroups, including persons with diabetes mellitus, men and women, and across age groups.

The most recent clinical trials suggested that the LDL-C lowering effect of statins between PLWHIV is similar to that seen in the general population. Several randomized studies of hypercholesterolemic HIV-infected patients showed that LDL-C decreased by 15% to 35% in patients taking statins as compared with placebo [50]. In a trial in which PLWHIV on protease inhibitors (PIs) were randomized to atorvastatin 10 mg, rosuvastatin 10 mg, or pravastatin 20 mg, the mean reductions in the LDL-C at one year were 20%, 25%, and 18%, respectively, after one year of therapy [51].

Recently, statins have also been shown to slow the progression or even promote regression of coronary atherosclerosis in the general population as well as in HIV-infected patients (Table 4).

Table 4 Effects of statin therapy on the progression of atherosclerosis in HIV- and non-HIV-infected patients

Finally, as rosuvastatin has demonstrated to significantly reduce several markers of vascular inflammation and CD4+ and CD8+ T lymphocyte and monocyte activation in HIV-infected subjects on antiretroviral therapy [52, 53], statins could exert a wide-reaching anti-inflammatory and immunomodulatory effect that extends well beyond CV disease prevention.

Although the effects of statins in HIV-infected patients are expected to be of a similar magnitude to that has been seen in the general population, many issues regarding the use of statins in HIV-infected patients are still unclear, and further studies are needed to determine whether statins reduce the number of CV events and mortality in HIV-infected patients.

The AIDS Clinical Trial network is currently enrolling in the REPRIEVE (Randomized Trial to Prevent Vascular Event in HIV) Study, which is a large-scale randomized trial to investigate daily pitavastatin versus placebo for the primary prevention of CV events in PLWHIV. Until the results of such studies specifically conducted in HIV-infected population will be available, we have to relay on guidelines for non-HIV-infected patients for the management of hypercholesterolemia in persons who are living with HIV.

For the use of statins in CV disease (CVD) prevention, the European Society of Cardiology and the European Atherosclerosis Society Guidelines, suggest to evaluate the total CV risk of the subjects using European SCORE tables and to identify the LDL-C target for that risk level. For these guidelines, since the response to statin treatment is variable, up-titration to reach that target is mandatory [54].

Differently from European guidelines, the 2013 American College of Cardiology and the American Heart Association guidelines (ACC/AHA) guidelines introduced a new risk calculator, and identified four groups of patients who should be treated with a statin (Table 5) [55]. Current available evidence suggests that the clinical benefit is largely independent of the type of statin but depends on the extent of LDL-C lowering; therefore, the type of statin used should reflect the degree of LDL-C reduction that is required to reach the target LDL-C in a given patient [56].

Table 5 The 2013 ACC/AHA guideline statin benefit group

At maximal recommended dose, the different statins differ in their LDL-C lowering capacity. The ACC/AHA guidelines classify statin doses by three levels of intensity, based on their ability to lower LDL-C levels in the general population (Table 6) [55]. On the other hand, this Expert Panel did not find evidence to support titrating statin therapy to achieve optimal LDL-C or non- high-density lipoprotein cholesterol (HDL–C) targets.

Table 6 The ACC/AHA guideline statin dose classification

Other considerations when deciding about statin therapy include: diabetes mellitus in individual aged less than 40 years or more than 75 years; a family history of premature CVD; elevated lifetime risk of CVD; LDL-C levels of 160 mg/dl or higher; a high sensitivity C-reactive protein level of 2.0 mg/L or higher; a coronary artery calcium score of 300 or higher; an ankle-brachial index below 0.9 [55].

In addition, as HIV-infected patients have been shown to have an increased risk for CVD compared with the general population [57], the presence of HIV infection per se should be considered as an additional risk factor.

The main objection to the ACC/AHA guidelines is that, if generally adopted, these would result in an increased number of patients treated, potentially at considerable costs. Moreover, the new pooled mixed cohorts equation used to assess atherosclerotic CVD risk, has been validated in an American population, different from European countries and requires more careful evaluation if applied in other contexts [58]. In summary, the debate between American and European guidelines is still open and considering the independent risk factor represented by HIV, specific guidelines for HIV-infected persons are warranted.

Statins are generally well tolerated, and serious adverse events are rare [59]. The most serious adverse effects associated with statin therapy is myopathy, which may progress to rhabdomyolisis, and that, in turn, can lead to a concomitantly increased risk of renal failure [59]. An elevation of creatine phosphokinase (CK) is the best indicator of statin-induced myopathy. The common definition of tolerable elevation is a rise of four times the upper limit of normal (ULN) of this enzyme measured in two occasions [59]. The incidence of myopathy is low (<1/1000 patients treated) and the excess risk in comparison with placebo-treated patients has been <1/10,000 patients treated in clinical trials. The incidence of rhabdomyolisis associated with statin therapy is about 1/100.000 per year. Myopathy is most likely to occur in persons with complex medical problems and/or who are taking multiple medications, or in elderly persons, especially women. Myalgia without CK elevation occurs in 5–10% of patients in clinical practice [59].

Combination of statins with fibrates may enhance the risk of myopathy. This risk is greater for gemfibrozil, and the association of gemfibrozil with statins should be avoided. The increased risk for myopathy, when combined statins and fibrates seems to be small [60]. The increased risk for myopathy with nicotinic acid has been debated, but in recent reviews no increased risk of myopathy was found with this agent [61].

The increased risk of diabetes with statin is unclear and high-dose statin are more likely to be associated with diabetes than lower doses [62]. In a randomized, placebo-controlled trial of rosuvastatin versus placebo in antiretroviral treated HIV-infected patients, statin therapy showed a more than 50% increase in insulin resistance, as measured by the homeostasis model assessment of insulin resistance (HOMA-IR), compared with placebo. Nevertheless, there were no increase in the incidence of diabetes and no significant change in oral glucose tolerance testing [63]. The main concern about the use of statins in HIV-infected patients is represented by their potential interactions with some antiretrovirals that may increase the risk of side effects. All current available statins, except pravastatin, rosuvastatin, and pitavastatin, undergo major hepatic metabolism through the cytochrome P (CYP) system thus, other pharmacological substrates of these CYPs may interfere with statin metabolism. Conversely, statin therapy may interfere with the catabolism of other drugs that are metabolized by the same enzymatic system. PIs and other antiretrovirals, such efavirenz, interact with statins because they potentially inhibit CYP3A4 or transporters or both. The potential interactions with antiretrovirals can be managed with careful selection of the appropriate statin, often at lower dose than that is used in the general population [9]. Simvastatin has greater toxicity when combined with PI-containing regimens and is contraindicated in PLWHIV on PIs. Pravastatin and rosuvastatin generally are considered the safer statins because their metabolism does not utilize CYP3A4. Pitavastatin appears to have a particularly favourable pharmacokinetic profile and is not known to interact with current available antiretroviral drugs, even in the setting of PI coadministration [64].

Non-statin drugs for the treatment of hypercholesterolemia

In patients either unable to achieve optimal LDL-C levels despite statin treatment or intolerant to statin, the availability of new drugs with LDL-C lowering effects may be beneficial for reducing atherosclerotic cardiovascular disease (ASCVD) risk.


Ezetimibe is a lipid lowering drug that inhibits the intestinal absorption of cholesterol withouth significant interaction with P-450 cytocromes [64].

Studies on PLWHIV with dyslipidemia evaluated ezetimibe alone or in combination with statins. Ezetimibe alone showed a statistically significant reduction of LDL-cholesterol (ranging from 5.3% to 20.4%) but no significant change in HDL-cholesterol and triglycerides [65, 66]. The studies that added ezetimibe to a stable statin therapy showed a significant reduction of total cholesterol (ranging from −12.9% to −21%) and LDL-C (from 20.8% to 35%) with conflicting results about HDL and triglycerides. Ezetimibe represents an affordable choice in statin-intolerant patient and a good option to intensify statin therapy with a very low toxicity profile [6773].

PCSK9 inhibitors

Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, discovered in 2003, encode for a serine protease protein that plays a central role for the regulation of cholesterol metabolism by targeting the LDL receptor (LDLR) for the degradation in the liver [74]. Gain-of-functions mutations in PCSK9 are one of the genetic causes of autosomal dominant hypercholesterolemia [75]. On the other hand, low-of-function mutations are associated with lower levels of LDL-C and reduced rates of coronary artery disease [76].

Several strategies have been developed to block PCSK9 function including binding of plasma PCSK9 with neutralizing monoclonal antibodies (mAbs) or targeting the intracellular PCSK9 by antisense oligonucleotides or small interfering RNA. Up to date the most studied and clinically advanced approach to PSCK9 inhibition is the use of mAbs.

Two mAbs (alirocumab and evolocumab) have been recently approved by the European Medicines Agency for the use in subjects with familial hypercholesterolemia, in patients who failed to achieve acceptable lipid control although an optimal lipid lowering therapy and in those intolerant to statins.

Efficacy and tolerability of alirocumab and evolocumab in the general population has been evaluated in different studies, as reported in Table 7 [7785].

Table 7 Efficacy and safety of evolocumab and alirocumab in different studies performed in the general population

Considering the high efficacy of PCSK9 inhibitors in reducing LDL-C levels when used alone or in combination with a statin, their use in HIV-infected subjects may help to control cholesterol levels and probably to reduce the risk of MACE in this patients’ population.

Unfortunately to date, no data on the efficacy of evolocumab and alirocumab among HIV-infected subjects are available. However, a forthcoming randomized trial (NCT02833844) will evaluate safety, tolerability, and efficacy on LDL-C of evolocumab in 450 subjects with HIV and with hyperlipidemia and/or mixed dyslipidemia. Start date is scheduled on May 2017.

Drugs for the treatment of hypertriglyceridemia

Isolated hypertriglyceridemia is rare in the setting of PLWHIV on cART in the modern era, the lipid profile usually shows a mixed dyslipidemia [83, 84]. The role of hypertrigliceridemia in cardiovascular disease is still debated [85, 86] and the treatment is reccomended for severe cases (e.g. triglycerides >500 mg/dl) especially for the risk of acute pancreatitis [87].


Fibrates represent the first choice for treatment of hypertriglyceridemia in HIV infected patients. They bind and regulate nuclear receptor peroxisome proliferator activator receptor-α (PPAR- α) and regulate gene expression [88]. Fenofibrate is the most commonly used fibrate in HIV-associated dyslipidemia both for the once daily dose and for the reduced interaction with statin with a lower risk of rhabdomyolisis [89, 90]. Studies on HIV-population evaluating fenofibrate showed a significant reduction of triglycerides (from 18% to 58%) depending on cART regimen, study design, and on grade of hypertriglyceridemia [91]. An observational analysis including 80 patients with HIV infection on fenofibrates with a mean baseline triglycerides value of 347 mg/dl showed a reduction of 18% of triglycerides [91]. A randomized trial evaluating fish-oil therapy versus fenofibrate enrolling 50 patients with HIV infection in each arm demonstrated a reduction of 58% of triglycerides in fenofibrate arm with a median baseline of triglycerides of 694 mg/dl [92]. Few studies evaluated the use of fibrates and statins in HIV associated dyslipidemia [93] and they demonstrated an higher efficacy as reported in general population [94]. An important issue is the increased renal toxicity associated with the use of fibrates and statins that should be considered [93].

Fish oil

Omega 3 fatty acids have a good safety profile and have been used in HIV-associated dyslipidemia. They demonstrated a reduction of triglycerides ranging from 7% to 38% in a retrospective analysis of 73 patients on PI based regimen vs a non-nucleoside reverse-transcriptase inhibitors (NNRTI) regimen respectively [91]. In three recent randomized trial including less than 50 patients per arm a triglycerides reduction of 9–48% was observed [9298]. The association with statins results in a more favorable lipid profile with a very low toxicity [99, 100] but the introduction of ezetimibe that shows an higher efficacy has limited the use of omega 3 only for patients with a low-moderate dyslipidemia and isolated hypertrigliceridemia. Another concern is the higher dose (2–4 g/die) needed to obtain a real efficacy with development of side effects such as flatulence.

Studies evaluating fibrates and fish oil in mixed dyslipidemia and isolated trigliceridemia are summarized In Table 8.

Table 8 studies evaluating fibrates and fish oil in mixed dyslipidemia and isolated trigliceridemia


HIV-infected subjects, particularly those treated with antiretroviral therapy, may experience significant accumulation of visceral fat. The increased visceral adiposity has been associated with dyslipidemia and with reductions in growth hormone (GH) secretion [101,102,103].

The use of tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) and concomitantly reduces tryglicerides, total cholesterol concentration and non-HDL-C among HIV-infected subjects.

In a study by Falutz et al. [104] the measure of VAT decreased by 15.2% in the tesamorelin group and increased by 5.0% in the placebo group; the levels of triglycerides decreased by 50 mg per deciliter and increased by 9 mg per deciliter, respectively, and the ratio of total cholesterol to HDL cholesterol decreased by 0.31 and increased by 0.21, respectively (P < 0.001 for all comparisons).

In another study by the same author [105] the use of tesamorelin reduced trygliceride levels by approximately 40 mg/dL in pooled analysis of the ITT population.

Similarly a study by Stanley et al. showed that individuals who responded to tesamorelin (defined as a ≥ 8% reduction in VAT) experienced significantly greater improvements in levels of tryglicerides compared to nonresponders [106].

The observed reduction in tryglicerides is probably mediated at least in part by the direct effect of tesamorelin in increasing GH levels and probably by a possible role of VAT reduction itself in decreasing tryglicerides levels [107].

Tesamorelin is usually well tolerated. The most commonly reported adverse events (>10%) were injection site erythema, pruritus, headache and arthralgia [108].

Fat redistribution in HIV-infected subjects

Long-term ART use has been associated with the occurrence of lipodystrophy, a medical condition characterized by an abnormal fat redistribution [109].

Fat redistribution among HIV-infected subjects is usually classified in specific entities: lipoatrophy, lipohypertrophy and mixed syndromes [110, 111].

Lipoatrophy (LA) is the loss of subcutaneous peripheral fat usually at the face, buttocks and limbs [112, 113] and has been associated with the use of thymidine analogues (zidovudine and stavudine). Decline in the use of these drugs resulted in a significant decrease in severe LA prevalence [114].

On the contrary, lipohypertrophy (LH) that is the accumulation of visceral and central fat in the abdomen, anterior neck, dorsocervical region (“buffalo hump”), trunk and/or breasts [115, 116], still occur in some treated patients [117]. In the general population, increased visceral adipose tissue (VAT) increases the risk of type II diabetes mellitus (T2DM), cardiovascular disease (CVD) and overall mortality. In HIV-infected subjects VAT has been also independently associated with mortality [118]. The main hypothesis regarding the development of LH suggests that alterations in peripheral adipocytes result in an increased levels of circulating fatty acid (CFA). The CFA are then deposited in VAT due to the higher rate of lipid turnover and uptake in visceral adipocytes [119]. These alterations in metabolism of adipocyte may be secondary to a direct action of HIV itself via viral protein Vpr or to a deleterious effect of cART [115, 120]. Moreover, ectopic fat deposition is associated with inflammation and adverse metabolic impact beyond that seen with generalized obesity [121]. Associations between intra-abdominal VAT and increased metabolic disease risk (including CVD) are well described both in cross-sectional and longitudinal studies [122124]. In a cross-sectional study of nearly 600 HIV-infected men on stable ART, greater VAT, liver fat, and epicardial fat were independently associated with CVD after adjusting for traditional CVD risk factors [125]. PLWHIV in the CHARTER study with increased visceral adiposity had significantly worse neurocognitive function. Furthermore, an association between higher IL-6 levels and poorer neurocognitive function was found only among those with the largest waist circumferences, supporting a link between visceral adiposity, inflammation, and neurocognitive function in HIV-infected persons [126].


Cardiovascular disease and dyslipidemia among PLWHIV remain nowadays challenging issues. Prevention of CVD risk is the first and essential step of medical intervention on these patients. The lifestyle modification and the education on healthy dietary practices are fundamental tools for reducing CVD risk.

Current antiretroviral regimens are easier to take, better tolerated, and more effective than regimens used in the past, therefore optimization of ART in terms of side effects tolerability is essential, since HIV infection requires life-long therapy. The optimal treatment strategies are based on the assumption that not all antiretroviral agents have similar toxicities. PI/ritonavir may cause dyslipidemia and lipodystrophy, while INI have a minimal impact on lipids profile, and not reported evidence of lipodystrophy. There is still much to discover with the introduction of new drugs in clinical practice: dolutegravir, TAF and cobicistat.

Statins are the cornerstone of the treatment of hypercholesterolemia. They slow the progression or even promote regression of coronary atherosclerosis and also could exert a wide-reaching anti-inflammatory and immunomodulatory effect. The 2013 ACC/AHA guidelines introduced a new CV risk calculator different from the ESC and EAS Guidelines for the management of dyslipidaemia and identified 4 groups of patients who should be treated with a statin. These guidelines classify statin doses by 3 levels of intensity based on their ability to lower LDL-C levels in the general population. At present, the debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines for HIV-infected persons are warranted.

Another effective drug for the hypercholesterolemia is ezetimibe that markedly reduces the intestinal absorption of cholesterol. In HIV-infected subjects, ezetimibe already showed to be effective in reducing the total cholesterol and LDL-C levels when used alone or in combination with rosuvastatin. PCSK9 inhibitors, MTP inhibitors, antisense oligonucleotide against apolipoprotein B, adenosine Triphosphate Citrate Lyase Inhibitors are experimental and sometimes promising new classes of drugs for the treatment of hypercholesterolemia.

Fibrates represents the first choice for treatment of hypertriglyceridemia in HIV infected patients. Few studies evaluated the use of fibrates and statins in HIV associated dyslipidemia and demonstrated an higher efficacy as reported in the general population. Omega 3 fatty acids have a good safety profile and has been used in HIV-associated dyslipidemia, but their efficacy is limited to patients with a low-moderate dyslipidemia and isolated hypertrigliceridemia. Other drugs for hypertrigliceridemia are: acipimox, that showed a low efficacy; niacin that, in spite of its efficacy can induce insulin resistance and hepatotoxicity; and tesamorelin that has demonstrated a good efficacy in lowering triglycerides and total cholesterol.


- α:

nuclear receptor peroxisome proliferator activator receptor-α




American College of Cardiology


adenosine Triphosphate Citrate Lyase


American Heart Association


antiretroviral therapies


atherosclerotic cardiovascular disease




combination antiretroviral therapy


C-C chemokine receptor type 5


circulating fatty acid


creatine phosphokinase




cardiovascular disease


cytochrome P


Data Collection on Adverse Events of Anti-HIV Drugs study


European Atherosclerosis Society




European Medicines Agency


European Society of Cardiology






familial hypercholesterolemia




emtricitabine-efavirenz-tenofovir DF


emtricitabine-rilpivirine-tenofovir DF


high-density lipoprotein cholesterol


hydroxy-3-methylglutaryl coenzyme A


integrase inhibitors




low-density lipoprotein cholesterol


LDL receptor






monoclonal antibodies


myocardial infarction


mitochondrial DNA


microsomal triglyceride transport protein


non-nucleoside reverse-transcriptase inhibitors


nucleoside/nucleotide reverse transcriptase inhibitors




protease Inhibitors


people living with HIV infection


patient-Reported Outcomes








single-tablet regimen


total cholesterol






upper limit of normal


very-low-density lipoproteins


  1. 1.

    Oguntibeju OO. Quality of life of people living with HIV and AIDS and antiretroviral therapy. HIV/AIDS. 2012:117–24.

  2. 2.

    World Health Organization. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva: WHO; 2009.

  3. 3.

    Prescott E, Hippe M, Schnohr P, Hein HO, Vestbo J. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316:1043–7.

  4. 4.

    Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, Group ES. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16:121–37.

  5. 5.

    Centers for Disease Control and Prevention. How Tobacco Smoke Causes Disease: The Biology and Behavioural Basis for Smoking-attributable Disease 2010. A Report of the Surgeon General.

  6. 6.

    He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK. Passive smoking and the risk of coronary heart disease-a meta-analysis of epidemiologic studies. N Engl J Med. 1999;340:920–6.

  7. 7.

    Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis. 2013;56:727–34.

  8. 8.

    Rasmussen LD, Helleberg M, May MT, et al. Myocardial infarction among Danish HIV-infected individuals: population-attributable fractions associated with smoking. Clin Infect Dis. 2015;60:1415–23.

  9. 9.

    Helleberg M, May MT, Ingle SM, et al. Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America. AIDS. 2015;29:221–9.

  10. 10.

    Guidelines for the use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 14/07/2016. Available at

  11. 11.

    Antinori A, DI Biagio A, Marcotullio S, et al. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2016. New Microbiol. 2017;40:86–98.

  12. 12.

    Sun D, Wu Y, Yuan Y, Wang Y, Liu W, Yang J. Is the atherosclerotic process accentuated under conditions of HIV infection, antiretroviral therapy, and protease inhibitor exposure? Meta-analysis of the markers of arterial structure and function. Atherosclerosis. 2015;242:109–16.

  13. 13.

    Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646–55.

  14. 14.

    Ryom L, Lundgren JD, El-Sadr WM, et al. Association between cardiovascular disease and contemporarily used protease inhibitors. Conference on Retroviruses and Opportunistic Infections (CROI), February 13–16, 2017, Seattle. Abstract 128LB.

  15. 15.

    Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral- naive patients: a 3-year randomized trial. JAMA. 2004;292:191–201.

  16. 16.

    Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23:1547–56.

  17. 17.

    Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1: a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238–46.

  18. 18.

    Girard PM, Campbell TB, Grinsztejn B, et al. Pooled week 96 results of the phase III DUET-1 and DUET-2 trials of etravirine: further analysis of adverse events and laboratory abnormalities of special interest. HIV Med. 2012;13:427–35.

  19. 19.

    Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77–85.

  20. 20.

    Quercia R, Roberts J, Martin-Carpenter L. Comparative changes of lipid levels in treatment-naive, HIV-1-infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks. Clin Drug Investig. 2015;35:211–9.

  21. 21.

    Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379(9835):2439–48.

  22. 22.

    Sierra-Madero J, Di Perri G, Wood R, et al. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. HIV Clin Trials. 2010;11:125–32.

  23. 23.

    Moyle GJ, Orkin C, Fisher M, et al. A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals. PLoS One. 2015;10(2):e0116297.

  24. 24.

    Campo R, DeJesus E, Bredeek UF, et al. A prospective 48-week study to evaluate efficacy and safety of switching to emtricitabine/tenofovir from lamivudine/abacavir in virologically suppressed HIV-1 infected patients on a boosted protease inhibitor containing antiretroviral regimen. Clin Infect Dis. 2013;56:1637–45.

  25. 25.

    Fisac C, Fumero E, Crespo M, et al. Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine. AIDS. 2005;19:917–25.

  26. 26.

    Martínez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med. 2003;349:1036–46.

  27. 27.

    Palella FJ Jr, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS. 2014;28(3):335–44.

  28. 28.

    Echeverría P, Bonjoch A, Puig J, et al. Randomised study to assess the efficacy and safety of once-daily etravirine-based regimen as a switching strategy in HIV-infected patients receiving a protease inhibitor-containing regimen. Etraswitch study PLoS ONE. 2015;9:e84676.

  29. 29.

    Di Biagio A, Riccardi N, Taramasso L, et al. Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides. Int J of Antimicrobial Agents. 2016;48:551–4.

  30. 30.

    Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396–40.

  31. 31.

    Saumoy M, Sánchez-Quesada JL, Martínez E, et al. LDL subclasses and lipoprotein-phospholipase A2 activity in suppressed HIV-infected patients switching to raltegravir: Spiral substudy. Atherosclerosis. 2012;225:200–7.

  32. 32.

    Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis. 2014;14:581–9.

  33. 33.

    Hileman CO, Wohl DA, Tisch DJ, Debanne SM, McComsey GA. Initiation of an abacavir-containing regimen in HIV-infected adults is associated with a smaller decrease in inflammation and endothelial activation markers compared to non-abacavir-containing regimens. AIDS Res Hum Retrovir. 2012;28:1561–4.

  34. 34.

    Martínez E, D'Albuquerque PM, Llibre JM, et al. SPIRAL trial group. Changes in cardiovascular biomarkers in HIV-infected patients switching from ritonavir-boosted protease inhibitors to raltegravir. AIDS. 2012;26:2315–26.

  35. 35.

    Chastain DB, Henderson H, Stover KR. Epidemiology and management of antiretroviral-associated cardiovascular disease. Open AIDS J. 2015;9:23–37.

  36. 36.

    Sabin CA, Worm SW, Weber R, 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(9622):1417–26.

  37. 37.

    Ding X, Andraca-Carrera E, Cooper C, Miele P, Kornegay C, Soukup M, Marcus KA. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr. 2012;61(4):441–7.

  38. 38.

    Imaz A, Podzamcer D. Tenofovir alefenamide, emtricitabine, elvitegravir and cobicistat combination therapy for the treatment of HIV. Exp Review of Anti-infective therapy. 2017:1–15.

  39. 39.

    Spreen W, Ford SL, Chen S, et al. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects. J Acquir Immune Defic Syndr. 2014;67(5):481–6.

  40. 40.

    Spreen W, Williams P, Margolis D, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J Acquir Immune Defic Syndr. 2014;67:487–92.

  41. 41.

    Lou Y, Buchanan AM, Chen S, et al. Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects. Clin Pharmacol Drug Dev. 2016;5:509–516.

  42. 42.

    Spreen W, Min S, Ford SL, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials. 2013;14:192–203.

  43. 43.

    Margolis DA, Brinson CC, Smith GHR, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15:1145–55.

  44. 44.

    Anderson MS, Gilmartin J, Cilissen C, et al. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 2015;20:397–405.

  45. 45.

    Schürmann D, Sobotha C, Gilmartin J, et al. A randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naïve HIV-infected patients. AIDS. 2016;30:57–63.

  46. 46.

    Gatel J, Morales-Ramirez J, Hagins D, et al. Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naïve HIV-positive patients. J Int AIDS Soc. 2014;17(Suppl 3):19532.

  47. 47.

    Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010;376:1670–81.

  48. 48.

    Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ. 2009;338:b2376.

  49. 49.

    Mills EJ, Rachlis B, Wu P, Deveraux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol. 2008;52:1769–81.

  50. 50.

    Feinstein MJ, Achenbach CJ, Stone NJ, Lloyd-Jones DM. A systematic review of the usefulness of statin therapy in HIV-infected patients. Am J Cardiol. 2015;115:1760–6.

  51. 51.

    Calza L, Manfredi R, Colangeli V, Pocaterra D, Pavoni M, Chiodo F. Rosuvastatin, pravastaton, and atorvastatin gor the treatmenet of hypercholesterolemia in HIV-infected patients receiving protease inhibitors. Curr HIV Res. 2008;6:572–8.

  52. 52.

    Longenecker CT, Sattar A, Gilkeson R, McComsey GA. Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection. AIDS. 2016;30:2195–203.

  53. 53.

    Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;68:396–404.

  54. 54.

    ESC/EAS Guidelines for the management of dyslipidaemia: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769–818.

  55. 55.

    ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 24;129(25 Suppl 2):S1–45.

  56. 56.

    Catapano AL. Perspectives on low-density lipoprotein cholesterol goal achievement. Curr Med Res Opin. 2009;25:431–47.

  57. 57.

    Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92:2506–12.

  58. 58.

    Ray KK, Kastelein JJ, Boekholdt SM, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J. 2014;35:960–8.

  59. 59.

    Singh S, Willig JH, Mugavero MJ, et al. Comparative effectiveness and toxicity of statins among HIV-infected patients. Clin Infect Dis. 2011;52:387–95.

  60. 60.

    Fransen R, Vergeer M, Stroes ES, Kastelein JJ. Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab. 2009;11:89–94.

  61. 61.

    Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007;99(Suppl):22–31C.

  62. 62.

    Preiss D, Seshasai D, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305:2556–64.

  63. 63.

    Cziraki MJ, Willey VJ, McKenney JM, et al. Statin safety: an assessment using an administrative claims database. Am J Cardiol. 2006;97:61C–8C.

  64. 64.

    Phan B, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag. 2012;8:415–27.

  65. 65.

    Savarese G, De Ferrari GM, Rosano GM, Perrone-Filardi P. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247–52.

  66. 66.

    Wohl DA, Waters D, Simpson RJ Jr, Richard S, Schnell A, Napravnik S, et al. Ezetimibe alone reduces low-density lipoprotein cholesterol in HIV-infected patients receiving combination antiretroviral therapy. Clin Infect Dis. 2008;47:1105–8.

  67. 67.

    Ambegaonkar BM, Tipping D, Polis AB, Tomassini JE, Tershakovec AM. Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. Atherosclerosis. 2014;237:829–37.

  68. 68.

    Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol. 2004;93:1487–94.

  69. 69.

    Morrone D, Weintraub WS, Toth PP, Hanson ME, Lowe RS, Lin J, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223:251–61.

  70. 70.

    Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181–92.

  71. 71.

    Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.

  72. 72.

    Chow D, Chen H, Glesby MJ, et al. Short-term ezetimibe is well tolerated and effective in combination with statin therapy to treat elevated LDL cholesterol in HIV-infected patients. AIDS. 2009;23:2133–41.

  73. 73.

    Saeedi R, Johns K, Frohlich J, Bennett MT, Bondy G. Lipid lowering efficacy and safety of Ezetimibe combined with rosuvastatin compared with titrating rosuvastatin monotherapy in HIV-positive patients. Lipids Health Dis. 2015;14:57.

  74. 74.

    Stoekenbroek RM, Kastelein JJ, Huijgen R, et al. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. BMC Med. 2015;13:258.

  75. 75.

    Abifadel M, Rabès JP, Devillers M, et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat. 2009;30:520–9.

  76. 76.

    Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

  77. 77.

    Navarese EP, 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.

  78. 78.

    Zhang XL, Zhu QQ, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med. 2015;13:123.

  79. 79.

    Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996–3003.

  80. 80.

    Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341–50.

  81. 81.

    Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.

  82. 82.

    Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541–8.

  83. 83.

    Farnier M. Future lipid-altering therapeutic options targeting residual cardiovascular risk. Curr Cardiol Rep. 2016;18:65.

  84. 84.

    Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.

  85. 85.

    Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017. doi:10.1056/NEJMoa1615664.

  86. 86.

    Frick MH, Elo O, Haapa K, et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.

  87. 87.

    Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med. 1999;341:410–8.

  88. 88.

    Miller J, Brown D, Amin J, Kent-Hughes J, Law M, Kaldor J, et al. A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia. AIDS. 2002;8(16):2195–200.

  89. 89.

    Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.

  90. 90.

    Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.

  91. 91.

    Enger C, Gately R, Ming EE, Niemcryk SJ, Williams L, McAfee AT. Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. Am J Cardiol. 2010;106(11):1594–601.

  92. 92.

    Gerber JG, Kitch DW, Fichtenbaum CJ, et al. Fish oil and fenofibrate for the treatment of hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: results of ACTG A5186. J Acquir Immune Defic Syndr. 2008;47:459–66.

  93. 93.

    Choi HD, Shin WG, Lee JY, Kang BC. Safety and efficacy of fibrate-statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta-analysis. Vasc Pharmacol. 2015;65-66:23–30.

  94. 94.

    Paranandi A, Asztalos BF, Mangili A, et al. Efects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retrovir. 2014;30:800–5.

  95. 95.

    Muñoz MA, Liu W, Delaney JA, et al. Comparative effectiveness of fish oil versus fenofibrate, gemfibrozil, and atorvastatin on lowering triglyceride levels among HIV-infected patients in routine clinical care. J Acquir Immune Defic Syndr. 2013;64:254–60.

  96. 96.

    Rao A, D'Amico S, Balasubramanyam A, Maldonado M. Fenofibrate is effective in treating hypertriglyceridemia associated with HIV lipodystrophy. Am J Med Sci. 2004;327:315–8.

  97. 97.

    Aberg JA, Zackin RA, Brobst SW, et al. A randomized trial of the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities: AIDS Clinical Trials Group study 5087. AIDS Res Hum Retrovir. 2005;21:757–67.

  98. 98.

    Metkus TS, Timpone J, Leaf D, Bidwell Goetz M, Harris WS, Brown TT. Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013;14:530–9.

  99. 99.

    Davidson MH, Stein EA, Bays HE, et al. COMBination of prescription omega-3 with Simvastatin (COMBOS) investigators. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354–67.

  100. 100.

    Durrington PN, Bhatnagar D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart. 2001;85:544–8.

  101. 101.

    Nguyen A, Calmy A, Schiffer VL, et al. Lipodystrophy and weight changes: data from the Swiss HIV cohort study, 2000-2006. HIV Med. 2008;9:142–50.

  102. 102.

    Wohl D, Scherzer R, Heymsfield S, et al. The associations of regional adipose tissue with lipid and lipoprotein levels in HIV-infected men. J Acquir Immune Defic Syndr. 2008;48(1):44–52.

  103. 103.

    Shlay JC, Bartsch G, Peng G, et al. Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor, nonnucleoside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based strategy. J Acquir Immune Defic Syndr. 2007;44:506–17.

  104. 104.

    Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357:2359–70.

  105. 105.

    Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. 2010;95:4291–304.

  106. 106.

    Stanley TL, Falutz J, Marsolais C, et al. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis. 2012;54(11):1642–51.

  107. 107.

    Schwarz JM, Mulligan K, Lee J, et al. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab. 2002;87(2):942.

  108. 108.

    Spooner LM, Olin JL. Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. Ann Pharmacother. 2012;46:240–7.

  109. 109.

    Mallon PW, Miller J, Cooper DA, et al. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS. 2003;17:971–9.

  110. 110.

    Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS. 1999;13:2493–505.

  111. 111.

    Finkelstein JL, Gala P, Rochford R, et al. HIV/AIDS and lipodystrophy: implications for clinical management in resource-limited settings. J Int AIDS Soc. 2015;18:19033.

  112. 112.

    Baril JG, Junod P, Leblanc R, et al. HIV-associated lipodystrophy syndrome: a review of clinical aspects. Can J Infect Dis Med Microbiol. 2005;16:233–43.

  113. 113.

    Falutz J. HIV infection, body composition changes and related metabolic complications: contributing factors and evolving management strategies. Curr Opin Clin Nutr Metab Care. 2011;14:255–60.

  114. 114.

    Scherzer R, Heymsfield SB, Lee D, et al. Decreased limb muscle and increased central adiposity are associated with 5-year all-cause mortality in HIV infection. AIDS. 2011;25:1405–14.

  115. 115.

    Miller KD, Jones E, Yanovski JA, et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet. 1998;351:871–5.

  116. 116.

    Lo JC, Mulligan K, Tai VW et al. “buffalo hump” in men with HIV-1 infection. Lancet. 1998 21; 351: 867-870.

  117. 117.

    Justman JE, Hoover DR, Shi Q, et al. Longitudinal anthropometric patterns among HIV-infected and HIV-uninfected women. J Acquir Immune Defic Syndr. 2008;47:312–9.

  118. 118.

    Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr. 2006;42:562–71.

  119. 119.

    Van Harmelen V, Lönnqvist F, Thörne A, et al. Noradrenaline-induced lipolysis in isolated mesenteric, omental and subcutaneous adipocytes from obese subjects. Int J Obes Relat Metab Disord. 1997;21:972–9.

  120. 120.

    Kino T, Gragerov A, Kopp JB, et al. The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor. J Exp Med. 1999;189:51–62.

  121. 121.

    Guaraldi G, Stentarelli C, Zona S, et al. HIV-associated lipodystrophy: impact of antiretroviral therapy. Drugs. 2013;73:1431–50.

  122. 122.

    Lim S, Meigs JB. Links between ectopic fat and vascular disease in humans. Arterioscler Thromb Vasc Biol. 2014;34:1820–6.

  123. 123.

    Erlandson KM, Lake JE. Fat matters: understanding the role of adipose tissue in health in HIV infection. Curr HIV/AIDS Rep. 2016;13:20–30.

  124. 124.

    Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233:104–12.

  125. 125.

    Orlando G, Guaraldi G, Zona S, et al. Ectopic fat is linked to prior cardiovascular events in men with HIV. J Acquir Immune Defic Syndr. 2012;59:494–7.

  126. 126.

    Sattler FR, He J, Letendre S, et al. Abdominal obesity contributes to neurocognitive impairment in HIV-infected patients with increased inflammation and immune activation. J Acquir Immune Defic Syndr. 2015;68:281–8.

  127. 127.

    European Heart Network. Diet, Physical Activity and Cardiovascular Disease Prevention in Europe. Brussels, Belguim: European Heart Network, 2011.

  128. 128.

    Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-Varela O, Menotti A, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004;292:1433–9.

  129. 129.

    Roman B, Carta L, Martinez-Gonzalez MA, Serra-Majem L. Effectiveness of the Mediterranean diet in the elderly. Clin Interv Aging. 2008;3:97e109.

  130. 130.

    Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010;92:1189–96.

  131. 131.

    Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. For the PREDIMED study investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90.

  132. 132.

    Gallien S, Braun J, Delaugerre C, et al. Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of therandomized EASIER ANRS 138 trial. J Antimicrob Chemother. 2011;66:2099–106.

  133. 133.

    Reliquet V, Chirouze C, Allavena C, et al. Nevirapine-raltegravir combination, an NRTI and PI/r sparing regimen, as maintenance antiretroviral therapy in virologically suppressed HIV-1-infected patients. Antivir Ther. 2014;19:117–23.

  134. 134.

    Calcagno A, Montrucchio C, Capetti A, et al. Raltegravir plus Nevirapine as maintenance antiretroviral therapy in HIV-positive patients: safety. Efficacy and PharmacokineticsCurr HIV Res. 2016;14:54–60.

  135. 135.

    Trottier B, Lake JE, Logue K, et al. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label. Antivir Ther: Phase IIIb study; 2017 Apr 12.

  136. 136.

    Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238–46.

  137. 137.

    Ciaffi L, Cavassini M, Genne D, et al. Switch to etravirine for HIV-positive patients receiving statin treatment: a prospective study. Eur J Clin Investig. 2015;45:720–30.

  138. 138.

    Banach M, Serban C, Sahebkar A, Mikhailidis DP, Ursoniu S, Ray KK, et al. Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies. BMC Med. 2015;13:229.

  139. 139.

    Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomized, double-blind, placebo-controlled trial. Lancet HIV. 2015;2:e52–63.

  140. 140.

    Erlandson K, Jiang Y, Debanne S, Mc Comsay G. Rosuvastatin worsens insulin resistance in HIV-infected adults on antiretroviral treatment. Clin Infect Dis. 2015;61:1566–71.

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The authors are grateful to Mrs. Paulene Butts for assistance with English language.

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PM and ADB cohordinated the project of the paper, collected the contributions, wrote the “Background” and the “Conclusions”, and prepared the final version of the paper. PM and MDA cured the section: “Prevention of Cardiovascular Events”. SC and NS cured the section: “Pharmacological treatment of dyslipidemia”. VS cured the section: “Experimental molecules”. SR, GDE and LS cured the section: “Combination antiretroviral therapy (cART) switching”. GN cured the section: “New antiretroviral drugs and cardiovascular risk”. CM, GN and VS cured the section: “Lipodystrophy in the Current cART era”. All authors read and approved the final manuscript.

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Correspondence to Paolo Maggi.

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Maggi, P., Di Biagio, A., Rusconi, S. et al. Cardiovascular risk and dyslipidemia among persons living with HIV: a review. BMC Infect Dis 17, 551 (2017).

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  • HIV
  • Cardiovascular risk
  • Statins
  • Ezetimibe
  • Fibrates
  • Omega 3 fatty acids ART
  • Lipodystrophy
  • Dyslipidemia