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

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].

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).

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].

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.

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].

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 [67‐73].

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 [77‐85].

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.

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].

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 [92‐98]. 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.

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 [101‐103].

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].

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 [122‐124]. 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].