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The Brazilian Journal of Infectious Diseases logoLink to The Brazilian Journal of Infectious Diseases
. 2013 Jul 31;17(6):691–700. doi: 10.1016/j.bjid.2013.05.004

A literature review on cardiovascular risk in human immunodeficiency virus-infected patients: implications for clinical management

Mansueto Gomes Neto 1,⁎, Ricardo Zwirtes 1, Carlos Brites 1
PMCID: PMC9427374  PMID: 23916459

Abstract

Introduction

In recent years, there has been growing concern about an increasing rate of cardiovascular diseases in human immunodeficiency virus-infected patients, which could be associated with side effects of highly active antiretroviral therapy. It is likely that the metabolic disorders related to anti-human immunodeficiency virus treatment will eventually translate into a increased cardiovascular risk in patients submitted to such regimens.

Objective

To evaluate if human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy are at higher risk of cardiovascular diseases than human immunodeficiency virus infected patients not receiving highly active antiretroviral therapy, or the general population.

Research design and methods

We conducted a computer-based search in representative databases, and also performed manual tracking of citations in selected articles.

Result

The available evidence suggests an excess risk of cardiovascular events in human immunodeficiency virus-infected persons compared to non-human immunodeficiency virus infected individuals. The use of highly active antiretroviral therapy is associated with increased levels of total cholesterol, triglycerides, low-density lipoprotein and morphological signs of cardiovascular diseases. Some evidence suggested that human immunodeficiency virus-infected individuals on highly active antiretroviral therapy regimens are at increased risk of dyslipidemia, ischemic heart disease, and myocardial infarction, particularly if the highly active antiretroviral therapy regimen contains a protease inhibitor.

Conclusion

Physicians must weigh the cardiovascular risk against potential benefits when prescribing highly active antiretroviral therapy. Careful cardiac screening is warranted for patients who are being evaluated for, or who are receiving highly active antiretroviral therapy regimens, particularly for those with known underlying cardiovascular risk factors. A better understanding of the molecular mechanisms responsible for increased risk of cardiovascular diseases in human immunodeficiency virus-infected patients will lead to the discovery of new drugs that will reduce cardiovascular risk in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy.

Keywords: AIDS, Therapeutics, Highly active antiretroviral therapy, Cardiovascular diseases

Introduction

The widespread use of highly active antiretroviral therapy (HAART) – comprising protease inhibitors (PIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) combined with nucleoside reverse-transcriptase inhibitors (NRTIs) – has dramatically decreased the morbidity and mortality associated with human immunodeficiency virus (HIV) infection in the developed world.1, 2

Since the introduction of HAART in 1995, a significant decrease in mortality was observed in HIV-infected patients associated with a marked reduction in the incidence of opportunistic infections and certain kind of cancers.3, 4 However, current evidence suggests that patients on HAART are at increased risk of developing cardiovascular disease (CVD), and recent studies reported a higher prevalence of traditional risk factors for CVD in HIV-infected patients than in non-infected controls, such as arterial hypertension, dyslipidemia, and diabetes mellitus. These abnormalities may be associated with the use of certain antiretroviral drugs.5

HIV infection leads to a chronic systemic inflammatory process, which is increasingly accepted as having an important role in the pathogenesis of atherosclerosis and acute cardiovascular events. HIV-infected patients have been described as presenting unique histological features of coronary artery disease, including a rapid progression of diffuse circumferential arterial lesions with proliferation of smooth muscle cells, elastic fibers, and endoluminal protrusions.6

HIV-infected patients with acute coronary syndrome tend to be younger, with lower high-density lipoprotein (HDL) levels, higher prevalence of smoking, and less angiographically apparent coronary artery disease, when compared to non-HIV patients, which represents a different epidemiological pattern. HIV-infected patients may have concomitant traditional risk factors for CVD such as smoking, hypertension, and dyslipidemia, but the HIV and HAART may interact with these factors and contribute to the increased incidence of CVD. The long-term benefits of HAART are remarkable, but the associated complications make the overall management of HIV-infected patients more complex and costly.7

Because of the dissemination of HIV infection and its potential association with CVD, some authors have proposed a routine and systematic evaluation of HIV-infected adults and children, including medical history, cardiac examination and systematic echocardiographic monitoring, since asymptomatic cardiac disease and cardiac symptoms can often be misled by secondary effects of HIV infection.8

The aim of this review was to evaluate if HIV-infected patients receiving HAART are at higher risk of CVD in relation to HIV-infected patients not receiving HAART and to the general population.

Methods

We performed a computer-based search, querying Ovid MEDLINE (1950 to July 2012), CINAHL (Cumulative Index to Nursing and Allied Health, 1982 to July 2012), EMBASE (1980 to July 2012), and the Cochrane Central Register of Controlled Trials for original research articles published in English, Spanish and Portuguese. Medical Subject Headings (MeSH) were used as search terms when available, and keywords were used when appropriate. Terms for Anti-HIV Agents, HIV Infections, Cardiovascular Diseases, and Cardiovascular Diseases/complications were combined with a variety of MeSH terms to delimit relevant study designs and populations.

The selected outcome measures were common clinical cardiovascular outcomes (e.g. ischemic heart disease (IHD), heart failure (HF), cerebrovascular disease, acute coronary syndrome, myocardial infarction (MI) and peripheral vascular disease), or established traditional risk factors for CVD (e.g. hypertension and hypercholesterolemia).

One reviewer made the search and the initial selection of potentially relevant studies meeting the inclusion criteria and two independent reviewers selected articles that met the established inclusion and exclusion criteria. Studies were assessed for use of an appropriate source population, measurement methods of exposure and outcome, methods to deal with design-specific issues such as bias and lost to follow-up, use of analytical methods and use of statistics for primary analysis of effect. A manual tracking of citations in articles selected was also performed.

The structure of the search is shown in Table 1. Abstracts and relevant full-text articles were reviewed by one researcher.

Table 1.

PICO.

Population HIV-infected adults
Intervention Antiretroviral therapy (when applicable)
Comparator HIV-infected adults without antiretroviral therapy
General population
Outcome Cardiovascular Disease or Cardiovascular Risk Factors
Type of study Randomized Clinical Trials (RTC) and Observational Studies
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Results

Design of clinical trials and subjects

The search strategy identified 205 titles, 159 of which were excluded because they did not match the source population, outcome or study design did not address the research question. Of 46 potential articles, only 26 were directly related to the main goal of this review, and two studies were added after manual search. A total of 28 articles were included in the review: four randomized clinical trials and 24 observational studies being 22 prospective cohorts and two case–control studies.

Table 2 summarizes the main characteristics and results of studies included in this review.

Table 2.

Study characteristics and results.

Study Type of study Population-follow-up Drugs Results Outcomes
Coplan et al., 20039 Prospective cohort 10,986 HIV-patients which 7951 received PI therapy – 12 months IDV, NFV, SQV
Ritonavir		 RR of MI were 1.69 (0.54, 7.48) in PI-containing HAART and 1.74 (0.5, 9.0) for patients with NRTI-only regimens. No difference in MI incidence between the PI containing or not containing groups



Llibre et al., 200610 Prospective cohort 352 HIV-patients in use of 3 antiretroviral drugs – 48 weeks Substitution of TDF by d4T Reduction in TC (−17.5 mg/dL; p < 0.001), LDL-C (−8.1 mg/dL; p < 0.001) and TG (−35 mg/dL; p < 0.001) at 48 weeks of follow up. TC reduction
HDL and LDL-C reduction
TG reduction



Velenzuela et al., 200711 Prospective cohort 276 patients:
168 – HAART and PI
108 – HAART – 4 months		 NS Low CVR but higher TC and TG in the subpopulation of patients who received PI Low CVR; higher TC and TG in the subpopulation of patients who received PI



Brothers et al., 200912 Prospective cohort HIV received ABC (n = 9502) or not (n = 4672) – 24 week ABC and NS MI were comparable among subjects exposed n = 16 (0.168%); or not n = 11 (0.235%) to ABC-containing therapy. CAD and MI events were similar across ABC-exposed and non-ABC-exposed groups



Worm et al., 201013 Prospective cohort 33,308 HIV-patients
(D:A:D Study) – >1 year		 AZT, ddI, ddC, d4T, 3TC, ABC, TDF, IDV, NFV, LPV, SQV, NVP, EFV Recent exposure to ABC or ddi was associated with an increased risk of MI. Cumulative exposure to IDV and LPV was associated with an increased risk of MI. Increased risk of MI associated with IDV, LPV, ddI, ABC



Cahn et al., 201014 Prospective cohort 4010 HIV-patients receiving HAART for at least 1 month – 2 years NS The overall 10-year risk of CVD, as measured by the FRF, was 10.4 (24.7). The FRF score increased with duration of HAART. 80.2% of dyslipidemia
20.2% of metabolic syndrome



Obel et al., 201015 Prospective cohort 2952 HIV-patient ABC, AZT, d4T, ddI, 3TC RR of MI hospitalization with ABC was 2.22 (95% CI 1.31–3.76). The risk of MI increased after initiation of ABC IRR adjusted for confounders = 2.00 (95% CI 1.10–3.64).



Saint-Martin et al., 201016 Prospective cohort 33 ATV/r > 6 months
99 ATV/r naive controls – 18 months		 ATV/R
Others		 The CIMT course significantly decreased (p = 0.018) in cases at 18 months. CIMT significantly decreased (p = 0.018)



Ribaudo et al., 201117 Prospective cohort 1704 received ABC
3352 no ABC – 3.1 years		 NS 6 years after ART initiation, 36 MI events were observed in 17,404 person-years. No evidence of an increased hazard of MI in subjects using ABC vs. no ABC was seen (over a 1-year period: p = 0.50; HR = 0.7 [95% CI, 0.2–2.4]). No evidence that initial ART containing ABC increases MI risk over short-term and long-term periods



Durand et al., 201118 Prospective cohort 7053 HIV-positive patients were matched to 27,681 HIV-negative patients ABC
LPV
EFV		 The drugs that were associated with an increased risk of AMI for any exposure were ABC OR = 1.79, lopinavir OR = 1.98, ritonavir OR = 2.29 and EFZ OR = 1.83. HIV+ were at higher risk of AMI than the general population, and several ARTs were associated with an increased risk of AMI



Friis-Moller et al., 200319 Prospective cohort 17,852 patients enrolled in DAD from nine of 11 participating cohorts PIs, NNRTIs Increased prevalence of elevated TC among subjects receiving an NNRTI but no PI OR = 1.79, PI but no NNRTI OR = 2.35, or NNRTI + PI OR = 5.48 compared to the prevalence among antiretroviral therapy (ART)-naïve subjects. CVD risk factors were prevalent. With the highest prevalence among patients receiving PI, NNRTI or both of these drug classes



Choi et al., 201121 Prospective cohort 10,931 HIV-infected patients initiating antiretroviral therapy in the Veterans Health Administration from 1997 to 2007 ABC
TDF		 123 cardiovascular events in 15,142 person-years of <6 months ABC use and 90 in 22 551 person-years TDF use. Incidence of any CVD event were higher in the setting of ABC use compared with TDF use or other ART (13.4 vs. 9.4 per 1000 person-years p < 0.01. Recent ABC exposure was significantly associated with higher risk of atherosclerotic vascular events, and recent TDF exposure was significantly associated with HF



DAD Study Group, 200322 Prospective cohort 23,468 HIV-patients were enrolled from 11 previously cohorts PIs
NRTIs		 The incidence of MI increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; p < 0.001). Combination ART was independently associated with a 26% relative increase in MI per year of exposure



Masiá et al., 200723 Prospective cohort 245 consecutive HIV-infected patients during a 2-month period Naïve
NNRTIs
PI		 Among patients on ART, peroxide concentrations (PC) were significantly lower in NNRTI regimens than in those receiving PIs ([IQR], 331.2 vs. 472.8 t∼mol/L; p = 0.003). PC used as a marker of OS was associated with CVD factors. NNRTIs were associated with low PC vs. patients receiving PI



Reinsch et al., 201024 Cohort 698 HIV-positive patients PIs
NRTIs
NNRTIs		 DD was present in 336 (48%) of the total HIV infected population. While not statistically significant, NRTI and PI use showed a trend toward a greater prevalence in the DD group. High prevalence of DD in HIV patients was demonstrated. Traditional CVD risk factors contributed to the DD



Silva et al., 200925 Cohort 215 patients receiving HAART and 69 HAART-naive patients G A:
G B:
G C:
G D:
G E:		 TC, HDL, TG and glucose were higher in the HAART group than in the non-HAART group p < 0.001). According to the FRS, the CVD risk was moderate to high in 11% receiving HAART. Although the mean values for TC, HDL-c and TG were higher in the HAART group, a higher CVR was not identified in the former



Triant et al., 200726 Prospective cohort 3851 HIV and 1,044,589 non-HIV patients PIs
NRTIs
NNRTIs		 AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates were increased in HIV vs. non-HIV patients 11.13 vs. 6.98 (p < 0.001). AMI rates and CVR factors were increased in HIV compared with non-HIV patients



Alvarez et al., 201027 Prospective cohort 4010 HIV patients The overall prevalence of MS was 20.2% (812/4010). The 10-year risk of developing CVD was 10.4% (24.7). Patients with MS had higher CVD risk 22.2% vs. 7.4%, respectively, p < 0.001. MS in HIV-infected patients receiving ART is comparable to populations. Patients with MS had higher estimated risk for CVD



Kwiatkowska et al., 201128 Prospective cohort 72 HIV infected patients and 27 healthy individuals PIs, NNRTIs,
NRTIs		 HIV infected patients show more advanced subclinical atherosclerosis in the carotid arteries (cIMT and plaques incidence). Patients treated with ARV therapy for over 5 years have a higher value of cIMT. HIV shows significant progression of subclinical atherosclerosis and incidence of atherosclerotic plaques



D:A:D Study Group*, 200829 Prospective cohort 33,347 HIV-1-infected Associations between the rate of MI and cumulative or recent use of AZT, d4T, or 3TC. Recent use of ABC or ddI was associated with an increased rate of MI relative rate 1.90 with ABC and 1.49 with ddI [p = 0.003]). There exists an increased risk of MI in patients exposed to ABC and ddI. The excess risk does not seem to be explained by underlying established CVD risk factors



SMART/INSIGHT and DAD Study, 200830 Prospective cohort 4544 HIV patients NRTIs
PIs		 Use of ABC was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical MI (n = 19), major CVD (MI, stroke, surgery for CAD, and CVD death; n = 70). Current use of ABC was associated with an excess risk of CVD compared with other NRTIs. The drug may cause vascular inflammation, which may precipitate a CVD event



Obel et al., 200731 Prospective cohort 3953 HIV-infected patients and 373,856 Control subjects PIs,
NNRTIs,
NRTIs		 In HAART period, the risk of ischemic heart disease (IHD) increase was substantially higher RR = 2.12. 1 year after receiving a diagnosis of HIV infection, RR of IHD was 2.38. Compared with the general population, HIV-infected patients receiving HAART have an increased risk of IHD



Van Vonderen 200933 Case–control 55 HIV-patients ART, 22 HIV-patients ART naive
23 HIV-patients with LD
52 controls – NA		 NS HIV infected patients had a 0.067 mm (10.8%) greater CIMT than controls. Patients exposed to ART had similar CIMT compared with ART-naive patients but 25.9% lower DC and 21.7% lower CC of the femoral artery. HIV infection is independently associated with C-IMT and generally increased arterial stiffness



Lang et al., 201034 Case–control 289 HIV-patients with history of MI
884 HIV-patients with no history of MI – 6 years		 ABC, AZT, d4T, 3TC, TDF Recent exposure to ABC was associated with an increased risk of MI (OR, 2.01; 95% CI, 1.11–3.64) Cumulative exposure to all PIs except SQV was associated with an increased risk of MI. Short-term/recent exposure to ABC was associated with an increased risk of MI



Wand et al., 200735 RTC 288 ddI/d4T with EFV
305 ddI/d4T with NFV
288 ddI/d4T with EFV+ NFV – 3 years		 ddI
d4T
EFV
NFV		 MS association with increased risk of CVD HR = 2.56 and was associated with an increased risk of T2DM (ATP-III: HR = 4.34; p = 0.001). Incident MS was associated with an increased risk of both CVD (ATP-III: HR = 2.73; p = 0.036) and T2DM (ATP-III: HR = 4.89; p < 0.0001). Progression to MS



Van Vonderen et al., 200936 RTC 19 HIV-patients with LPV/r plus ZDV/3TC
18 LPV/r plus NVP-
3 years		 LPV/r
ZDV
3TC
NVP		 CIMT increased by 0.061 mm (p < 0.001) in the ZDV/3TC/LPV/r arm and by 0.044 mm (p = 0.012) in the NVP/LPV/r arm. Femoral artery DC and CC decreased in the ZDV/3TC/LPV/r arm and femoral DC decreased in the NVP/LPV/r arm. CIMT and femoral artery stiffness increased after the initiation of HAART



Martınez et al., 201037 RTC 46 ABC/3TC
34 TDF/emtricitabine)
48 weeks		 ABC
3TC
TDF
Emtricitabine		 TC increased significantly in the ABC/3TC vs. TFV/ETB group, found no significant changes in the biomarkers (p = 0.12 for all comparisons) ABC/3TC increase TCl and LDL
Did not cause inflammation,
endothelial dysfunction, insulin resistance



Murphy 201038 RTC 26 ATV/r
24 remained on PI regimen
24 weeks		 ATV/r
Others		 Changes in the ATV/r vs. continued PI group were observed for TC (−25 vs. +1.5 mg/dl, p = 0.009), TG (−58 vs. +3.5 mg/dl, p = 0.013), and non HDL-C (−27 vs. −0.5 mg/dL, p = 0.014). ATV/r improved lipid profile
Did not change endothelial function, inflammatory and metabolic markers
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TC, total cholesterol; HDL-C and LDL-C, high and low-density lipoprotein cholesterol; TG, triglycerides; CVR, cardiovascular risk; MI, myocardial infarction; AMI, acute myocardial infarction; FRF, Framingham risk score; CAD, coronary artery disorder; CIMT, carotid intima–media thickness; LD, lipodystrophy; MS, metabolic syndrome; 3TC, lamivudine; AZT, zidovudine; d4T, stavudine; ddC, zalcitabine; ddI, didanosine; EFV, efavirenz; IDV, indinavir; LPV, lopinavir/ritonavir; NFV, nelfinavir; NVP, nevirapine; SQV, saquinavir; TDF, tenofovir; ATV/r, atazanavir; ABC, Abacavir; ETB, emtricitabine; OPG, osteoprotegerin; ADT, adiponectin.

G A: (AZT) + (3TC) + EFV; G B: AZT + 3TC + LPV e AZT + 3TC + NFV; G C: AZT + 3TC + ATV/r; G D: (d4T) + 3TC + EFV; G E: d4T + 3TC + LPV e d4T +3 TC + NFV e d4T + ddI + LPV (RTI) – reverse transcriptase inhibitors not specified (NS); not applicable (NA); relative risk (RR).

Evidence from the included studies indicates that exposure to antiretroviral drugs is associated with an increased rate of CVD events. HIV infection decreases good cholesterol, increases triglycerides (TG), total cholesterol (TC), and vascular inflammation.10, 16, 17, 18, 19, 22, 24, 25, 30 Traditional cardiovascular risk (CVR) factors substantially contribute to the development of diastolic dysfunction (DD) in the HIV-infected patients.15

The use of several antiretroviral agents favors the occurrence of multiple metabolic and morphologic abnormalities, including dyslipidemia, insulin resistance, subcutaneous fat loss, visceral fat accumulation, and metabolic syndrome (MS), which are associated with an increased risk of premature atherosclerosis and MI.6, 9, 11, 13, 16, 18, 28 HAART may also indirectly or directly induce endothelial dysfunction.19, 24

HIV infection itself is an independent risk factor for acute myocardial infarction (AMI), and increase arterial stiffness. Compared with the general population, HIV-infected patients receiving HAART have an increased risk of AMI and IHD,18, 26, 31, 33, 36 and increase in thickness of the intima–media complex.28, 33

Combination antiretroviral therapy is associated with MI,9, 13, 22, 29 and longer exposure to HAART and/or PIs seem to increase the risk of MI.29, 32 HIV-infected patients using PI had slightly higher CVD risk than those using NNRTI, and slightly increased risk for patients using abacavir (ABC) or didanosine (ddI).18, 26 Recent ABC exposure was significantly associated with higher risk of atherosclerotic vascular events, CVD, and an increased risk of MI.21, 30, 34 There exists an increased risk of MI in patients exposed to ABC and ddI within the preceding six months.29

Discussion

Cardiovascular complications of HIV disease are generally late manifestations and may be related to prolonged effects of immunosuppression and a complex interplay of mediator effects from opportunistic infections, autoimmune response to viral infection, drug-related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression.39

There are many ways to assess the risk of CVD and multiple risk factors can be examined, such as age, gender, body mass index (BMI), TC, LDL, TG, MS, MS, carotid intima–media thickness (CIMT). These traditional risk factors for CVD increase risk of cardiovascular events in both HIV-infected and uninfected individuals.

For HIV-infected patients the retroviral chronic infection per se, the use of HAART and/or at least some of the antiretroviral drugs, and lipodistrophy can be considered additional risk factors. HIV infection plays a substantial role on blood lipids disorders and can induce endothelial cells injury which leads to a local inflammatory response that could promote thrombosis, impair vessel responsiveness, and is an important factor for arterial plaque formation. HIV replication may activate endothelial surfaces directly or via up-regulation of pro-inflammatory cytokines.

Some studies suggested that even though the overall cardiovascular event rate is low, there is an excess risk of cardiovascular events in HIV-infected persons compared to non-HIV-infected individuals. Some evidence suggested that HIV-infected individuals on HAART regimens are at increased risk of dyslipidemia, IHD, and MI, particularly if the HAART regimen contains a PI. While lipid-lowering drugs are a routine strategy for CVR reduction in the general population, HIV-infected people are usually not on those drugs even when clinically indicated.40

In this review we observed some different outcomes associated with different results. When the outcome was MI and the use of ABC was investigated, in three studies increased MI incidence was detected13, 15, 34 and in two studies there were no significant differences.12, 17 Recently, the U.S. Food and Drug Administration (FDA) conducted a meta-analysis in which ABC use was randomized as part of a combined antiretroviral regimen and found no association between the use of ABC and MI.41

When the outcome was the change in lipid profile, two studies showed a reduction on TC, LDL, TG,10, 38 and two demonstrated an increase in blood lipids.11, 37 Two studies showed an increase in CIMT,10, 33 and one demonstrated a decrease in CIMT.16

We must be aware that the population studied in all of the reviewed studies are HIV-infected adult patients, but with different characteristics. The studied populations had different age ranges and gender; different stages of HIV infection and most of them were receiving different antiretroviral drugs regimens, which could have different effects not only in the surrogate markers of CD risk but mainly in the incidence of CVD.

In spite of individual studies suggesting that currently available PIs could increase the CVR,18, 26, 29, 32 the PI class remained a very effective class of antiretroviral drugs for HIV infection therapy. Life expectancy for HIV-infected patients has improved by 20 years for those diagnosed at age 25–33 years, and it is still improving. The HIV-infected population is becoming more susceptible to all chronic diseases that are observed in non-HIV-infected patients with the presence of additional risk factors for CVD due to infection and the treatment itself.42

The clinical expression of cardiac involvement is variable and is affected by the stage of HIV disease, the degree of immunodeficiency, and the use of drugs to treat HIV disease or to treat or prevent opportunistic infections and neoplasms.43 CVR must be considered in the overall care of adults with HIV infection. However, such risk should not influence the decision of when to initiate antiretroviral therapy, and the decision of which antiretroviral regimen to use should be made based on risk and benefit analysis that includes the clear survival benefit associated with maximal viral suppression.

HIV-infected patients confront an escalating epidemic of CVD that is comparable to that faced by the general population more than half a century ago. Stratifying risk among HIV-infected patients and devising cardiovascular preventive strategies are priorities.44 The initial choice of ART regimen and subsequent modifications also may be considered in planning CVD prevention strategies, because the risks of inadequately treated HIV infection outweigh any increase in CVD risk that may be associated with ART, and with the understanding that uncontrolled viral infection may itself contribute to CVD risk.45, 46

CVD risk assessment and risk reduction are essential components of preventive medical care that are increasingly important for patients with HIV. Physicians should systematically assess their HIV-infected patients for CVR factors and should closely monitor patients receiving HAART, especially those with additional risk factors for CVD.47

The role of the cardiologist in the evaluation and treatment of patients with HIV infection should therefore be expanded to include patients who are being evaluated for or who are receiving HAART regimens, especially those with underlying CVR. It may be important to consider traditional coronary risk profiles and to alter those that can be modified in the evaluation and continued therapy of patients with HAART.48 It is especially important to develop simple and clear messages to educate patients about the importance of CVD prevention, the importance of identifying and treating CVD risk factors or high CVD risk, and how smoking, adverse dietary habits, and physical inactivity increase CVD risk.49

Treatment options include the use of pharmacological and non-pharmacological methods for managing dyslipidemia and hyperglycemia, as well as considering lipid-neutral HAART regimens for their patients, especially with the availability of drugs in this class with less adverse impact on lipid profile.47 One potential strategy to manage dyslipidemia is switching the ARV drug that promotes the lipids increase. However, it should be taken into consideration that it depends on the availability of remaining active drugs without impact on plasma lipids. In addition, switching requires a careful evaluation of the risks of virological failure, especially for patients with previous failure to ARV regimens.

Dyslipidemic HIV/HAART patients have elevated levels of lipoprotein-associated phospholipase A2 (Lp-PLA2). The main physiological action of Lp-PLA2 is the hydrolysis of strongly inflammatory phospholipids, such as platelet-activating factor which may increase risk of CVD.50, 51 Elevated plasma Lp-PLA2 can be reduced by an intensive diet and exercise program in patients with HIV/HAART-associated dyslipidemia.51

Current guidelines recommend dietary intervention as first line treatment for HIV dyslipidemia.52, 53 Omega-3 supplementation has a triglyceride-lowering effect that may impact on cardiac outcomes. Triglyceride levels represent an important biomarker of CVD, because of their association with atherogenic remnant particles. The 33,308 HIV-infected included in the study of Worm et al., with elevated triglyceride levels, experienced 580 MIs over 178,835 person-years. The risk of MI increased by 67%, per doubling in triglyceride level.54

Recently, Stradling et al. conducted a Systematic Review and Meta-Analysis which provides evidence for a comparable clinical benefit of dietary intervention or omega-3 supplementation in reducing triglycerides.55 Diet supplementation with fish oil is prescribed when a suppression of lipid mobilization is desired. The use of antihyperlipidemic drugs should be reserved for patients at high risk of cardiovascular events.56

Lifestyle changes (healthy diet, smoking cessation, and daily physical exercise) reduce the probability of a coronary event by up to 80% in the general population. Dietary, pharmacological interventions and exercise are established interventions to reduce metabolic changes and the relevant risk.56

Exercise is consistently listed among the three most common complementary and alternative therapies utilized by HIV-infected persons. A training program that involves concurrent endurance and strength training must be prescribed. Exercise aerobic should be performed at a moderate intensity: from 11 to 14 on the Borg Rating of Perceived Exertion Scale, or 50–85% of peak heart rate and resistance training should focus on large muscle groups, with intensity of 60–80% of one maximal repetition and 8–12 repetitions.56, 57

A significant body of evidence suggests that there is a measurable increase in the risk of CVD in HIV-infected patients with varying effects from different antiretroviral drugs. In spite of studies, the impact of HIV and different HAART regimens on the risk of CVD in HIV-infected patients remains somewhat obscure. Differences in study design, endpoints, patient populations and limited follow-up in some studies prevent definitive comparisons.58

This review has several limitations, most of them due to the varying methodologies and study designs and inherent limitations of observational studies, which makes it difficult to control for population or selection bias. Furthermore, substantial variations in study design complicate the analysis of the associations between HAART and CVD risk. Considering its descriptive purpose and the findings of this review, it seems reasonable to believe that both HIV infection and HAART have potential adverse impact on CVR factors and on the incidence of CVD.

Conclusion

There are many studies addressing the relationship between HAART and CVD and it is an issue still under debate. However, it is clear that this combined antiretroviral therapy remarkably decreased the overall mortality associated with HIV infection. Our review confirms that HIV-infected patients present risk of CVD, and for this reason preventive strategies should be focused on smoking cessation, increase physical exercise, and diet.

Conflicts of interest

The authors declare no conflicts of interest.

References

  • 1.Mocroft A., Ledergerber B., Katlama C., et al. Changes in the AIDS and death rates in the EuroSIDA study, an observational study. Lancet. 2003;362:22–29. doi: 10.1016/s0140-6736(03)13802-0. [DOI] [PubMed] [Google Scholar]
  • 2.Sterne J.A.C., Hernán M.A., Ledergerber B., et al. Long-term effectiveness of potent antiterroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet. 2005;366:378–384. doi: 10.1016/S0140-6736(05)67022-5. [DOI] [PubMed] [Google Scholar]
  • 3.Hulten E., Mitchell J., Scally J., Gibbs B., Villines T.C. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies. Heart. 2009;95:1826–1835. doi: 10.1136/hrt.2009.177774. [DOI] [PubMed] [Google Scholar]
  • 4.Baker J.V., Henry W.K., Neaton J.D. The consequences of HIV infection and antiretroviral therapy use for cardiovascular disease risk: shifting paradigms. Curr Opin HIV AIDS. 2009;4:176–182. doi: 10.1097/COH.0b013e328329c62f. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Amado L.E.M., Ruiz I.S. Enfermedad cardiovascular e infección por el virus de la inmunodeficiencia humana. Cardiovascular disease and infection with the human immunodeficiency virusRev Panam Infectol. 2007;9:39–49. [Google Scholar]
  • 6.Subramanian S., Tawakol A., Burdo T.H., et al. Arterial inflammation in patients with HIV. JAMA. 2012;308:379–386. doi: 10.1001/jama.2012.6698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Manfredi R., Calza L. The risk of myocardial infarction during HIV infection treated with antiretroviral combinations. A review. Rev Latinoameric Hipertensión. 2009;4:86–104. [Google Scholar]
  • 8.Cecchi E., Imazio M., Pomari F., et al. A clinical approach for cardiovascular monitoring of HIV-infected patients. Results from an observational cohort study. Ital Heart J. 2005;6:972–976. [PubMed] [Google Scholar]
  • 9.Coplan P.M., Nicas A., Japour A., Cormier K., Maradit-Kremers H., Lewis R. Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors. AIDS Res Hum Retrovirus. 2003;19:449–455. doi: 10.1089/088922203766774487. [DOI] [PubMed] [Google Scholar]
  • 10.Llibre J.M., Domingo P., Palacios R., Santos J., Perez-Elıasd M.J., Rosae R.S. Sustained improvement of dyslipidaemia in HAART treated patients replacing stavudine with tenofovir. AIDS. 2006;20:1407–1414. doi: 10.1097/01.aids.0000233574.49220.de. [DOI] [PubMed] [Google Scholar]
  • 11.Velenzuela G.R., Mendo F.U., Espichan G.M. Prevalencia de factores de riesgo cardiovascular em uma población peruana de pacientes coninfección por el virus de inmunodeficiencia humana em terapia antiretroviral de gran actividad. Rev Med Hered. 2007;18:10–14. [Google Scholar]
  • 12.Brothers C.H., Hernandez J.E., Cutrell A.G., et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr. 2009;51:20–28. doi: 10.1097/QAI.0b013e31819ff0e6. [DOI] [PubMed] [Google Scholar]
  • 13.Worm S.W., Sabin C., Weber R., et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. J Infect Dis. 2010;201:318–330. doi: 10.1086/649897. [DOI] [PubMed] [Google Scholar]
  • 14.Cahn P., Leite O., Rosales A., et al. Metabolic profile and cardiovascular risk factors among Latin American HIV-infected patients receiving HAART. Braz J Infect Dis. 2010;14:158–166. doi: 10.1590/s1413-86702010000200008. [DOI] [PubMed] [Google Scholar]
  • 15.Obel N., Farkas D.K., Kronborg G., et al. Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study. HIV Med. 2010;11:130–136. doi: 10.1111/j.1468-1293.2009.00751.x. [DOI] [PubMed] [Google Scholar]
  • 16.Saint-Martin L., Bressollette L., Perfezouc P., Bellein V., Ansart S., Vallet S. Impact of atazanavir-based HAART regimen on the carotid intima–media thickness of HIV-infected persons: a comparative prospective cohort. AIDS. 2010;24:2797–2801. doi: 10.1097/QAD.0b013e328340a21f. [DOI] [PubMed] [Google Scholar]
  • 17.Ribaudo H.J., Benson C.A., Zheng Y., et al. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short and long-term results from ACTG A5001/ALLRT. Clin Infect Dis. 2011;52:929–940. doi: 10.1093/cid/ciq244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Durand M., Sheehy O., Baril J.G., Lelorier J., Tremblay C.L. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a Cohort and Nested Case–Control Study using Que’bec's Public Health Insurance Database. J Acquir Immune Defic Syndr. 2011;57:245–253. doi: 10.1097/QAI.0b013e31821d33a5. [DOI] [PubMed] [Google Scholar]
  • 19.Friis-Moller N., Weber R., Reiss P., et al. Cardiovascular disease risk factors in HIV patients – association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179–1193. doi: 10.1097/01.aids.0000060358.78202.c1. [DOI] [PubMed] [Google Scholar]
  • 21.Choi A.I., Vittinghoff E., Deeks S.G., Weekley C.C., Li Y., Shlipak M.G. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS. 2011;25:1289–1298. doi: 10.1097/QAD.0b013e328347fa16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Data Collection on Adverse Events of Anti-HIV Drugs Study, Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993–2003. doi: 10.1056/NEJMoa030218. [DOI] [PubMed] [Google Scholar]
  • 23.Masiá M., Padilla S., Bernal E., et al. Influence of antiretroviral therapy on oxidative stress and cardiovascular risk: a prospective cross-sectional study in HIV-infected patients. Clin Ther. 2007;29 doi: 10.1016/j.clinthera.2007.07.025. [DOI] [PubMed] [Google Scholar]
  • 24.Reinsch N., Neuhaus K., Esser S., et al. Prevalence of cardiac diastolic dysfunction in HIV-infected patients: results of the HIV-HEART study. HIV Clin Trials. 2010;11:156–162. doi: 10.1310/hct1103-156. [DOI] [PubMed] [Google Scholar]
  • 25.Silva E.F.R., Bassichetto K.C., Lewi D.F. Lipid profile, cardiovascular risk factors and metabolic syndrome in a group of AIDS patients. Arq Bras Cardiol. 2009;93:107–111. doi: 10.1590/s0066-782x2009000800008. [DOI] [PubMed] [Google Scholar]
  • 26.Triant V.A., Lee H., Hadigan C., Grinspoon S.K. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92:2506–2512. doi: 10.1210/jc.2006-2190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Alvarez C., Salazar R., Galindez J., et al. Metabolic syndrome in HIV-infected patients receiving antiretroviral therapy in Latin America. Braz J Infect Dis. 2010;14:256–263. [PubMed] [Google Scholar]
  • 28.Kwiatkowska W., Knysz B., Drelichowska-Durawa J., et al. Subclinical carotid atherosclerosis and cardiovascular risk factors in HIV-infected patients. Postepy Hig Med Dosw. 2011;65:770–783. doi: 10.5604/17322693.967075. [DOI] [PubMed] [Google Scholar]
  • 29.D:A:D Study Group Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371:1417–1426. doi: 10.1016/S0140-6736(08)60423-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.The SMART/INSIGHT and the DAD Study Groups Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17–F24. doi: 10.1097/QAD.0b013e32830fe35e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Obel N., Thomsen H.F., Kronborg G., et al. Ischemic heart disease in HIV-infected and HIV uninfected individuals: a population-based cohort study. Clin Infect Dis. 2007;44:1625–1631. doi: 10.1086/518285. [DOI] [PubMed] [Google Scholar]
  • 32.Iloeje U.H., Yuan Y., L’italien G., et al. Protease inhibitor exposure and increased risk of cardiovascular disease in HIV-infected patients. HIV Med. 2005;6:37–44. doi: 10.1111/j.1468-1293.2005.00265.x. [DOI] [PubMed] [Google Scholar]
  • 33.Van Vonderen M.G., Smulders W.M., Stehouwer C.D., et al. Carotid intima–media thickness and arterial stiffness in HIV-infected patients: the role of HIV, antiretroviral therapy, and lipodystrophy. J Acquir Immune Defic Syndr. 2009;50:153–161. doi: 10.1097/QAI.0b013e31819367cd. [DOI] [PubMed] [Google Scholar]
  • 34.Lang S., Mary-Krause M., Cotte L., et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients. Arch Intern Med. 2010;170:1228–1238. doi: 10.1001/archinternmed.2010.197. [DOI] [PubMed] [Google Scholar]
  • 35.Wand H., Calmy A., Carey D.L., et al. Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS. 2007;21:2445–2453. doi: 10.1097/QAD.0b013e3282efad32. [DOI] [PubMed] [Google Scholar]
  • 36.Van Vonderen M.G.A., Hassink E.A.M., van Agtmael M.A., et al. Increase in carotid artery intima–media thickness and arterial stiffness but improvement in several markers of endothelial function after initiation of antiretroviral therapy. J Infect Dis. 2009;199:1186–1194. doi: 10.1086/597475. [DOI] [PubMed] [Google Scholar]
  • 37.Martınez E., Larrousse M., Podzamczer D., et al. Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction. AIDS. 2010;24:F1–F9. doi: 10.1097/QAD.0b013e32833562c5. [DOI] [PubMed] [Google Scholar]
  • 38.Murphy R.L., Berzins B., Zala C., et al. Change to atazanavir/ritonavir treatment improves lipids but not endothelial function in patients on stable antiretroviral therapy. AIDS. 2010;24:885–890. doi: 10.1097/QAD.0b013e3283352ed5. [DOI] [PubMed] [Google Scholar]
  • 39.Barbaro G., Silva E.F.R. Cardiovascular complications in the acquired immunodeficiency syndrome. Rev Assoc Med Bras. 2009;55:621–630. doi: 10.1590/s0104-42302009000500031. [DOI] [PubMed] [Google Scholar]
  • 40.McDonald C., Kaltman J.R. Cardiovascular disease in adult and pediatric HIV/AIDS. J Am Coll Cardiol. 2009;54:1185–1188. doi: 10.1016/j.jacc.2009.05.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Ding X., Andraca-Carrera E., Cooper C., et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr. 2012;28 doi: 10.1097/QAI.0b013e31826f993c. [DOI] [PubMed] [Google Scholar]
  • 42.Wierzbicki A.S., Purdon S.D., Hardman T.C., Kulasegaram R., Peters B.S. HIV lipodistrophy and its metabolic consequences: implication for clinical practice. Curr Med Res Opin. 2008;24:609–624. doi: 10.1185/030079908X272742. [DOI] [PubMed] [Google Scholar]
  • 43.Rerkpattanapipat P.I., Wongpraparut N., Jacobs L.E., et al. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med. 2000;160:602–608. doi: 10.1001/archinte.160.5.602. [DOI] [PubMed] [Google Scholar]
  • 44.D’Agostino R.B. Cardiovascular risk estimation in 2012: lessons learned and applicability to the HIV population. J Infect Dis. 2012;205:S362–S367. doi: 10.1093/infdis/jis196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr W.M., Lundgren J.D., et al. CD4_count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–2296. doi: 10.1056/NEJMoa062360. [DOI] [PubMed] [Google Scholar]
  • 46.Stein J.H. Cardiovascular risks of antiretroviral therapy. N Engl J Med. 2007;356:1773–1775. doi: 10.1056/NEJMe078037. [DOI] [PubMed] [Google Scholar]
  • 47.Maggi P., Quirino T., Ricci E., et al. Cardiovascular risk assessment in antiretroviral-naive HIV patients. AIDS Patient Care STDS. 2009;23:809–813. doi: 10.1089/apc.2009.0102. [DOI] [PubMed] [Google Scholar]
  • 48.Barbaro G., Fisher S.D., Giancaspro G., Lipshultz S.E. HIV-associated cardiovascular complications: a new challenge for emergency physicians. Am J Emerg Med. 2001;19:566–574. doi: 10.1053/ajem.2001.28323. [DOI] [PubMed] [Google Scholar]
  • 49.Stein J.H., Hadigan C.M., Brown T.T., Chadwick E., Feinberg J., Friis-Møller N. Prevention strategies for cardiovascular disease in HIV-infected patients. Circulation. 2008;118:e54–e60. doi: 10.1161/CIRCULATIONAHA.107.189628. [DOI] [PubMed] [Google Scholar]
  • 50.Saumoy M., Ordoñez-Llanos J., Martınez E., et al. Low-density lipoprotein size and lipoprotein-associated phospholipase A2 in HIV-infected patients switching to abacavir or tenofovir. Antivir Ther. 2011;16:459–468. doi: 10.3851/IMP1785. [DOI] [PubMed] [Google Scholar]
  • 51.Wooten J.S., Nambi P., Gillard B.K., et al. Intensive lifestyle modification reduces Lp-PLA2 in dyslipidemic HIV/HAART patients. Med Sci Sports Exerc. 2013 doi: 10.1249/MSS.0b013e3182843961. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Gazzard B.G., Anderson J., Babiker A., et al. British HIV association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med. 2008;9:563–608. doi: 10.1111/j.1468-1293.2008.00636.x. [DOI] [PubMed] [Google Scholar]
  • 53.Lundgren J.D., Battegay M., Behrens G., et al. European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Med. 2008;9:72–81. doi: 10.1111/j.1468-1293.2007.00534.x. [DOI] [PubMed] [Google Scholar]
  • 54.Worm S.W., Kamara D.A., Reiss P., et al. Elevated triglycerides and risk of myocardial infarction in HIV-positive persons. AIDS. 2011;25:1497–1504. doi: 10.1097/QAD.0b013e32834917c6. [DOI] [PubMed] [Google Scholar]
  • 55.Stradling C., Chen Y.F., Russell T., Connock M., Thomas G.N., Taheri S. The effects of dietary intervention on HIV dyslipidaemia: a systematic review and meta-analysis. PLoS ONE. 2012;7:e38121. doi: 10.1371/journal.pone.0038121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Scevola D., Di Matteo A., Lanzarini A., et al. Effect of exercise and strength training on cardiovascular status in HIV-infected patients receiving highly active antiretroviral therapy. AIDS. 2003;17(Suppl. 1):S123–S129. doi: 10.1097/00002030-200304001-00015. [DOI] [PubMed] [Google Scholar]
  • 57.Ciccolo J.T., Jowers E.M., Bartholomew J.B. The benefits of exercise training for quality of life in HIV/AIDS in the post-HAART era. Sports Med. 2004;34:487–499. doi: 10.2165/00007256-200434080-00001. [DOI] [PubMed] [Google Scholar]
  • 58.Das S. Risk of cardiovascular disease in HIV-infected patients. J Antimicrob Chemother. 2010;65:386–389. doi: 10.1093/jac/dkp460. [DOI] [PubMed] [Google Scholar]

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