The Impact of Contemporary Antiretroviral Drugs on Atherosclerosis and Its Complications in People Living With HIV: A Systematic Review

With the advent of modern antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection has been modified into a chronic manageable condition, prolonging the lifespan of people living with HIV (PLHIV). This has resulted in an increased non-AIDS-related morbidity in the HIV-infected population. Our aim is to study the role of contemporary ART in tackling the risk of atherosclerosis and cardiovascular disease (CVD) in PLHIV. We searched through the databases of PubMed, PubMed Central, and Cochrane Library for pertinent articles using the medical subject headings (MeSH) “HIV infection”, “Atherosclerosis”, and “Antiretroviral agents”. The articles published in the past five years were retrieved, screened for relevance, and assessed for quality before being included in the review. This review was performed following the PRISMA 2020 guidelines. The results indicate that the incidence of dyslipidemia with integrase strand transfer inhibitors (INSTIs) is greater than with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and lesser than with protease inhibitors (PIs). INSTIs are indispensably associated with weight gain and obesity. High triglyceride (TG) and oxidized low-density lipoproteins to low-density lipoproteins (oxLDL/LDL) ratio levels and low high-density lipoprotein (HDL) levels are seen in patients taking PIs. A higher incidence of hypertension and metabolic syndrome (MetS) was noticed with INSTIs compared to NNRTIs. PI intake for >5 years increases the risk of subclinical atherosclerosis. Increased risk of myocardial infarction with INSTIs was observed in a study, while another study reported decreased risk. HIV infection independently increases the risk for atherosclerosis and CVD. Although contemporary ART decreases this enhanced risk, it inherently increases the risk for abnormal lipid profile, MetS, weight gain, and obesity. Further research into the risk of atherosclerosis and CVD with newer ART drugs is essential for decoding the underlying mechanisms and preventing adverse cardiac outcomes in PLHIV.


Introduction And Background
Human immunodeficiency virus (HIV) infection remains a major global public health issue, with 1.3 million people acquiring HIV in 2022 and an estimated 39.0 million people living with HIV at the end of 2022 [1].Having claimed 40.4 million lives so far, 630,000 in 2022 alone, transmission continues in all countries globally [1].However, with access to effective HIV prevention, early diagnosis, treatment, and care, HIV infection has become a manageable, long-term/life-long health condition, enabling people living with HIV (PLHIV) to lead protracted, healthy lives -"The Graying of the HIV Epidemic" [1].
In the wake of modern antiretroviral drugs, the importance of acquired immunodeficiency syndrome (AIDS)related comorbidities and deaths in PLHIV is waning and the significance of cardiovascular disease (CVD) in this respect is rising [2].It has been well-documented that HIV infection is an independent risk factor for coronary artery disease [2][3][4].The risk of CVD in PLHIV is a result of the coaction of traditional CVD risk factors, risk from HIV infection, and the adverse effects of certain antiretroviral drugs [5,6].The increased risk of CVD, including myocardial infarction (MI) and stroke, is 2.2-fold compared to the general population [7].This increased risk related to HIV infection could be due to viremia and the associated chronic inflammation and immune dysregulation.Though the initial antiretroviral drugs aided in reducing the viral load and restoring the immune system function to an extent, they came with significant adverse effects [8].The relation between HIV infection, antiretroviral therapy (ART) drugs, and atherosclerosis risk is depicted in Figure 1.In this new "test-and-treat" era, with expanded access and usage of contemporary ART drugs, the question about their efficacy and safety arises.The adverse metabolic effects of contemporary antiretroviral drugs have been studied to a decent extent, but there is limited knowledge available about their contribution to atherosclerotic cardiovascular disease (ASCVD).

Research question
In this review, we aim to highlight the effects of newer ART drugs on the risk factors and complications of atherosclerosis in PLHIV.This includes the effects of integrase strand transfer inhibitors (INSTIs) and protease inhibitors (PIs) on the lipid and metabolic parameters of HIV-infected patients, along with their influence on the risk for CVD.

Clinical implications
A better understanding of the cardiovascular safety of the newer drugs helps establish better protocols and guidelines for the prescription of these drugs in PLHIV.Avoidance of drugs associated with higher rates of adverse effects in at-risk patients can benefit them by reducing the need for further medication to treat the risk factors or comorbidities, preventing the occurrence of undesirable adverse events, and improving the overall quality of life.

Methodology and Search Strategy
The methods and results reported in our systematic review are as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines following our screening and selection [9].
We searched through PubMed, PubMed Central, and Cochrane Library for the most relevant original studies and reviews using medical subject headings (MeSH), keywords, and Booleans.The search strategies used in different databases and the number of articles identified are presented in Table 1.

HIV: Human immunodeficiency virus; HTLV-III: human T-lymphotropic virus type III
The articles were then screened to highlight those most relevant to the research question based on the title and abstract and selected per the inclusion/exclusion criteria.

Inclusion and Exclusion Criteria
The selection preference was systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies published from 2018 to 2023.All the articles selected were peer-reviewed and published in the English language.Grey literature was excluded.Reviews without a clear methods section, animal studies, in-vivo, and in-vitro studies were also excluded.Our eligibility criteria were built on the population, intervention, comparison, and outcomes (PICO) model.The inclusion and exclusion criteria are disclosed in Table 2.

Inclusion Criteria Exclusion Criteria
Studies involving adult patients with HIV infection (age  Three separate authors extracted and reviewed the essential data independently.In case of disagreements, the researchers discussed the conformity of the data to the eligibility criteria to reach a consensus.A fourth researcher was consulted for objectivity if a decision could not be made.

Critical Appraisal of Studies
All the studies selected for the review were critically appraised using the appropriate quality assessment tool.There are seven cohort studies, seven cross-sectional studies, and one RCT included in this review.We used the respective Joanna Briggs Institute (JBI) critical appraisal checklist for the quality check of cohort studies and cross-sectional studies [10].We used the Cochrane risk of bias assessment tool for the RCT [11].The quality assessment of the included studies has been presented in Tables 3-5.

Literature Search and Study Selection
The PubMed MeSH search strategy generated 10,758 articles.The search in PubMed Central generated nine articles.The search through the Cochrane Library revealed 41 trials.Four articles were excluded due to duplication.After filtering to include the articles published in the last five years only, we had 3,298 articles.Upon screening through the titles and abstracts of the articles, we obtained 73 articles.Full-text assessment of these articles for the eligibility criteria and risk of bias finally provided us with the 15 articles included in this review.Our PRISMA flow diagram is shown in Figure 2
General obesity was defined as body mass index (BMI) ≥30 Kg/m² or waist circumference of ≥80 cm in women and ≥94 cm in men or waist-to-hip ratio (WHR) ≥0.90 in men and ≥0.85 in women [23].
Hypertension was defined as two consecutive systolic blood pressure (SBP) measurements ≥140 mmHg and/or diastolic blood pressure (DBP) measurements ≥90 mmHg, performed on different days (or) one single SBP measurement ≥140 mmHg and/or DBP measurement ≥90 mmHg, with the use of antihypertensives within 6 months of this measurement [13].
Metabolic syndrome was defined as the presence of three or more of the following factors: Waist circumference >94 cm in men and >80 cm in women, TGs ≥1.7 mmol/L, HDL cholesterol (HDL-c) <1.0 mmol/L in men and <1.3 mmol/L in women, SBP ≥130 or DBP ≥ 85 mmHg, or fasting glucose ≥5.6mmol/L [19].

Role of HIV Infection in the Pathogenesis of Atherosclerosis
It has been established that HIV infection independently increases the risk for ASCVD [2][3][4].This elevated risk is an amalgam of the greater burden of traditional cardiovascular risk factors in PLHIV [23], the side effects of antiretroviral drugs, and the chronic inflammation from HIV viremia [5,6] as depicted in Figure 3.
Oxidized low-density lipoprotein (oxLDL), a biomarker of oxidative stress and inflammation, is purported to play a key role in atherogenesis [27] and has been linked to ASCVD [28].oxLDL levels of the HIV-infected are higher compared to HIV-negative individuals [29] and positively correlate with the Framingham coronary heart disease risk score and carotid IMT (cIMT), a marker for subclinical atherosclerosis [30].Statins help with lessening the levels of oxidative stress biomarkers, resulting in a reduced coronary plaque number independent of LDL levels [27,31].

Risk of Dyslipidemia
Dyslipidemia is the most prevalent cardiovascular risk factor in PLHIV contributing approximately 50% to the overall CVD risk [32,33].The mechanisms professed to be involved in the pathogenesis of dyslipidemia in PLHIV are HIV-mediated chronic inflammation, immune activation [34,35], and ART-induced dyslipidemia [36][37][38].Hypertriglyceridemia is the chief variety of ART-or HIV-related dyslipidemia [15].In a retrospective cohort study by Zhang et al., in 2022, a PI-based regimen further bolstered the non-nucleoside reverse transcriptase inhibitor (NNRTI)-related hypertriglyceridemia in patients who switched from an NNRTI-based regimen.However, patients with normal TG levels just before the switch tend to sustain the normal levels of TGs [15].In an analysis of the International Cohort Consortium of Infectious Disease (RESPOND) by Byonanebye et al., in 2021, dyslipidemia was less common with INSTI-based therapy than with PI-based therapy in both ART-naïve and ART-experienced individuals [16].Other studies have also reported that INSTIs are less associated with the incidence of dyslipidemia than PIs [39][40][41], due to deterrence of endoplasmic reticulum stress [42].INSTIs, therefore, remain the ART of choice in PLHIV owing to higher efficacy and safety.Rilpivirine (RPV), an NNRTI, had a lower risk of dyslipidemia than dolutegravir (DTG), an INSTI, while other INSTIs like elvitegravir/cobicistat (EVG/c) and raltegravir (RAL) had a greater risk than DTG [16].Another retrospective cohort study by O'Halloran et al., in 2020, mentions no association between INSTIs and increased dyslipidemia risk [17].A cross-sectional study by Bastard et al., in 2019, revealed an association between PI use and atherogenic dyslipidemia, but not LDL-related dyslipidemia [22].All this evidence points to the need for follow-up, monitoring, and lifestyle counseling in patients taking ART, especially PIs.

Risk of Weight Gain and Obesity
A cohort study by Pantazis et al., in 2022, found that although the BMI levels increased in all ART groups, INSTIs were associated with acute BMI rise compared to NNRTIs [14].The boosted PI group had a moderate rate of increase, almost comparable to that of the NNRTI group [14].Further analysis of the INSTI group based on the core drug (DTG, EVG, or RAL) revealed that when compared to DTG or RAL, EVG was associated with piddling increases in BMI [14].WHR was determinately higher with the NNRTI-based regimen of zidovudine (AZT)/emtricitabine (3TC)/nevirapine (NVP) compared with the boosted PI-based regimen of tenofovir disoproxil fumarate (TDF)/emtricitabine (3TC)/lopinavir-ritonavir (LPV/r) [23].The retrospective cohort study by Bakal et al., in 2018, reinforced INSTI use as a prime risk factor for weight gain and obesity in PLHIV [18].Individuals who are underweight at baseline have the greatest rise in BMI, with the plausible explanation of relatively superior immune reconstitution after ART initiation in individuals with more advanced HIV infection [43].A steeper rise in weight or BMI in individuals receiving INSTI-based therapy has been substantiated in both clinical trials [44][45][46][47] and observational studies [18,[48][49][50][51][52].However, the mechanism of INSTI-associated weight gain remains unclear warranting further studies in this regard.

Risk of Metabolic Syndrome and Hypertension
In a cohort study by Byonanebye et al., in 2022, the incidence of hypertension with INSTI-based therapy was higher than with NNRTI-based therapy, but not different from PI-based therapy [13].This was consistent with the findings of previous cohort studies [53][54][55].The underlying mechanism though not clear yet, could be due to INSTI-associated metabolic derangements like weight gain, dyslipidemias, insulin resistance, adipogenesis, oxidative stress, and diabetes [13].Although prior studies linked the use of older PIs to hypertension, this cohort showed a proportionately lower risk of hypertension, probably due to the use of newer PIs.
In the cross-sectional study by Hamooya et al., in 2021, participants receiving a DTG-based regimen had 2fold higher odds of metabolic syndrome (MetS) than those receiving an NNRTI-based regimen [19].The mechanisms through which INSTIs lead to MetS are currently little known, stressing the need for further research.Another cross-sectional study by Bastard et al., in 2019, depicted a positive correlation between diabetes and oxidative stress in PLHIV [22].This justifies that oxidative stress, in addition to inflammation, could be a contributor to the greater burden of diabetes, insulin resistance, and MetS observed in PLHIV.

Risk of Lipodystrophy
In contrast to the findings by Domingo et al. [56], Martin et al. [57], and McComsey et al. [44], the crosssectional study by Alikhani et al., in 2019, concluded that amassed exposure to RAL was autonomously associated with the elevated risk of lipodystrophy, as indicated by higher FMR values in these individuals [25].This variation can be attributed to reverse causality: Prescription of RAL to highly experienced patients with heightened baseline levels of lipodystrophy.

Risk of CVD
Traditional risk factors like older age, male sex, smoking, hypertension, diabetes, and dyslipidemia increase the risk for ASCVD in the general population.In PLHIV, adverse effects of antiretroviral drugs may add to this.In an RCT by Llibre et al., in 2022, participants from the SWORD studies (SWORD-1 and SWORD-2) were tested for the biomarkers of inflammation and atherogenesis over 148 weeks [26].Comparison of these values between the randomized continued antiretroviral regimen (CAR) and early-switch groups (CAR group: those who continued the three-drug or four-drug current antiretroviral regimen; early-switch group: those who switched to the two-drug regimen DTG+RPV) over 48 weeks revealed a decrease in fatty acidbinding protein-2 (FABP-2) levels favoring DTG+RPV [26].In the non-comparative analysis of atherogenesis biomarkers through week 148, FABP-2 and soluble vascular cell adhesion molecule-1 (sVCAM-1) manifested a slight decline from the baseline values [26].This study proves the non-inferiority of the two-drug regimen [26].[17].Most of the HIV-1-infected patients aged 50 years or older, from the cross-sectional study by Serrão et al., in 2019, had at least one non-AIDS-related comorbidity (NARC) with a mean of 2.1 [21].The most prevalent NARC in this study population was hypercholesterolemia, followed by arterial hypertension [21].Another cross-sectional study, by Calza et al., in 2019, recorded that cumulative exposure to PIs for > 5 years was greatly associated with an increased risk of subclinical atherosclerosis [24].The lack of consistency on the risk of CVD with INSTIs in PLHIV should be addressed in order to frame evidence-based guidelines and appropriately dispense these drugs to patients with existing risk factors.
Early identification and management of these risks and NARCs among PLHIV, especially the aged PLHIV, is essential.However, we should be wary of polymedication and drug-drug interactions while treating these conditions.A comprehensive inclusion of the different fields of healthcare using a multidisciplinary approach is vital in cutting down the load of complex multi-morbid HIV infection in the elderly [21].
Whether the development and recent introduction of long injectable antiretroviral drugs addresses these issues remains to be seen.

Limitations
This systematic review is not without limitations.The articles selected for this review did not follow a uniform, standard tool/definition to assess the outcomes.For example, some of the studies on obesity only used BMI to diagnose obesity.There was a lack of standard parameters/measurement tools across the studies for assessing the risk of atherosclerosis.Certain studies had used cIMT, some had used common carotid artery (CCA)-IMT, and some had used ultrasonography to determine the number of plaques and plaques at high risk.The criteria for diagnosing diabetes, dyslipidemia, and other outcomes differed from one another.Further, only articles published within the last five years, with full text available for free were included.Studies that were not available in the English language, not in the database search, unpublished articles, reviews, editorials, and animal studies were all excluded.Studies with a sample population size of less than 100 were also excluded.Studies on patients with perinatally acquired HIV and a prior history of CVD were also excluded.

FIGURE 1 :
FIGURE 1: Correlation Between HIV Infection, Antiretroviral Drugs, and Atherosclerotic CVD Risk HIV: Human immunodeficiency virus; CVD: cardiovascular disease This figure is the author's own creation.
≥18 years) taking antiretroviral drugs belonging to the drug classes of INSTIs or PIs.Articles published within the last five years.Patients from any geographical region of the world.Articles discussing the effects of INSTIs and/or PIs on atherosclerosis, its risk factors, or its cardiac complications.Studies involving children (age <18 years), pregnant patients with HIV, patients with perinatally acquired HIV, HIV patients with opportunistic infections or AIDS-defining illnesses, or HIV patients with a history of coronary heart disease or stroke.Studies that have not specified the class of ART used by the participants.Studies with a sample population size of less than 100.Narrative reviews, editorials, animal studies, in-vivo and in-vitro studies.Articles on guidelines.

FIGURE 3 :
FIGURE 3: Contributors to CVD Risk in PLHIV ART: Antiretroviral therapy; CVD: cardiovascular disease; PLHIV: people living with HIV This figure is the author's own creation.

TABLE 4 : Quality Assessment of the Cross-Sectional Studies
JBI: Joanna Briggs institute; Y: Yes; N: No; UC: Unclear Cochrane Risk of Bias Tool for RCTs

TABLE 5 : Quality Assessment of the RCT
RCT: Randomized controlled trial

PRISMA Flow Diagram Showing the Process of Study Selection Article Study Population Size Outcome of Interest Study Findings Conclusion
[9].FIGURE 2: