HIV-associated dyslipidemia: pathogenesis and its management

With the development of combination antiretroviral therapy (cART), human immunodeficiency virus (HIV) infection has transitioned from a generally fatal disease to a manageable chronic condition over the past two decades.[1] cART provides rapid control of HIV and partial restoration of immune function, thus preventing various HIV-related complications. However, this does not mean that people living with HIV (PLWH) completely return healthy after receiving cART. HIV-infected individuals receiving long-term cART remain at higher risk for major cardiovascular disease (CVD) than uninfected individuals.[2] Atherosclerotic cardiovascular disease (ASCVD), which involves myocardial infarction (MI), stroke, and sudden cardiac death, is currently one of the leading causes of mortality in PLWH. Dyslipidemia is a major risk factor for CVD in PLWH, accounting for approximately 50% of the overall CVD risk.[3] Not only there is an increased cardiovascular risk, but dyslipidemia in PLWH may also be associated with an increased risk of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus. In addition, dyslipidemia in PLWH differs from the general population because treatment for HIV may not only induce dyslipidemia but also interact with lipid-lowering agents. Therefore, the management of dyslipidemia and CVD risk among PLWH is challenging and requires the cooperation of multidisciplinary professional teams working together to deliver appropriate care. Mechanisms of HIV-associated dyslipidemia: It is widely recognized that the prevalence of dyslipidemia is higher in PLWH than in the general population,[4] in which ART and HIV infection itself play a crucial role in addition to traditional risk factors. The relationship between dyslipidemia and elevated CVD risk among PLWH is shown in Supplementary Figure 1, https://links.lww.com/CM9/B761. Impact of HIV infection on blood lipids: Previous study demonstrated that HIV accessory protein Vpr could inhibit intracellular proliferator-activated receptors gamma (PPAR-γ), which leads to free fatty acid (FFA) overaccumulation and lipotoxicity.[5] HIV Nef protein was identified to impair cholesterol efflux from infected macrophages by affecting ATP-binding cassette transporter protein A1 (ABCA1) function, which ultimately leads to circulating high-density lipoprotein cholesterol (HDL-C) deficiency.[5] Additionally, HIV Tat protein promotes the up-regulation of cholesterol biosynthesis genes, leading to elevated free cholesterol cholesteryl esters levels.[6] On the other hand, chronic immune activation and inflammation caused by HIV infection also have complicated impacts on lipid metabolism. Interferon-alpha (IFN-α) and tumor necrosis factor-alpha (TNF-α) were found to be associated with impaired oxidation of plasma FFA in PLWH, contributing to enhanced hepatic re-esterification of triglycerides (TG) and elevated plasma TG level.[4] TNF-α, TNF-β, IFN-γ, and interleukin (IL)-1 could stimulate the activity and expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which leads to a reduction of cholesterol synthesis eventually. Furthermore, inflammatory cytokines could also down-regulate ABCA1 expression and thereby subsequently impair reverse cholesterol transport.[4] Impact of ART on blood lipids: Dyslipidemia associated with ART administration usually manifests as elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TG levels, and decreased HDL-C level. However, the exact pattern and severity depend on the specific antiretroviral drugs [Supplementary Table 1, https://links.lww.com/CM9/B761]. Increased blood lipids were found in PLWH with ritonavir boosted protease inhibitors (PI), including lopinavir/ritonavir, darunavir/ritonavir, and azanavir/ritonavir, which may be the result of the interaction between ritonavir and pregnane X receptor (PXR).[7] For nucleoside reverse transcriptase inhibitors (NRTIs), stavudine and zidovudine, abacavir, and tenofovir alafenamide (TAF) were associated with elevated TG and LDL-C, whereas tenofovir disoproxil fumarate (TDF) exhibited an intrinsic lipid-lowering effect.[8] For non-NRTI (NNRTI), compared to rilpivirine, efavirenz has the adverse effect of elevated TG and LDL-C, which may involve PXR-mediated signaling pathways. Furthermore, a lipidomic study reveals lower inflammatory and storage lipid species after switching from efavirenz to rilpivirine.[9] Novel integrase strand transfer inhibitors (INSTI), such as dolutegravir (DTG), bictegravir (BIC), have superior lipid profiles compared with elvitegravir/cobicistat (EVG/c), boosted-PI, and efavirenz.[4] Management Strategies for Dyslipidemia in PLWH: PLWH are recommended to screen blood lipid levels at routine clinical visits before ART initiation, 1–3 months after ART initiation, and every 6–12 months thereafter.[4] Additionally, CVD risk assessment was recommended before and annually post-ART for men >40 years of age or women >50 years of age. The Framingham risk score and D:A:D risk score are validated tools for estimating CVD risk in PLWH. The thresholds and lipid targets for intervention vary according to specific CVD risk. Increased LDL-C is a well-known risk factor in the development of CVD; therefore, LDL-C has been identified as the primary interventional target for protecting from CVD. The European acquired immune deficiency syndrome (AIDS) Clinical Society (EACS) Guideline suggested that LDL-C should be controlled to at least 3.0 mmol/L or less in PLWH and that treatment goals should be adjusted according to CVD risk.[1] Given the elevated residual lipoproteins in patients with hypertriglyceridemia, which are likely to have atherogenic effects, non-HDL-C is considered a secondary target for therapeutic intervention. Furthermore, small dense LDL-C (sdLDL-C), a subfraction of LDL-C, was proved to be robustly associated with an increased risk of ischemic stroke and should be considered as a novel target for preventing CVD.[10] Lifestyle modification: For PLWH with dyslipidemia, the first interventions to consider are lifestyle modification and ART switching.[1] Lifestyle modification, with minimal side effects, underpins the management of dyslipidemia, which includes healthy eating, physical exercise, smoking cessation, and weight loss.[4] Additionally, physical exercise has been shown to have an effect on numerous immunological processes and exhibit an anti-inflammatory effect in particular, which is associated with metabolic health in PLWH. ART switching: Switching ART regimens which could avoid pill burden and potential drug–drug interactions (DDIs) associated with the lipid-lowering agents is a viable strategy. In general, the principles of ART conversion in the setting of dyslipidemia are to improve compliance and tolerability and to reduce medicine-related adverse effects while maintaining virological suppression. PLWH who present dyslipidemia together with intermediate CVD risk or multiple CVD risk factors such as smoking, diabetes, obesity, or hypertension are recommended to switch ART regimen based on lifestyle modification.[4] It was found that among the NNRTI except for rilpivirine, doravirine had the same neutral effect on lipids.[11] For NRTIs, switching from TAF to TDF may be a strategy to control lipids for PLWH due to its lipid-lowering effect.[8] BIC and DTG showed only little effect on blood lipids profile and could be an alternative switching option.[4] One caution, however, is that the effect of this switch on body weight needs to be considered for PLWH. Pharmacological interventions: If lipid goals are not achieved despite lifestyle modification and ART switching, the use of lipid-lowering medications should be considered. Statin has served as a cornerstone of pharmacological therapy for dyslipidemia given its pleiotropic properties, including lipid-lowering, antioxidant, and anti-inflammatory effects. A previous study revealed that PLWH treated with pitavastatin had a lower LDL-C and lower risk of major cardiovascular events.[12] The lipid-lowering efficacy of statin therapy in PLWH may, nevertheless, be lower than expected with limited apparent short-term vascular benefit.[13] Furthermore, given the myotoxicity, hepatotoxicity, and DDI with PIs and rifampin, etc., the clinical application of statins requires attention. For PLWH with statin intolerance or suboptimal LDL-C lowering response, ezetimibe is a suitable option to reduce LDL-C with low toxicity.[14] Proprotein convertase subtilisin-kexin type 9 (PCSK-9) inhibitor, a novel LDL-C lowing drug and it was demonstrated to rapidly reduce LDL-C level and reverse coronary endothelial dysfunction among PLWH with well-tolerated.[15] However, several obstacles persist in the clinical implementation of PCSK-9 inhibitors, encompassing the possibility of autoantibody production, inconvenience of subcutaneous administration, and high cost. Additionally, bempedoic acid was proven to be effective in decreasing LDL-C among statin-intolerant individuals and it warrants further study in PLWH.[16] Saroglitazar, a dual PPAR α/γ agonist, which lowers atherogenic sdLDL-C in patients with NAFLD has not yet been studied in PLWH.[17] Previous studies demonstrated that high TG is associated with enhanced CVD risk, thus TG is another intervention target for PLWH. Although the EACS Guideline has not identified a specific therapy goal of TG, it was revealed that CVD risk was significantly decreased among patients with TG-lowing therapy based on the use of statins.[18] Subjects with CVD or at high risk of CVD was recommended to receive TG-lowing therapy if the TG is >2.3 mmol/L after receiving statin therapy according to a Chinese guideline for lipid management.[19] The intervention threshold and target of TG should be more stringent for PLWH due to their higher CVD risk. The main TG-lowing agent, currently, includes fibrates, niacin, and omega-3 fatty acids (omega-3). However, the latest research suggests that fibrates, niacin, and omega-3 failed to significantly reduce CVD risk despite their TG-lowing effect.[19,20] Several studies have demonstrated that omega-3 could reduce CVD risk significantly; however, there are no data on the effectiveness of reducing cardiovascular events in PLWH.[18] Tesamorelin, a hypothalamic growth hormone-releasing hormone analog was thought to reduce circulated TG level and prevent fibrosis progression of NAFLD in PLWH and its cardiovascular benefits deserve further exploration.[21] In conclusion, dyslipidemia has become a relatively prevalent complication of HIV infection. In addition to general risk factors, dyslipidemia is mainly related to HIV infection and antiretroviral drugs. Further research should be done to build a dyslipidemia risk assessment system and identify exact therapeutic targets for preventing CVD events onset. In addition, how to best improve the management of lipid levels and achieve individualized treatment and precision medicine in PLWH remains an important topic for future work. Funding This work was supported by the National Key R&D Program of China (No. 2021YFC2301900-2021YFC2301901). Conflicts of interest None.