Table 1.

Interventions Targeting Cardiovascular Inflammation in HIV‐1: Outcomes, Benefits, and Limitations

Intervention	Mode of Action	Effect on Markers of Inflammation and Immune Activation in PLWH	Benefits	Limitations
Traditional interventions
Aspirin	Inhibition of the COX‐1 pathway	No effect on sCD14, IL‐16, SCD163, d‐dimer and endothelial function after 12‐weeks62	Primary prevention of cardiovascular events in individuals with high ASCVD risk63	Non‐negligible risk of bleeding especially in elderly No effect on HIV‐mediated inflammation and immune activation
Dipyramidole	Adenosine reuptake inhibitor	No effect on sCD14, sCD163and IL‐664 Modest decrease in CD8+ T cells and decrease in activated CD4+ T cells64	FDA approved for treatment of peripheral arterial disease and coronary artery disease	Associated bleeding risk
Statins	Inhibition of HMA‐CoA enzyme	Rosuvastatin reduced markers T‐cell activation, vascular inflammation, and immune activation65 Atorvastatin reduced noncalcified plaque volumes66	Established benefits and safety in reducing ASCVD risk in HIV‐negative individuals	Unclear benefit in a more‐generalizable population of PLWH Ongoing REPRIEVE trial should provide more information
Canakinumab	Monoclonal antibody that binds IL‐1β	Reduced markers of inflammation and monocyte activation as well as aortic inflammation measured by FDG‐PET67	Reduces rates of recurrent cardiovascular events in HIV‐negative individuals68 Demonstrated to be safe in PLWH67	Expensive intervention Unclear medium‐ and long‐term efficacy and safety in PLWH
Novel interventions
Bilirubin	Scavenges free radicals	Elevated bilirubin levels correlated with decreased CVD in HIV‐positive and ‐negative individuals	Elevated bilirubin levels can be induced be pharmacologically induced, thus potential for harnessing this effect to target CVD	No large clinical trial of interventions raising bilirubin levels as a strategy for targeting CVD in PLWH
Tocilizumab	Monoclonal antibody that binds IL‐6	Modest effect on markers of inflammation and immune activation in small group of PLWH69	Effective anti‐inflammatory in rheumatological disease with some improvement of endothelial function in high‐risk populations of HIV‐negative individuals70	Elevation of LDL‐ cholesterol and alterations in lipid profiles in both HIV‐positive and ‐negative individuals of unclear significance Expensive intervention
Sirolimus	mTOR inhibitor	Reduced CCR5 expression Reduced markers of cell cycling and immune exhaustion71	FDA approved as immunosuppressive therapy in organ transplant recipients	Associated hypercholesterolemia and ‐triglyceridemia Well‐described drug‐related toxicities and increased risk for infections
Valgancyclovir	Competitive inhibitor of deoxyguanosine triphosphate inhibiting viral DNA polymerases	Reduced markers of T‐cell activation72	FDA approved for treatment of invasive cytomegalovirus disease	Unclear benefit in reducing the risk for CVD in PLWH Associated renal toxicity
Probiotics	Alters gut microbiome	May cause changes in gut‐associated lymphoid tissues and improve biomarkers of microbial translocation73, 74, 75 No effect on markers of inflammation and immune activation76	Potentially a low‐cost intervention with favorable tolerance profile	Unclear impact, if any, on gut microbial translocation and HIV pathogenesis Optimal timing of intervention, duration, and dosing present challenges
Methotrexate	Inhibits dihydrofolate reductase enzyme Inhibits binding of IL‐1B to its surface receptor	No effect on endothelial function No effect on markers of inflammation and immune activation Significant decrease in CD8+ T cells77	Demonstrated safety in select population of PLWH	Failed to show any benefit as tool for reducing CVD risk Pre‐existing T‐cell abnormalities in people with chronic HIV may overpower immune‐modulatory effects of low‐dose methotrexate Well‐described adverse effects of increased risk for infection
Edoxaban	Direct inhibitor of factor Xa	Reduction in D‐dimer levels No effect on markers of inflammation or immune activation78	May impact HIV‐associated hypercoagulability through effect on D‐dimer	Non‐negligible bleeding risk Unknown impact on markers of endothelial function and atherosclerosis
Jak‐inhibitors	Small molecules targeting specific JAKs in the JAK/STAT pathway	Modest decrease in sCD14 No significant effect on IL‐6 levels noted79	Good tolerability and specificity in targeting inflammation Ruxolitinib shown to be safe in PLWH Role in impeding seeding of the HIV reservoir gives them potential for use in functional cure strategies80	Effect on endothelial function and atherosclerosis yet to be determined High‐dose tofacitinib and baricitinib associated with increased risk for thrombosis Relatively new molecules and some may be associated with significant associated cost

ASCVD indicates atherosclerotic cardiovascular disease; CCR5, C‐C chemokine receptor type 5; COX‐1, cyclooxygenase 1; CVD, dardiovascular disease; FDA, US Food and Drug Administration; FDG‐PET, fluorodeoxyglucose positron emission tomography; HMA‐CoA, β‐hydroxy β‐methylglutaryl coenzyme A; IL‐1β, interleukin‐1 beta; IL‐16, interleukin‐16; JAK, Janus kinase; LDL, low‐density lipoprotein; mTOR, mammalian target of rapamycin; PLWH, people living with HIV; REPRIEVE, Randomized Trial to Prevent Vascular Events in HIV; sCD14, soluble CD14; sCD163, soluble CD163; STAT, signal transducer and activator of transcription.