Changes in Cardiovascular Disease Risk Factors With Immediate Versus Deferred Antiretroviral Therapy Initiation Among HIV‐Positive Participants in the START (Strategic Timing of Antiretroviral Treatment) Trial

Abstract

Introduction HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors.Methods and ResultsWe studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV‐positive persons with CD4+ cell counts >500 cells/mm3. Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups. The characteristics among 4685 HIV‐positive START trial participants include a median age of 36 years, a CD4 cell count of 651 cells/mm3, an HIV viral load of 12 759 copies/mL, a current smoking status of 32%, a median systolic/diastolic blood pressure of 120/76 mm Hg, and median levels of total cholesterol of 168 mg/dL, low‐density lipoprotein cholesterol of 102 mg/dL, and high‐density lipoprotein cholesterol of 41 mg/dL. Mean follow‐up was 3.0 years. The immediate and deferred ART groups spent 94% and 28% of follow‐up time taking ART, respectively. Compared with patients in the deferral group, patients in the immediate ART group had increased total cholesterol and low‐density lipoprotein cholesterol and higher use of lipid‐lowering therapy (1.2%; 95% CI, 0.1–2.2). Concurrent increases in high‐density lipoprotein cholesterol with immediate ART resulted in a 0.1 lower total cholesterol to high‐density lipoprotein cholesterol ratio (95% CI, 0.1–0.2). Immediate ART resulted in 2.3% less BP‐lowering therapy use (95% CI, 0.9–3.6), but there were no differences in new‐onset hypertension or diabetes mellitus.ConclusionsAmong HIV‐positive persons with preserved immunity, immediate ART led to increases in total cholesterol and low‐density lipoprotein cholesterol but also concurrent increases in high‐density lipoprotein cholesterol and decreased use of blood pressure medications. These opposing effects suggest that, in the short term, the net effect of early ART on traditional cardiovascular disease risk factors may be clinically insignificant."Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00867048.

Evaluation of Cardiovascular Disease Risk in HIV-1–Infected Patients Treated with Darunavir

“…CVD is an important clinical concern for HIV-1–infected individuals because of the many factors linking these conditions; HIV-1 infection increases the risk of developing CVD, while some CVD risk factors are more common in HIV-1–infected patients relative to their peers [ 2 – 5 ]. While antiretroviral therapy has been associated with decreased risk of CVD events, the connection is complex [ 9 , 10 ]. Given the association between older PIs and CVD events [ 11 – 17 ], we examined the relationship between darunavir and CVD events using multiple approaches and datasets.…”

“…There are multiple factors that can increase the risk of CVD in people living with HIV-1, including the HIV-1 infection itself as well as conventional CVD risk factors (e.g., tobacco use, alcohol consumption, other substance abuse, hypercholesterolemia, hypertension, elevated blood glucose, aging, male gender) [ 7 , 8 ]. In HIV-1–infected individuals, continued use of antiretroviral therapy has been associated with decreased risk of fatal or nonfatal CVD events compared with episodic antiretroviral therapy (based on CD4+ cell count), although a more recent study suggests a complex relationship between antiretroviral therapy and CVD risk [ 9 , 10 ]. In the case of protease inhibitors (PIs), the use of older PIs has been associated with an increased risk of CVD-related events due to these drugs causing metabolic abnormalities such as dyslipidemia and insulin resistance; however, newer PIs have demonstrated improved CVD risk profiles [ 11 – 18 ].…”

HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

“…In terms of the PIs, cumulative exposure to lopinavir/RTV or darunavir/RTV is associated with an increased incidence of AMI, but atazanavir/RTV is not,18 28 87 even though atazanavir has been linked to platelet activation in vivo 30. As suggested above, lipid alterations cannot account for this difference; darunavir/RTV and atazanavir/RTV both cause similar, minimal changes in lipids 39 42…”

“…However, review of 4685 participants from 35 countries in the Strategic Timing of Antiretroviral Treatment (START) trial, a randomised study of immediate versus deferred cART initiation among HIV-infected individuals with CD4+ T cell counts in the normal range (>500 cells/mm 3 ), concluded that the net effect of cART on traditional CVD risk ‘may be clinically insignificant’, at least in the short term, with a mean follow-up of 3.0 years 39. In fact, cART had opposing effects on serum lipids in START, increasing total cholesterol and low-density lipoprotein cholesterol and also increasing high-density lipoprotein cholesterol and decreasing the need for blood pressure medication 39.…”

“…However, review of 4685 participants from 35 countries in the Strategic Timing of Antiretroviral Treatment (START) trial, a randomised study of immediate versus deferred cART initiation among HIV-infected individuals with CD4+ T cell counts in the normal range (>500 cells/mm 3 ), concluded that the net effect of cART on traditional CVD risk ‘may be clinically insignificant’, at least in the short term, with a mean follow-up of 3.0 years 39. In fact, cART had opposing effects on serum lipids in START, increasing total cholesterol and low-density lipoprotein cholesterol and also increasing high-density lipoprotein cholesterol and decreasing the need for blood pressure medication 39. While accelerated CVD risk linked to RTV, used alone or at much lower doses in many RTV-boosted PI regimens, is accompanied by changes in lipid metabolism,14 18 hyperlipidaemia was not a factor in the high CVD risk related to darunavir/RTV in humans,18 and RTV-driven cardiac disease could be dissociated from hyperlipidaemia in two rodent models 40 41.…”