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 results: We 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.

Conclusions: Among 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.

Keywords: HIV; antiretroviral therapy; cholesterol; risk factor.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1

Antiretroviral therapy (ART) use by treatment group in the START (Strategic Timing of Antiretroviral Treatment) trial (n=4685). Shown is the percentage of participants taking ART by follow‐up month in the immediate and deferred ART groups. Data were previously reported but the results shown here are truncated at month 48.16

Figure 2

Cardiovascular risk factor changes by treatment group. Shown in the first 3 rows are the unadjusted mean changes from baseline at annual visits for participants in the immediate (I) and deferred (D) antiretroviral therapy (ART) groups for the following measures: total cholesterol (A), low‐density lipoprotein cholesterol (LDL‐C; B), high‐density lipoprotein cholesterol (HDL‐C; C), total cholesterol to HDL‐C ratio (D), systolic blood pressure (BP; E), and diastolic BP (F). Presented within (A through F) are the estimated mean differences (with 95% CIs and P values) during follow‐up between the 2 groups (I minus D), adjusting for the baseline value and visit from longitudinal mixed models. Shown in the last row is the unadjusted prevalence (percentage) at baseline and follow‐up annual visits for participants in both ART groups for use of BP‐lowering drugs (G) and lipid‐lowering drugs (H). Presented within (G and H) are the overall estimated differences in prevalence during follow‐up (with 95% CIs and P values) between the 2 groups (I minus D), adjusting for the baseline prevalence and visit from generalized estimating equations. Figures are truncated at month 48.

Figure 3

Cumulative incidence of comorbid conditions by treatment group. Shown are Kaplan–Meier estimates of the cumulative incidence of participants with dyslipidemia, excluding high‐density lipoprotein (HDL) in the definition (A), dyslipidemia, including HDL <40 mg/dL in the definition* (B), hypertension† (C), and diabetes mellitus (D) during follow‐up for participants in the immediate (I) and deferred (D) antiretroviral therapy (ART) groups. Presented within the figures are the estimated hazard ratios (HRs) for the immediate (I) vs deferred (D) groups (with 95% CIs and P values) from Cox proportional hazards regression models. Figures are truncated at month 48. The cumulative incidence plots have jumps annually because measurements were obtained only at annual visits. *A total of 2203 (49%) START (Strategic Timing of Antiretroviral Treatment) trial participants had dyslipidemia at baseline when including the criteria of HDL <40 mg/dL. The incidence computation during follow‐up for this definition is limited to the 2402 participants without baseline dyslipidemia. †For the incidence computation, an individual was defined as being hypertensive at the first visit when systolic blood pressure (BP) was ≥140 mm Hg, diastolic BP was ≥90 mm Hg, or BP medication use was reported. In some individuals classified as hypertensive based on BP alone, the BP may be lower at subsequent visits. This definition leads to a higher incidence.