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."

Full text

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
Jason V. Baker, MD, MS; Shweta Sharma, MS; Amit C. Achhra, MD, PhD, MPH; Jose Ignacio Bernardino, MD; Johannes R. Bogner, MD;
Daniel Duprez, MD, PhD; Sean Emery, PhD; Brian Gazzard, MD; Jonathan Gordin, MD; Greg Grandits, MS; Andrew N. Phillips, PhD; Siegfried
Schwarze, Dipl Bio; Elsayed Z. Soliman, MD, PhD; Stephen A. Spector, MD; Giuseppe Tambussi, MD; Jens Lundgren, MD for the INSIGHT
(International Network for Strategic Initiatives in Global HIV Trials) START (Strategic Timing of Antiretroviral Treatment) Study Group*
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/mm
3
. 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/mm
3
, 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. (J Am Heart Assoc. 2017;6:
e004987. DOI: 10.1161/JAHA.116.004987.)
Key Words: antiretroviral therapy •cholesterol •HIV •risk factor
From the Department of Medicine (J.V.B., D.D.) and Division of Biostatistics, School of Public Health (S. Sharma, G.G.), University of Minnesota, Minneapolis, MN;
Division of Infectious Diseases, Hennepin County Medical Center, Minneapolis, MN (J.V.B.); Kirby Institute, University of New South Wales, Sydney, Australia (A.C.A.,
S.E.); Department of Medicine, Hospital La Paz, IdiPAZ, Madrid, Spain (J.I.B.); Division of Infectious Diseases, MedIV, University Hospital of Munich, Germany (J.R.B.);
Chelsea and Westminster Hospital, London, United Kingdom (B.G.); Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles, CA
(J.G.); HIV Epidemiology & Biostatistics Group, University College London, London, United Kingdom (A.N.P.); European AIDS Treatment Group, Berlin, Germany (S.
Schwarze); Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.); Division of Pediatric Infectious Diseases,
University of California San Diego and Rady Children’s Hospital, San Diego, CA (S.A.S.); San Raffaele Scientific Institute, Milano, Italy (G.T.); CHIP, Department of
Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark (J.L.).
Accompanying Table S1, Figure S1, and Appendix S1 are available at http://jaha.ahajournals.org/content/6/5/e004987/DC1/embed/inline-supplementary-mate
rial-1.pdf
*A complete list of the INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) START (Strategic Timing of Antiretroviral Treatment) Study Group
members are given in Appendix S1.
Data were presented as a research abstract at the 24th Conference on Retroviruses and Opportunistic Infections, February 22–25, 2016, in Boston, MA.
Correspondence to: Jason V. Baker, MD, MS, 701 Park Avenue, MC G5, Minneapolis, MN 55417. E-mail: baker@umn.edu
Received November 22, 2016; accepted March 30, 2017.
ª2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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HIV-positive persons are at increased risk for premature
cardiovascular disease (CVD),
1
which is currently a
leading cause of morbidity and mortality.
2
Atherosclerotic
disease accounts for a substantial proportion of HIV-related
CVD among contemporary patients. This atherosclerotic dis-
ease manifests as excess risk for coronary heart disease (CHD;
eg, myocardial infarction)
1
and stroke,
3
and may also contribute
to excess risk for heart failure
4
and sudden cardiac death.
5
It is well established that features of both HIV infection and
certain antiretroviral medications increase the risk for CVD.
Some of this excess CVD risk may be caused by long-term
systemic inflammation that is mitigated, in part, via antiretroviral
therapy (ART)–associated viral suppression,
6–9
whereas some
may be caused by exposure to specific antiretrovirals (eg,
certain protease inhibitors [PIs] and abacavir)
10
with potential
for adverse changes in blood cholesterol, platelet dysfunction,
and/or endothelial dysfunction.
10–13
Despite unique features of
HIV disease, traditional risk factors are highly predictive for CVD
among HIV-positive patients
1,10,14
and can be adversely affected
by HIV infection and ART treatment (eg, dyslipidemia).
15
Given the potential for ART to both increase (via drug toxicity
and low-density lipoprotein cholesterol [LDL-C] increases) and
decrease (via viral suppression and reduced inflammation)
atherosclerosis, it is important to study this pathophysiology in
the context of randomized comparisons. The START (Strategic
Timing of Antiretroviral Treatment) trial is a randomized
controlled study of immediate initiation of ART (“immediate”
group) versus deferral of ART initiation until CD4
+
cell counts
decline to <350 cells/mm
3
or clinical symptoms develop
(“deferred”group) among participants naive to ART with CD4
+
cell counts >500 cells/mm
3
at entry.
16
The START trial used an
ideal design to compare CVD risk factors between ART-treated
and untreated HIV infection in a controlled fashion among
persons at low risk for AIDS. CVD events were a component of
the composite end point in the START trial, and participants with
a recent CVD event (<6 months from entry) were not eligible.
The START trial did not have sufficient power to specifically
assess CVD event risk (12 and 14 CVD events in the immediate
and deferred groups, respectively).
16
In this study, we charac-
terized the influence of immediate versus deferred ART on CVD
risk factor changes and incidence of CVD-related comorbidities.
Methods
Study Design and Data Collection
The design and primary findings from the START trial have
been described.
16,17
The START protocol was approved by the
human subjects institutional review committee at the Univer-
sity of Minnesota and at all international coordinating centers
and participating clinical sites. After informed consent was
obtained, data collection occurred at baseline, months 1 and
4, and every 4 months thereafter. Participants were
instructed to fast (minimum of 8 hours) for annual blood
draws. Laboratory measures were performed using standard-
ized clinical assays at the sites. HIV RNA level, CD4
+
cell
count, weight, and blood pressure (BP) were ascertained at
every study visit. The BP values used in the analyses were the
average of 2 measurements separated by a brief rest. Glucose
and serum lipid levels (total cholesterol, high-density lipopro-
tein cholesterol [HDL-C], LDL-C, and triglycerides) and
concomitant medication use were obtained at baseline and
annually. At screening, clinicians together with participants
prespecified the intended ART regimen a participant would
initiate if randomized to the immediate group. This regimen
was required to include 2 background nucleoside reverse
transcriptase inhibitors plus either a non-nucleoside reverse
transcriptase inhibitor (NNRTI) or a ritonavir-boosted PI, or an
integrase strand transfer inhibitor (INSTI). Defining subgroups
by the prespecified ART regimen allowed a randomized
comparison between the immediate and deferred groups
among those who were designated to start the same
antiretroviral medication. Data for this report included visits
up to the START trial unblinding date of May 26, 2015.
Clinical Comorbidities and Risk Factor Scores
Dyslipidemia was defined as an LDL-C level ≥160 mg/dL or
use of lipid-lowering therapy. Hypertension was defined as a
systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, or use
of BP-lowering therapy. Diabetes mellitus was defined as a
fasting glucose level >126 mg/dL, use of medication for
diabetes mellitus, or a clinical diagnosis of diabetes mellitus
(adjudicated as confirmed or probable). Body mass index
(BMI) was computed using visit-specific weight and baseline
height. Ten-year risk scores were calculated at baseline and
updated during follow-up for the following
18–21
: (1) Framing-
ham Risk Score for a CVD or CHD event; (2) D:A:D (Data
Collection on Adverse Events of Anti-HIV Drugs) risk score for
a CVD or CHD event; and (3) the pooled cohort risk
assessment for an atherosclerotic CVD event.
Statistical Methods
The mean changes from baseline between the immediate and
deferred groups for continuous measures were compared
using longitudinal mixed models with random intercepts,
including treatment group, visit, and baseline value in the
model. The differences between groups for the prevalence of
binary measures were compared using generalized estimating
equations (binomial regression) with treatment group, visit,
and baseline prevalence in the model. Histograms showed
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that total cholesterol, LDL-C, HDL-C, and BP were approxi-
mately normally distributed and were analyzed untrans-
formed. The proportional hazards assumption was tested
using log-time as a covariate in the model. Comparisons
within subgroups defined by prespecified ART drug or class
(efavirenz [EFV], PI, or INSTI) are reported. EFV-based ART was
included as a subgroup in analyses by ART class, given that
EFV represented 95% of the NNRTI use in the START trial.
Incidence for binary risk factors was determined in partici-
pants without that condition at baseline using a single factor
for treatment in Cox regression models. To directly compare
treated versus untreated HIV infection we repeated the
analyses by excluding immediate group participants who
never started ART (n=39) and censoring the deferred group at
the time of ART initiation. Analyses were performed using SAS
software version 9.3 (SAS Institute Inc) and R software
version 3.2.3 (R Foundation for Statistical Computing).
Results
Participant Characteristics
A total of 4685 HIV-positive individuals from 215 sites in 35
countries were enrolled into the START trial. The median age
of participants was 36 years and 27% were female
(Table 1).
22
Self-reported race/ethnicity reflected global
enrollment from the United States (11%), South America
and Mexico (25%), Europe, Israel and Australia (35%), Africa
(21%), and Asia (8%). The CD4
+
cell count at entry was 651
cells/mm
3
, and the median time since HIV diagnosis was
1 year. Mean (SD) and median [interquartile range] follow-up
time was 3.0 (1.2) and 2.8 [2.1–3.9] years, respectively, with
no difference in follow-up time between the immediate and
deferred groups. Baseline characteristics did not differ
between groups (Table 1). In addition to a high smoking
prevalence, START trial participants were at low risk for CVD
based on the median values for BMI, BP, cholesterol, and
CVD/CHD risk scores.
The percentage of participants taking ART during follow-
up is presented in Figure 1; 98% of the immediate group and
48% of the deferred group initiated ART, with a median time
to initiation of 36 months in the deferred group. The
percentage of follow-up time spent taking ART was 94%
and 28% for the immediate and deferred groups, respec-
tively. The frequency of specific antiretrovirals in the initial
ART regimen reflects contemporary clinical practice
(Table S1). Among the 2287 immediate group participants
who initiated therapy, ART included tenofovir disoproxil
fumarate in 89%, an NNRTI in 77% (73% EFV), a ritonavir-
boosted PI in 19% (10% atazanavir and 7% darunavir), and an
INSTI in 5% (4% raltegravir); corresponding values for the
1134 deferred group participants who initiated therapy
included tenofovir disoproxil fumarate in 89%, an NNRTI in
64% (51% EFV), a PI in 22% (11% darunavir), and an INSTI in
14% (8% raltegravir).
Changes in Serum Cholesterol Levels and Lipid-
Lowering Therapy
Mean changes in lipid levels (Figure 2) and the incidence of
dyslipidemia (Figure 3) are presented for each group.
Compared with the ART deferral group, the immediate ART
group had 11 mg/dL higher total cholesterol (95% CI, 10–
13), 6 mg/dL higher LDL-C (95% CI, 4–7), and 5 mg/dL
higher HDL-C (95% CI, 4–5) levels. The rise in total
cholesterol and LDL-C in the immediate group was associ-
ated with a 1.2% greater use of lipid-lowering therapy (95%
CI, 0.2–2.2) and a higher incidence rate of dyslipidemia
(hazard ratio, 1.7; 95% CI, 1.4–2.02). Among the 346
participants taking lipid-lowering therapy at entry or during
follow-up, 68% were taking a statin. Increases in HDL-C
levels resulted in a marginally lower total cholesterol to HDL-
C ratio in the immediate versus the deferred group (0.1;
95% CI, 0.2 to 0.1). When HDL <40 mg/dL was included
in the criteria for dyslipidemia, 49% (2283) of participants
had dyslipidemia at study entry. When including low HDL in
the definition, the incidence rate for dyslipidemia was lower
in the immediate ART group compared with the deferred ART
group (hazard ratio, 0.7; 95% CI, 0.6–0.8) (Figure 3).
Immediate ART also resulted in higher triglyceride (8 mg/
dL; 95% CI, 3–12) and non–HDL-C (7 mg/dL; 95% CI, 5–8)
levels than deferred ART. Participants were fasting for 91%
of blood draw visits and the findings were similar when
analyses were restricted to fasting specimens. In analyses of
treated versus untreated HIV infection, the treatment
differences in lipid changes from baseline were of higher
magnitude but similar.
Table 2 presents analyses of subgroups defined by
prespecified ART, with comparisons for EFV-, PI-, and INSTI-
based ART. These data represent the effect of starting a
specific antiretroviral when compared with a group random-
ized to defer ART but who intended to start the same
antiretroviral medication or class. Time spent during follow-up
taking the prespecified ART varied between 75% and 80% for
the immediate group and 15% and 20% for the deferred group.
There was a significant interaction between the prespecified
ART regimen and the treatment difference for several
cholesterol measures. Specifically, participants who prespec-
ified EFV use had a greater difference in both total cholesterol
and HDL-C level between the immediate and deferred groups,
when compared with those who prespecified PI use. Similarly,
when compared with those who prespecified an INSTI, the
EFV subgroup had greater differences in total cholesterol,
LDL-C, and HDL-C levels between the immediate and deferred
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groups. Notably, there was no difference in any lipid
parameters between immediate and deferred ART among
the subgroup that prespecified INSTI use. In analyses of
treated versus untreated HIV infection, the magnitude of the
treatment differences in lipid changes from baseline was
higher for EFV- and PI-based ART.
Changes in BP
When compared with patients who underwent ART deferral,
those who took immediate ART demonstrated no difference
in systolic BP, a lower diastolic BP that was not significant
(Figure 2), and a lower prevalence of BP-lowering therapy
(2.2%; 95% CI, 3.6 to 0.93). At entry, 19% of
participants had hypertension (per our definition), and when
new-onset hypertension rates were compared between the
immediate and deferred groups, the hazard ratio for reduced
incidence of hypertension did not reach significance (0.87;
95% CI, 0.74–1.02; [P=0.10]) (Figure 3). After analyses of
treated versus untreated HIV infection, there remained no
difference in use of BP-lowering therapy or incident hyper-
tension between the groups, whereas diastolic BP was
significantly lower in the immediate ART group (0.4; 95%
CI, 0.1 to 0.7 [P=0.02]).
Changes in Metabolic Parameters
Patients in the immediate group had a higher mean glucose
level of 2 mg/dL (95% CI, 1–3) than patients in the deferred
group (Figure S1), but there was no difference in the incidence
Table 1. Baseline Characteristics of Patients in the START
Trial (n=4685)
Median [IQR] or % (No.)
Demographics
Age, y 36 [29–44]
Female sex 26.8 (1257)
Race
Asian 8.3 (388)
Black 30.1 (1410)
Latino/Hispanic 13.6 (638)
White 44.5 (2086)
Other 3.5 (163)
HIV history and laboratory
Time known to be HIV positive, y 1.0 [0.4–3.1]
CD4, cells/mm
3
* 651 [584–765]
Nadir CD4, cells/mm
3†
553 [488–654]
HIV RNA, copies/mL 12 759 [3019–43 391]
Clinical measures
BMI, kg/m
2
24.6 [22.1–27.9]
Systolic BP, mm Hg 120 [111–130]
Diastolic BP, mm Hg 76 [70–83]
Risk factors
Current smoker 31.9 (1496)
Diabetes mellitus 3.3 (156)
Prior CVD diagnosis
‡
0.8 (36)
Hypertension 19.2 (898)
BP-lowering drugs 8.1 (281)
Dyslipidemia 8.2 (386)
Lipid-lowering drugs 3.5 (163)
Glucose and lipids
Glucose, mg/dL 85 [79–92]
Total cholesterol, mg/dL 168 [144–195]
LDL-C, mg/dL 102 [82–124]
HDL-C, mg/dL 41 [35–50]
Triglycerides, mg/dL 97 [71–142]
Total cholesterol to HDL-C ratio 4.0 [3.2–5.0]
Non–HDL-C, mg/dL 124 [102–150]
10-year predicted risk scores
CVD FRS, %
§
2.3 [0.7–6.5]
CHD FRS, %
§
1.9 [0.5–5.0]
CVD D:A:D, %
k
1.8 [0.9–3.5]
CHD D:A:D, %
k
1.4 [0.7–2.9]
Pooled cohort ASCVD, %
¶
2.2 [1.0–4.4]
Lifetime ASCVD risk score, %
#
31.2 [15.6–39.6]
Continued
Table 1. Continued
Median [IQR] or % (No.)
Prespecified ART regimen
EFV 75.1 (3516)
PI 17.4 (815)
INSTI 3.9 (183)
Non-EFV NNRTI 3.7 (171)
ART indicates antiretroviral therapy; BMI, body mass index; BP, blood pressure; CHD,
coronary heart disease; CVD, cardiovascular disease; EFV, efavirenz; HDL-C, high-density
lipoprotein cholesterol; INSTI, integrase strand transfer inhibitor; IQR, interquartile range;
LDL-C, low-density lipoprotein cholesterol; NNRTI, non-nucleoside reverse tra nscriptase
inhibitor; PI, protease inhibitor; START, Strategic Timing of Antiretroviral Treatment.
*Average of 2 screening values.
†
Documented in participant record.
‡
Diagnosis of any of the following prior to randomization: myocardial infarction, stroke,
coronary heart disease requiring drug treatment, coronary revascularization, congestive
heart failure, or peripheral arterial disease.
§
Framingham Risk Score (FRS) equations in Anderson et al.
18
k
Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) score equations in Friis-
Møller et al.
19
¶
Atherosclerotic cardiovascular disease (ASCVD) risk equation in Goff et al.
20
#
Lifetime ASCVD risk score in Berry et al.
22
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of type 2 diabetes mellitus (Figure 3). In contrast, BMI was
significantly lower among patients in the immediate versus
deferred groups (0.2 kg/m
2
; 95% CI, 0.3 to 0.1), although
the magnitude of this effect is of unclear clinical significance
(Figure S1). The treatment effect on BMI appeared greatest
early after randomization (P<0.001 for interaction of treatment
group by follow-up time). When comparing subgroups defined
by prespecified ART regimen, BMI showed a significantly
greater decline (with immediate versus deferred ART) among
patients in the EFV (0.3 kg/m
2
; 95% CI, 0.4 to 0.2) versus
PI (0.1 kg/m
2
; 95% CI, 0.2 to 0.1) subgroups. Finally, there
was no evidence of an interaction between prespecified ART
regimen and a treatment effect for serum glucose or incident
diabetes mellitus.
Differences in Risk Factor Profile and Predicted
Risk Scores
We studied the effect of immediate ART on CVD and CHD
predicted risk scores. Smoking contributed the most to
predicted risk, but rates did not differ between treatment
groups during follow-up (Figure S1). The mean difference
between groups was not significant for the atherosclerotic
CVD pooled cohort 10-year risk score (0.1; 95% CI, 0.2 to
0.1), the Framingham Risk Score 10-year CVD (0.1; 95%
CI, 0.3 to 0.0), or the Framingham Risk Score 10-year
CHD (0.1; 95% CI 0.3 to 0.0), but was slightly higher in
the immediate group for the D:A:D 10-year CVD (0.2; 95% CI,
0.1–0.3) and CHD (0.1; 95% CI, 0.1–0.2) estimates. Differ-
ences in the D:A:D scores were caused primarily by the fact
that this score considers exposure to certain antiretrovirals
(eg, abacavir, lopinavir); there were no differences when
censoring participants after initiation of these antiretrovirals.
After analyses of patients with treated versus untreated HIV
infection, the treatment differences in the Framingham Risk
Score estimates were of a similar low magnitude but reached
statistical significance.
Discussion
The START trial is the first randomized clinical investigation to
study the impact of immediate ART initiation, when compared
with deferral, on CVD risk factors among a large global HIV-
positive cohort with high CD4
+
cell counts. It is in this context
that understanding and mitigating risk for CVD becomes a
high priority in clinical practice. When compared with ART
deferral, ART initiation increased total cholesterol and LDL-C
levels and use of lipid-lowering therapy, but also increased
HDL-C level and resulted in a decline in total cholesterol to
HDL-C ratio. Changes in CVD or CHD prediction scores
with immediate versus deferred ART were minimal or
nonsignificant.
A well-described consequence of untreated HIV infection is
a decline in most serum lipids levels (the primary exception
being an elevation in triglycerides), with ART initiation then
leading to a compensatory increase in total cholesterol and
LDL-C levels to a degree that often varies by regimen.
15,23,24
We present novel randomized data quantifying the absolute
effect of ART initiation on serum lipids, when compared with
initially untreated HIV disease. Increases in total cholesterol
were greatest among the subgroups that prespecified EFV.
Prior studies have lacked a comparison group of untreated
persons, but have reported greater within-participant
increases in total cholesterol (mean 19 and 55 mg/dL) and
LDL-C (mean 4 and 23 mg/dL) levels 1 year after starting
NNRTI- (eg, EFV) or PI-based ART, when compared with the
changes reported in the START trial.
15,25,26
It is unclear
whether the greater increases in LDL-C level with EFV-based
ART reflects greater CVD risk, given that increases in HDL-C
level were also greater with EFV and that epidemiologic data
demonstrate that exposure to certain PIs, but not to NNRTIs
(eg, EFV), are associated with greater risk for myocardial
infarction.
10,27
Data from comparative antiretroviral trials have shown
the greatest rises in HDL-C level after starting EFV (73% in
the START trial) or tenofovir (89% in the START trial), with
the effect from INSTIs (5% in the START trial) being
0
Months from Randomization
10
20
30
40
50
60
70
80
90
100
Patients, %
No. of Participants:
Immediate:
Deferred:
2326 2287 1809 1040 551
2359 2303 1837 1055 546
Immediate
Deferred
362412 48
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 immedi-
ate and deferred ART groups. Data were previously reported
but the results shown here are truncated at month 48.
16
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−5
0
5
10
15
20 A Total Cholesterol, mg/dL
I−D diff.: 11.4 (95% CI, 10.0–12.9): P<0.001 −5
0
5
10 B LDL-C, mg/dL
I−D diff.: 5.5 (95% CI, 4.2-6.8): P<0.001
−2
0
2
4
6
8C HDL−C (mg/dL)
I−D diff.: 4.8 (95% CI, 4.3–5.4): P<0.001 −0.3
−0.2
−0.1
0.0
0.1 D Total−C:HDL−C Ratio
I−D diff.: −0.1 (95% CI, –0.2 to –0.1): P<0.001
−1.5
−1.0
−0.5
0.0
0.5
1.0
1.5 E Systolic BP, mm Hg
I−D diff.: −0.1 (95% CI, –0.6 to –0.3) P=0.58 −1.5
−1.0
−0.5
0.0
0.5
1.0
1.5 F Diastolic BP, mm Hg
I−D diff.: −0.3 (95% CI, –0.6 to –0.0) P=0.07
6
8
10
12
14 G Use of BP-Lowering Drugs
I−D diff.: −2.3 (95% CI, –3.6 to –0.9): P<0.001
2
4
6
8
10 H Use of Lipid-Lowering Drugs
I−D diff.: 1.2 (95% CI, 0.1–2.2) P=0.03
Change From BaselinePrevalence, %
Months From Randomization
Immediate Deferred
0 12 24 36 48 0 12 24 36 48
Figure 2. Cardiovascular risk factor changes by treatment group. Shown in the first 3 rows are the
unadjusted mean changesfrom 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 Pvalues) 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 ARTgroups 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 Pvalues) between the 2 groups (I minus D), adjusting for the
baseline prevalence and visit from generalized estimating equations. Figures are truncated at month 48.
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mixed.
25,26,28–32
Our findings support that ART initiation with
EFV-based ART led to the greatest increases in HDL-C level.
Furthermore, the degree of HDL-C level increase attributable
to initiating EFV-based ART was large enough to result in a
concurrent decline in the ratio of total cholesterol to HDL-C,
which was not observed for PI- or INSTI-based ART. The
differential effect on HDL-C level by ART regimen and lack of
significant INSTI effects on any blood lipids suggests that
cholesterol changes may, in part, be mediated via effects
other than those related to HIV viral suppression.
Multiple factors contribute to dyslipidemia among ART-
treated HIV-positive patients, including altered hepatic syn-
thesis, inflammation, oxidative stress, direct drug toxicity (eg,
PI binding of the LDL-C receptor protein), and possibly genetic
factors.
23,33–35
The modest degree of ART-associated
increases in total cholesterol and LDL-C levels described in
the START trial was surprising, although, as noted, may be
caused by the fact that previous estimates cannot isolate the
net effect of ART versus no ART. One important caveat to the
increase in dyslipidemia with immediate ART in the START trial
was that if low HDL level was included as criteria, then
dyslipidemia was less with immediate ART. Another important
difference between findings from the START trial and most
prior ART trials is the health of the study population, raising
the question of whether ART-related effects on serum lipids
may be decreased when initiating treatment earlier in HIV
disease. Still, the effect of ART treatment on blood lipid levels
in the START trial emphasizes that cholesterol should remain
a key target for CVD risk factor modification within this
population.
0
5
10
15
20
25
30 A Dyslipidemia (no HDL)
I/D HR: 1.66 (95% CI, 1.36–2.02): P<0.001
0
10
20
30
40
50
60
70
80 B Dyslipidemia (with HDL)
I/D HR: 0.70 (95% CI, 0.61–0.8): P<0.001
0
5
10
15
20
25
30 C Hypertension
I/D HR: 0.87 (95% CI, 0.74–1.02) P=0.10
0
2
4
6D Diabetes
I/D HR: 1.13 (95% CI, 0.75–1.72) P=0.56
Cumulative Percent With Event
Months From Randomization
Immediate Deferred
0 12243648 0 12243648
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 Pvalues) 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.
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Although immediate ART initiation did not lead to significant
changes in BP or incident hypertension, the use of BP-lowering
therapy and the prevalence of hypertension were less with
immediate ART. Reasons for this discrepancy are unclear, but
incident hypertension does not reflect influences on the use of
BP-lowering therapy among patients with known hypertension
at entry. Associations between inflammatory cytokines and
vascular stiffness provide some biologic pretense for why
suppressing HIV replication may reduce the need for BP
therapy.
36–39
However, if a true ART-treatment effect on
absolute BP was present but not detected in this study (eg,
type 2 error), it is unlikely to be clinically significant.
ART is well known to be associated with body composition
changes, although contemporary ART regimens are less toxic
than early-era antiretrovirals.
40–42
In the START trial, imme-
diate ART initiation led to a clinically insignificant increase in
serum glucose (ie, with no change in incidence of diabetes
mellitus), but was also associated with a marginally lower BMI.
The BMI findings are counter to prior observations of ART
increases in abdominal fat, but, importantly, BMI assessments
do not delineate between changes in visceral and subcuta-
neous fat.
41,43
In addition, the relative immune preservation in
the START trial may be important in that toxicity from a given
antiretroviral medication may be more pronounced among
patients with more severe immune depletion. This hypothesis
was suggested by notable findings from HOPS (the HIV
Outpatient Study), in which starting ART at higher (versus
lower) CD4
+
cell counts reduced the incidence of peripheral
neuropathy, even when using antiretrovirals well known to
cause neuropathy.
44
Ultimately, the net effect of early ART initiation on
traditional risk factors appeared to have a clinically insignif-
icant effect on CVD and CHD risk algorithms. While 10-year
CVD/CHD predicted risk remained low in absolute terms, the
estimated lifetime atherosclerotic CVD risk at study entry
among this younger population was still >30%,
22
reinforcing
that traditional risk factor management remains an important
strategy to mitigate the cumulative effects of HIV, ART, and
advancing age over time. However, it does remain unclear
how well the atherosclerotic CVD lifetime risk estimation
reflects true clinical risk in this context as it has not been
validated among HIV-positive persons.
Study Limitations
These analyses have several limitations. We did not directly
assess or characterize other potentially important CVD risk
mechanisms (eg, HIV-related systemic inflammation) or
potential mechanisms of ART toxicity. There was potential
for confounding in terms of baseline lipid levels influencing
the choice of ART regimen; however, we did not see evidence
for this, as the prevalence of prespecified PI (17%) was the
same for persons with and without hyperlipidemia at baseline.
Also, analyses focused on the INSTI subgroup were limited by
small numbers. Finally, we are not able to characterize
whether the ART-related changes in CVD risk factors will
translate to differences in clinical event risk caused by the
limited number of events in the START trial, although findings
to date have not detected a significant effect of immediate
versus deferred ART on risk for CVD events (HR, 0.84; 95% CI,
0.39–1.81).
16
Conclusions
These data, among a diverse global population of HIV-positive
persons with high CD4 cell counts, suggest that immediate
ART initiation has both positive and negative influences on
CVD risk factors. Ultimately, long-term follow-up in the START
trial is needed to determine the net effect of ART treatment
initiation for CVD event risk among HIV-positive individuals
with preserved immunity.
Table 2. Overall Treatment Difference (I–D) in Metabolic Parameters by Subgroups Defined by Prespecified ART Regimen at
Baseline
Measure
Prespecified ART
Interaction
PValue
†
EFV (n=3516) PI (n=815) INSTI (n=183)
I–D
Mean Difference* (95% CI)
I–D
Mean Difference* (95% CI)
I–D
Mean Difference* (95% CI)
Total cholesterol, mg/dL 13.2 (11.5–14.9) 8.7 (5.2–12.1) 2.4 (10.1 to 5.3) <0.001
LDL-C, mg/dL 6.5 (5.0–7.9) 3.7 (0.7–6.7) 1.1 (7.8 to 5.7) 0.036
HDL-C, mg/dL 5.8 (5.2–6.4) 2.2 (0.9–3.5) 0.4 (2.5 to 3.4) <0.001
Total cholesterol to HDL-C ratio 0.2 (0.2 to 0.1) 0.0 (0.2 to 0.1) 0.2 (0.5 to 0.2) 0.13
EFV indicates efavirenz; HDL-C, high-density lipoprotein cholesterol; INSTI, integrase strand transfer inhibitor; LDL-C, low-density lipoprotein cholesterol; PI, protease inhibitor.
*Mean differences (immediate [I] minus deferred [D]) during all follow-up using longitudinal mixed models adjusting for baseline level and visit.
†
2df P value for interaction between treatment group and 3 prespecified antiretroviral therapy (ART) regimens comparing the I–D treatment difference among subgroups.
DOI: 10.1161/JAHA.116.004987 Journal of the American Heart Association 8
Cardiovascular Disease Risk Factors in the START Trial Baker et al
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Acknowledgments
The authors would like to specifically thank the participants in the
START trial. See supplemental material for the complete listing of the
INSIGHT (International Network for Strategic Initiatives in Global HIV
Trials) START (Strategic Timing of Antiretroviral Treatment) Study
Group (also published in N Engl J Med. 2015;373:795–807).
Sources of Funding
The START trial (NCT00867048) is registered at clinicaltrials.-
gov. The START trial is primarily funded by the National Institute
of Allergy and Infectious Diseases (NIAID) of the National
Institutes of Health (NIH) under award numbers UM1-AI068641
and UMN1-AI120197, with additional support from the NIH
Clinical Center; National Cancer Institute; National Heart, Lung,
and Blood Institute; Eunice Kennedy Shriver National Institute
of Child Health and Human Development; National Institute of
Mental Health; National Institute of Neurological Disorders and
Stroke; National Institute of Arthritis and Musculoskeletal and
Skin Diseases; Agence Nationale de Recherches sur le SIDA et
les H
epatites Virales (France); National Health and Medical
Research Council (Australia); National Research Foundation
(Denmark); Bundesministerium f€
ur Bildung und Forschung
(Germany); European AIDS Treatment Network; Medical
Research Council (United Kingdom); National Institute for
Health Research; National Health Service (United Kingdom);
and University of Minnesota. Antiretroviral drugs are donated to
the central drug repository by AbbVie, Bristol-Myers Squibb,
Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen
Scientific Affairs, and Merck. Dr Gordin is supported by the NIH
Cardiovascular Scientist Training Program under award number
T32 HL007895.
Disclosures
The content is solely the responsibility of the authors and
does not necessarily represent the official views of the NIH.
Dr Phillips received fees for speaking at 2 meetings sponsored
by Gilead Sciences, for consulting from GSK Biologicals, and
for attendance at an advisory board membership from AbbVie.
The remaining authors declare no relevant financial interests.
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antiretroviral therapy at CD4 cell counts >/=350 cells/mm
3
does not increase
incidence or risk of peripheral neuropathy, anemia, or renal insufficiency. J
Acquir Immune Defic Syndr. 2008;47:27–35.
DOI: 10.1161/JAHA.116.004987 Journal of the American Heart Association 10
Cardiovascular Disease Risk Factors in the START Trial Baker et al
ORIGINAL RESEARCH
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SUPPLEMENTAL MATERIAL
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Table S1. Distribution (number and percent) of specific ART used for the first regimen
and total follow-up time spent taking a specific ART (Person Years, percent of follow-up).
Immediate
Deferred
First Regimen
N(%)*
Cumulative
Follow-up Time
on Drug
PY(% time)†
First Regimen
N(%)*
Cumulative
Follow-up Time
on Drug
PY(% time)†
No. of participants
2326
2359
Any NRTI
2285 (98.2)
6582 (93.9)
1131 (47.9)
1954 (27.7)
Abacavir
72 (3.1)
344 (4.9)
70 (3.0)
154 (2.2)
Emtricitabine
2025 (87.1)
5794 (82.7)
1001 (42.4)
1724 (24.4)
Tenofovir
2026 (87.1)
5821 (83.1)
1012 (42.9)
1735 (24.6)
Lamivudine
260 (11.2)
779 (11.1)
129 (5.5)
225 (3.2)
Zidovudine
188 (8.1)
411 (5.9)
47 (2.0)
63 (0.9)
Other
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Any NNRTI
1759 (75.6)
4524 (64.6)
722 (30.6)
1122 (15.9)
efavirenz
1661 (71.4)
4097 (58.5)
573 (24.3)
855 (12.1)
rilpivirine
97 (4.2)
360 (5.1)
141 (6.0)
237 (3.4)
other
1 (0.0)
68 (1.0)
8 (0.7)
31 (0.4)
Any PI
424 (18.2)
1653 (23.6)
252 (10.7)
553 (7.8)
atazanavir
230 (9.9)
887 (12.7)
99 (4.2)
220 (3.1)
darunavir
165 (7.1)
611 (8.7)
125 (5.3)
290 (4.1)
fosamprenavir
11 (0.5)
33 (0.5)
6 (0.3)
13 (0.2)
lopinavir
18 (0.8)
121 (1.7)
21 (0.9)
30 (0.4)
ritonavir
422 (18.1)
1630 (23.3)
250 (10.6)
547 (7.8)
other
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Any INSTI
103 (4.4)
448 (6.4)
157 (6.7)
288 (4.1)
dolutegravir
1 (0.0)
10 (0.1)
19 (0.8)
21 (0.3)
elvitegravir
1 (0.0)
25 (0.4)
49 (2.1)
63 (0.9)
raltegravir
101 (4.3)
413 (5.9)
89 (3.8)
205 (2.9)
other
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Other ART‡
1 (0.0)
2 (0.0)
0 (0.0)
0 (0.0)
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Not on any ART
39 (1.7)
400 (5.7)
1225 (51.9)
5094 (72.2)
N – number; PY – Person years; ART – Antiretroviral therapy; NRTI – nucleoside reverse transcriptase inhibitor; NNRTI – non-
nucleoside reverse transcriptase inhibitor; PI – protease inhibitor; INSTI – integrase strand transfer inhibitor
* Denominator is all participants in the randomization group.
† Person years includes switches and accounts for stops and therefore includes time spent on drug for participant who did not
initiate ART with the given
drug. Denominator is over all follow-up time accumulated within the randomization group.
‡ 1 participant started a blinded study and the type of ART taken is unknown.
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Figure S1. Changes in the Prevalence of Selected CVD Risk Factors by Treatment Group
Shown in panels A-C is the unadjusted prevalence (%) at baseline and follow-up annual visits
for participants in the immediate (I, solid line) and deferred (D, dashed line) ART groups for
CVD (cardiovascular disease) risk factor, including hypertension (panel A), dyslipidemia (panel
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B), and current smoking (panel C). Presented within panels A-C are overall estimated
differences in prevalence (with 95% confidence interval and p-value) over follow-up between the
two groups (immediate minus deferred), adjusting for the baseline prevalence and visit from
generalized estimating equations. Shown in panels D-E are the unadjusted mean changes from
baseline at annual visits for participants in both ART groups for the following measures: body
mass index (BMI, panel D) and glucose (panel E). Presented within panels D-E is the estimated
mean difference (with 95% confidence interval and p-value) over follow-up between the two
groups (immediate minus deferred), adjusting for the baseline value and visit from longitudinal
mixed models. Figures are truncated at Month 48.
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Appendix: The INSIGHT START (Strategic Timing of AntiRetroviral Treatment) Study
Group
In addition to writing group, the following committee members contributed to the conduct of the START
trial:
Community Advisory Board: C. Rappoport (INSIGHT community liaison), P.D. Aagaard, S. Collins,
G.M. Corbelli, N. Geffen, C. Kittitrakul, T. Maynard, M. Meulbroek, D. Munroe, M.S. Nsubuga, D.
Peavey, S. Schwarze, M. Valdez.
Substudy Chairs: J.V. Baker, D. Duprez (arterial elasticity); A. Carr, J. Hoy (bone mineral density); M.
Dolan, A. Telenti (genomics); C. Grady (informed consent); G. Matthews, J. Rockstroh (liver fibrosis
progression); W.H. Belloso, J.M. Kagan (monitoring); E. Wright, B. Brew, R.W. Price, K. Robertson, L.
Cysique (neurology); K.M. Kunisaki, J.E. Connett, D.E. Niewoehner (pulmonary). Endpoint Review
Committee: A. Lifson (chair), W.H. Belloso, R.T. Davey Jr., D. Duprez, J.M. Gatell, J. Hoy, C. Pedersen,
R.W. Price, R. Prineas, J. Worley.
Central Drug Repository and Drug Distribution: K. Brekke, S. Meger, B. Baugh, J. Eckstrand, C.
Gallagher, J. Myers, J. Rooney, J. Van Wyk.
Network Laboratory Group: J. Baxter, C. Carey, A. DuChene, E.B. Finley, M. George, J. Grarup, M.
Hoover, R. Pedersen, C. Russell, B. Standridge.
Specimen Repositories: E. Flowers, M. Hoover, K. Smith (Advanced BioMedical Laboratories, LLC,
Cinnaminson, NJ, United States); M. McGrath, S. Silver (AIDS and Cancer Specimen Resource,
University of California, San Francisco, San Francisco, CA, United States).
Wake Forest ECG Reading Center, Winston-Salem, NC, United States: E.Z. Soliman, M. Barr, C.
Campbell, S. Hensley, J. Hu, L. Keasler, Y. Li, T. Taylor, Z.M. Zhang.
Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States: B.
AlstonSmith, E. DeCarlo, K. Klingman, M. Proschan.
Data and Safety Monitoring Board: S. Bangdiwala (chair), R. Chaisson, A.R. Fleischman, C. Hill, J.
Hilton, O.H.M. Leite, V.I. Mathan, B. Pick, C. Seas, P. Suwangool, G. Thimothe, F. Venter, I. Weller, P.
Yeni.
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Minnesota Coordinating Center, University of Minnesota, Minneapolis, MN, United States: J.D. Neaton,
K. Brekke, G. Collins, E.T. Denning, A. DuChene, N.W. Engen, M. George, B. Grund, M. Harrison, K.H.
Hullsiek, L.H. Klemme, E. Krum, G. Larson, S. Meger, R. Nelson, J. Neuhaus Nordwall, K. Quan, S.F.
Quan, T. Schultz, S. Sharma, G. Thompson.
International Coordinating Centers: Copenhagen HIV Programme, Rigshospitalet, University of
Copenhagen, Denmark: J.D. Lundgren, B. Aagaard, A.H.D. Borges, M. Eid, J. Grarup, P. Jansson, Z.
Joensen, B. Nielsen, M. Page 3 Pearson, R. Pedersen, A.N. Phillips; The Kirby Institute, University of
New South Wales, Sydney, Australia: S. Emery, N. Berthon-Jones, C. Carey, L. Cassar, M. Clewett, D.
Courtney-Rodgers, P. Findlay, S. Hough, S. Jacoby, J. Levitt, S.L. Pett, R. Robson, V. Shahamat, A.
Shambrook; Medical Research Council Clinical Trials Unit at UCL, London, United Kingdom: A.G.
Babiker, B. Angus, A. Arenas-Pinto, R. Bennett, N. Braimah, E. Dennis, N. Doyle, M. Gabriel, F.
Hudson, B. Jackson, A. Palfreeman, N. Paton, C. Purvis, C. Russell; Veterans Affairs Medical Center,
Washington, DC, United States: F. Gordin, D. Conwell, H. Elvis, E.B. Finley, V. Kan, L. Lynch, J.
Royal, A. Sánchez, B. Standridge, D. Thomas, M. Turner, M.J. Vjecha.
The following investigators participated in the START study, listed by country (country lead, numbers of
participants enrolled) and clinical site:
Argentina (M.H. Losso, n=216): CAICI (Instituto Centralizado de Assistencia e Investigación Clínica
Integral), Rosario Santa Fe: S. Lupo, L. Marconi, D. Aguila; FUNCEI, Buenos Aires: G. Lopardo, E.
Bissio, D. Fridman; Fundación IDEAA, Buenos Aires: H. Mingrone, E. Loiza, V. Mingrone; Hospital
General de Agudos JM Ramos Mejia, Buenos Aires: M. Losso, J.M. Bruguera, P. Burgoa; Hospital
Interzonal General de Agudos Dr. Diego Paroissien, Buenos Aires: E. Warley, S. Tavella; Hospital
Italiano de Buenos Aires, Buenos Aires: W. Belloso, M. Sanchez; Hospital Nacional Profesor Alejandro
Posadas, Buenos Aires: H. Laplumé, L. Daciuk; Hospital Rawson, Cordoba: D. David, A. Crinejo;
Argentinean SCC, Fundación IBIS, Buenos Aires: G. Rodriguez-Loria, L. Doldan, A. Moricz, I. Otegui,
I. Lanusse.
Australia (J. Hoy, n=109): Burwood Road General Practice, Burwood, VIC: N. Doong, S. Hewitt; Centre
Clinic, St Kilda, VIC: B.K. Tee; East Sydney Doctors, Darlinghurst, NSW: D. Baker, E. Odgers;
Holdsworth House Medical Practice, Darlinghurst, NSW: S. Agrawal, M. Bloch; Melbourne Sexual
Health Centre, Carlton, VIC: T.R.H. Read, S.J. Kent; Prahran Market Clinic, Prahran, VIC: H. Lau, N.
Roth; Royal Adelaide Hospital, Adelaide, SA: L. Daly, D. Shaw; Royal Perth Hospital, Perth, WA: M.
French, J. Robinson; Sexual Health & HIV Service - Clinic 2, Brisbane, QLD: M. Kelly, D. Rowling; St
Vincent's Hospital, Fitzroy, VIC: D.A. Cooper, A. J. Kelleher; Taylor Square Private Clinic, Surry Hills,
NSW: C. Pell, S. Dinning; The Alfred Hospital, Melbourne, VIC: J. Hoy, J. Costa; Westmead Hospital,
Westmead, NSW: D.E. Dwyer, P. King.
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Austria (A. Rieger, n=7): Otto-Wagner-Spital SMZ /Baumgartner Hoehe, Vienna: N. Vetter; B. Schmied;
University Vienna General Hospital, Vienna: A. Rieger, V.R. Touzeau.
Belgium (S. de Witt, n=102): Centre Hospitalier Universitaire St. Pierre (C.H.U. St. Pierre), Brussels: S.
de Witt, N. Clumeck, K. Kabeya; Institute of Tropical Medicine, Antwerp: E. Cleve, E. Florence, L. van
Petersen; Universitair Ziekenhuis Gasthuisberg, Leuven: H. Ceunen, E.H. van Wijngaerden; Universitaire
Ziekenhuizen Gent, Gent: T. James, L. Vandekerckhove.
Brazil (L.C. Pereira Jr., M. Schechter, n=619): Ambulatório de Imunodeficiências (LIM-56), Sao Paulo,
SP: J. Casseb, E. Constantinov, M.A. Monteiro; Center for ID at UFES, Vitoria, ES: L.N. Passos, T.
Reuter; Centro de Referência e Treinamento DST/AIDS, Sao Paulo, SP: S.T. Leme, J.V.R. Madruga, R.S.
Nogueira; Hospital Page 4 Escola Sao Francisco de Assis, Rio de Janeiro, RJ: M. Barbosa Souza, C.
Beppu Yoshida, M. Dias Costa; Instituto de Infectologia Emilio Ribas, Sao Paulo, SP: R. Castro, R.Cruz,
S. Ito, T.N. Lobato Souza; Instituto FIOCRUZ, Rio de Janeiro, RJ: B. Grinsztejn, V.G. Veloso, S.
Wagner Cardoso; SEI Serviços Especializados em Infectología LTDA, Salvador, Bahia: F. Bahia, C.
Brites, J. Correia.
Chile (M.J. Wolff, n=76): Fundación Arriarán, Santiago: M. Wolff, R. Northland, C. Cortés.
Czech Republic (D. Sedlacek, n=13): Faculty Hospital Na Bulovce, Prague: D. Jilich; University Hospital
Plzen, Plzen: D. Sedlacek.
Denmark (J. Gerstoft, n=33): Hvidovre University Hospital, Hvidovre: P. Collins, L. Mathiesen; Odense
University Hospital, Odense: L. Hergens, C. Pedersen; Rigshospitalet, Copenhagen: J. Gerstoft, L.P.
Jensen; Århus Universitetshospital, Skejby, Århus: I.R. Lofthiem, L. Østergaard.
Estonia (K. Zilmer, n=8): West Tallinn Central Hospital Infectious Diseases, Tallinn: K. Zilmer.
Finland (M. Ristola, n=23): Helsinki University Central Hospital, Helsinki: M. Ristola, O. Debnam.
France (B. Hoen, n=111): CHU Côte de Nacre – Caen, Caen: R. Verdon, S. Dargere; CHU de Besançon -
Hôpital Jean-Minjoz, Besancon: B. Hoen, C. Chirouze; Groupe Hospitalier Pitié-Salpêtrière, Paris: C.
Katlama, M-A. Valantin; Hôpital Antoine Béclère, Clamart: F. Boue, I. Kansau; Hôpital de Bicêtre, Le
Kremlin-Bicetre: C. Goujard, C. Chakvetadze; Hôpital Européen Georges Pompidou, Paris: L. Weiss, M
Karmochkine; Hôpital Foch, Suresnes: D. Zucman, C. Majerholc; Hôpital Gustava Dron, Tourcoing:
O.Robineau, R. Biekre; Hôpital Henri Mondor, Creteil: Y. Levy, J.D. Lelievre; Hôpital Hôtel Dieu, Paris:
J.P. Viard, J Ghosn; Hôpital Saint-Antoine, Paris: J. Pacanowski, B. Lefebvre; Hôpital Saint-Louis, Paris:
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J.-M. Molina, L. Niedbalski, M. Previlon; French SCC, ANRS-Inserm SC10, Paris: J.P. Aboulker, C.
Capitant, B. Lebas, N. Leturque, L. Meyer, E. Netzer.
Germany (G. Fätkenheuer, n=312): EPIMED, Berlin: K. Arastéh, T. Meier; Gemeinschaftspraxis Jessen-
JessenStein, Berlin: C. Zedlack, H. Jessen; ICH Study Center, Hamburg: S. Heesch, C. Hoffmann; Ifi -
Studien und Projekte GmbH, Hamburg: A. Plettenberg, A. Stoehr; Johann Wolfgang Goethe - University
Hospital, Frankfurt: G. Sarrach, C. Stephan; Klinik I für Innere Medizin der Universität zu Köln,
Cologne: G. Fätkenheuer, E. Thomas; Klinikum der Universität München, Munich: J.R. Bogner, I. Ott;
Klinikum Dortmund GmbH, Dortmund: M. Hower, C. Bachmann; Medizinische Hochschule Hannover,
Hannover: M. Stoll, R. Bieder; Medizinische Universitätsklinik - Bonn, Bonn: J. Rockstroh, B. Becker;
Universitätsklinikum Düsseldorf, Düsseldorf: B. Jensen, C. Feind; Universitätsklinikum Erlangen,
Erlangen: E. Harrer, T. Harrer; Universitätsklinikum Essen, Essen: S. Esser, H. Wiehler;
Universitätsklinikum Heidelberg, Heidelberg: M. Hartmann, R. Röger; Universitätsklinikum Regensburg,
Regensburg: B. Salzberger, E. Jäger; Universitätsklinikum Würzburg, Würzburg: H. Klinker, G. Mark;
Universitätsklinikum, Hamburg-Eppendorf: J. van Lunzen, N. Zerche; German SSC, Johann Wolfgang
Goethe - University Hospital, Frankfurt: V. Müller, K. Tillman.
Greece (G. Touloumi, n=101): AHEPA University Hospital, Thessaloniki Central Macedonia: S.
Metallidis, O. Tsachouridou; Attikon University General Hospital, Athens: A. Papadopoulos, K.
Protopapas; Evangelismos General Hospital, Athens: A. Skoutelis, V. Papastamopoulos; Hippokration
University General Hospital of Athens, Athens: H. Sambatakou, I. Mariolis; Korgialenio-Benakio
Hellenic Red Cross, Athens: M. K. Lazanas, M. Chini; Syngros Hospital, Athens: S. Kourkounti, V.
Paparizos; Greek SCC, National Kapodistrian University of Athens, Athens: G. Touloumi, V. Gioukari,
O. Anagnostou.
India (n=91): Institute of Infectious Diseases, Pune Maharashtra: A. Chitalikar, S. Pujari; YRGCARE
Medical Centre VHS, Chennai CRS: F. Beulah, N. Kumarasamy, S. Poongulali.
Ireland (P. Mallon, n=7): Mater Misericordiae University Hospital, Dublin: P. Mallon, P. McGettrick.
Israel (E. Kedem, n=28): Rambam Medical Center, Haifa: E. Kedem, S. Pollack; Tel Aviv Sourasky
Medical Center, Tel Aviv: D. Turner.
Italy (G. Tambussi, n=33): Lazzaro Spallanzani IRCSS, Rome: A. Antinori, R. Libertone; Ospedale San
Raffaele S.r.l., Milan: G. Tambussi, S. Nozza, M.R. Parisi.
Luxembourg (T. Staub, n=5): Centre Hospitalier de Luxembourg, Luxembourg: T. Staub, C. Lieunard.
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Malaysia (n=18): University Malaya Medical Centre, Kuala Lumpur: R.I.S.R. Azwa.
Mali (S. Dao, n=41): SEREFO/ CESAC Mali, Bamako, Bamako: B. Baya, M. Cissé, D. Goita.
Mexico (n=48): INCMNSZ (Instituto Nacional de Ciencias Médicas y Nutrición), Tlalpan D.F.: J. Sierra-
Madero, M.E. Zghaib.
Morocco (K.M. El Filali, n=44): University Hospital Centre Ibn Rochd, Casablanca: K.M. El Filali, I.
Erradey, H. Himmich.
Nigeria (n=50): Institute of Human Virology-Nigeria (IHVN), Garki, Abuja FCT: E. Ekong, N. Eriobu.
Norway (V. Ormaasen, n=15): Oslo University Hospital, Ulleval, Oslo: V. Ormaasen, L. Skeie.
Peru (A. La Rosa, n=215): Hospital Nacional Edgardo Rebagliati Martins, Lima, Lima: M. Espichan
Gambirazzio, F. Mendo Urbina; Hospital Nacional Guillermo Almenara Irigoyen, Lima, Lima: R. Salazar
Castro, J. Vega Bazalar; IMPACTA Salud y Educación, Lima, Lima: M.E. Guevara, R. Infante, J.
Sanchez, M. Sanchez; IMPACTA San Miguel, Lima, Lima: R. Chinchay, J.R. Lama, M. Sanchez; Via
Libre, Lima, Lima: E.C. Agurto, R. Ayarza, J.A. Hidalgo.
Poland (A.J. Horban, n=68): EMC Instytut Medyczny SA, Wroclaw: B. Knysz, A. Szymczak;
Uniwersytecki Szpital Kliniczny, Bialystok: R. Flisiak, A. Grzeszczuk; Wojewodzki Szpital Zakazny,
Warsaw: A.J. Horban, E. Bakowska, A. Ignatowska.
Portugal (L. Caldeira, n=67): Hospital Curry Cabral, Lisbon: F. Maltez, S. Lino; Hospital de Egas Moniz,
Lisbon: K. Mansinho, T. Bapista; Hospital de Santa Maria, Lisbon: M. Doroana, A. Sequeira, L. Caldeira;
Hospital Joaquim Urbano, Oporto: J. Mendez, R.S.E. Castro.
South Africa (R. Wood, n=518): 1 Military Hospital, Pretoria Gauteng: S.A. Pitsi; Desmond Tutu HIV
Centre - Cape Town, Cape Town, Western Province: R. Kaplan, N. Killa, C. Orrell, M. Rattley; Durban
International Clinical Research Site, Durban, KwaZulu Natal: U.G. Lalloo, R. Mngqibisa, S. Pillay;
Durban International Clinical Research Site WWH, Durban, KwaZulu Natal: J. Govender, M. John;
University of Witwatersrand, Johannesburg, Gauteng: S. Badal-Faesen, N. Mwelase, M. Rassool.
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Spain (J.R. Arribas, n=234): Complejo Hospitalario Xeral Cies, Vigo Pontevedra: A.O. Hermida, F.
Warncke; Hospital Clínic de Barcelona, Barcelona: J.M. Gatell, A. Gonzalez; Hospital Clínico San
Carlos, Madrid: V. Estrada, M. Rodrigo; Hospital de la Santa Creu i Sant Pau, Barcelona: P. Domingo,
M. Gutierrez; Hospital del Mar, Barcelona: H.J. Knobel, A. Gonzalez; Hospital La Paz, Madrid: J.R.
Arribas, M. Montes Ramirez; Hospital La Princesa, Internal Medicine and Infectious Disease Service
CRS, Madrid: I. de los Santo Gil, J. Sanz Sanz; Hospital Universitari Germans Trias i Pujol, Badalona: B.
Clotet, J.M. Llibre, P. Cobarsi; Hospital Universitari Mutua Terrassa, Terrassa Barcelona: D. Dalmau, C.
Badia; Hospital Universitario Doce de Octubre, Madrid: R. Rubio, M.M. del Amo; Hospital Universitario
Príncipe de Asturias, Alcala de Henares Madrid: J. Sanz Moreno; Hospital Universitario y Politécnico La
Fe, Valencia: J. López Aldeguer, S. Cuellar; Spanish SSC, Acoiba, Madrid: P. López, B. Portas, P.
Herrero.
Sweden (M. Gisslén, n=2): Sahlgrenska University Hospital, Sweden: M. Gisslén, L. Johansson; Skåne
University Hospital, Malmö: C. Håkangård, K. Törqvist.
Switzerland (H. Furrer, n=31): Bern University Hospital, Bern: H. Furrer, A. Rauch; Unite VIH/SIDA
Genèva, Genèva: A.L. Calmy, B. Hirschel (retd), T Lecompte; University Hospital Basel, Basel: M.
Stoeckle; University Hospital Zurich, Zürich: N. Muller, M. Rizo-Oberholzer; Swiss SCC, Bern
University Hospital, Bern: H. Furrer, C. Bruelisauer, A. Christen, M. Lacalamita.
Thailand (K. Ruxrungtham, n=248): Bamrasnaradura Infections Diseases Institute, Nonthaburi: W.
Prasithsirikul, S. Thongyen; Chiangrai Prachanukroh Hospital, Chiang Rai: P. Kantipong, S. Khusuwan;
Chonburi Regional Hospital, Chonburi: C. Bowonwatanuwong, U. Ampunpong; Chulalongkorn
University Hospital, Bangkok: K. Ruxrungtham, A. Avihingsanon, W. Thiansanguankul; Khon Kaen
University, Srinagarind Hospital, Khon Kaen: P. Chetchotisakd, P. Motsikapun, S. Anunnatsari;
Ramathibodi Hospital, Bangkok: S. Kiertiburanakul, N. Sanmeema; Research Institute for Health
Sciences (RIHES), Chiang Mai: K. Supparatpinyo, P. Sugandhavesa; Sanpatong Hospital, Chiang Mai:
V. Klinbuayaem, Y. Siriwarothai; Siriraj Hospital, Bangkok Noi: W. Ratanasuwan, T Anekthananon;
Thai SCC, The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok: W.
Harnnapachewin, T. Jupimai, P. Rerksirikul.
Uganda (P. Mugyenyi, n=349): Joint Clinical Research Center (JCRC), Kampala: P. Mugyenyi, C. Kityo,
H. Mugerwa; MRC/UVRI Research Unit on AIDS, Entebbe: P. Munderi, B. Kikaire, J. Lutaakome;
MRC/UVRI Research Unit on AIDS, Masaka – satellite site: Z. Anywaine.
United Kingdom (M.A. Johnson, n=339): Barts Health NHS Trust, London: C. Orkin, J. Hand; Belfast
Health and Social Care Trust (RVH), Belfast Northern Ireland: C. Emerson, S. McKernan; Birmingham
Heartlands Hospital, Birmingham West Midlands: D. White, C. Stretton; Brighton and Sussex University
Hospitals NHS Trust, Brighton East Sussex: M. Fisher, A. Clarke, A. Bexley; Chelsea and Westminster
Hospital, London: B. Gazzard, C. Higgs, A. Jackson; Coventry and Warwickshire NHS partnership Trust,
Coventry West Midlands: S. Das, A. Sahota; Gloucestershire Royal Hospital, Gloucester: A. de Burgh-
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Thomas, I. Karunaratne; Guy's and St.Thomas' NHS Foundation Trust, London: J. Fox, J.M. Tiraboschi;
Imperial College Healthcare NHS Trust, London: A. Winston, B. Mora-Peris; Leicester Royal Infirmary,
Leicester Leicestershire: M.J. Wiselka, L. Mashonganyika; Lewisham and Greenwich NHS Trust,
London: S. Kegg, T. Moussaoui; North Manchester General Hospital, Manchester: E. Wilkins, Y.
Clowes; Queen Elizabeth Hospital Birmingham, Birmingham West Midlands: J. Ross, J. Harding; Royal
Berkshire Hospital, Reading Berkshire: F. Chen, S. Lynch; Royal Bournemouth Hospital, Bournemouth
Dorset: E. Herieka, J. Ablorde; Royal Free London NHS Foundation Trust, London: M.A. Johnson, M.
Tyrer, M. Youle; Sheffield Teaching Hospital NHS Foundation Trust, Sheffield South Yorkshire: D.
Dockrell, C. Bowman; Southmead Hospital, Bristol: M. Gompels, L. Jennings; St. George's Healthcare
NHS Trust, London: P. Hay, O. Okolo; The James Cook University Hospital, Middlesbrough Cleveland:
D.R. Chadwick, P. Lambert; University College London Medical School, London: I. Williams, A. Ashraf.
United States (K. Henry, n=507): Adult Clinical Research Center, Newark, NJ: M. Paez-Quinde, S.
Swaminathan; Boston University Medical Center, Boston, MA: I. Bica, M. Sullivan; Bronx-Lebanon
Hospital Center, Bronx, NY: R.B. Cindrich, L.M. Vasco; Community Research Initiative of New
England, Boston, MA: J. Green, H.B. Olivet; Cooper University Hospital, Camden, NJ: J. Baxter, Y.
Smith; Cornell CRS, New York, NY: V. Hughes, T. Wilkin; Denver Public Health, Denver, CO: E.M.
Gardner, J. Scott; Duke University, Durham, NC: J. Granholm, N. Thielman; Florida Department of
Health in Orange/Sunshine Care Center, Orlando, FL: W.M. Carter, N.D. Desai; George Washington
University Medical Center, Washington, DC: D.M. Parenti, G.L. Simon; Georgetown University Medical
Center, Washington, DC: P. Kumar, M. Menna; Hennepin County Medical Center, Minneapolis, MN: J.
Baker, R. Givot; Henry Ford Hospital, Detroit, MI: L.H. Makohon, N.P. Markowitz; Hillsborough
County Health Department, Tampa, FL: M. Chow, C. Somboonwit; Infectious Disease Associates of
Northwest Florida, Pensacola, FL: A.B. Brown, B.H. Wade; Lurie Children's Hospital, Chicago, IL: J.
Jensen, A. Talsky; Maternal, Child and Adolescent Center for ID/Virology USC, Alhambra, CA: A.
Kovacs, L. Spencer; Mayo Clinic, Rochester, MN: S. Rizza, Z. Temesgen; Medical College of Wisconsin,
Milwaukee, WI: M. Frank, S. Parker; Montefiore Medical Center, Bronx, NY: C. Rosario, J. Shuter; Mt
Sinai Hospital, Chicago, IL: K. Rohit, R. Yogev; National Military Medical Center, Bethesda, MD: I.
Barahona, A. Ganesan; Naval Medical Center Portsmouth NMCP, Portsmouth, VA: S. Banks, T. Lalani;
Naval Medical Center San Diego NMCSD, San Diego, CA: M.F. Bavaro, S. Echols; NICE, Southfield,
MI: M. Farrough, R.D. MacArthur; NIH, Bethesda, MD: R.T. Page 8 Davey Jr., R. McConnell; Ohio
State University, Columbus, OH: H. Harber, S.L. Koletar; Orlando Immunology Center, Orlando, FL: E.
DeJesus, A.F. Garcia; Regional Center for Infectious Disease, Greensboro, NC: K. Epperson, C.N. Van
Dam; San Antonio Military Health System, JBSA Fort Sam Houston, TX: J.F. Okulicz, T.J. Sjoberg; San
Juan Hospital, San Juan, PR: M. Acevedo, L. Angeli; St. Jude Children's Research Hospital, Memphis,
TN: P.M. Flynn, N. Patel; Temple University, Philadelphia, PA: C. Geisler, E. Tedaldi; Texas Children's
Hospital- Baylor College of Medicine, Houston, TX: C. McMullen-Jackson, W.T. Shearer; The Research
& Education Group, Portland, OR: M.D. Murphy, S.M. Sweek; Tulane University Health Sciences
Center, New Orleans, LA: D. Mushatt, C. Scott; UCLA CARE 4 Families, Los Angeles, CA: M. Carter,
J. Deville; UCSD Mother-Child-Adolescent HIV Program, San Diego, CA: S.A. Spector, L. Stangl;
University of Florida, Department of Pediatrics, Jacksonville, FL: M.H. Rathore, K. Thoma; University of
Florida, Jacksonville, FL: M. Sands, N. Wilson; University of Illinois at Chicago, Chicago, IL: R.M.
Novak, T. Pearson; University of Miami, Miami, FL: M.A. Kolber, T. Tanner; University of North
Carolina, Chapel Hill, NC: M. Chicurel-Bayard, E. Hoffman; University of North Texas Health Science
Center, Fort Worth, TX: I. Vecino, S.E. Weis; University of Puerto Rico, San Juan, PR: I. Boneta, J.
Santana; University of Texas Southwestern Medical Center, Dallas, TX: M.K. Jain, M. Santos; Veterans
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Timing of Antiretroviral Treatment) Study Group (Strategicthe INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) START
Siegfried Schwarze, Elsayed Z. Soliman, Stephen A. Spector, Giuseppe Tambussi, Jens Lundgren and
Daniel Duprez, Sean Emery, Brian Gazzard, Jonathan Gordin, Greg Grandits, Andrew N. Phillips,
Jason V. Baker, Shweta Sharma, Amit C. Achhra, Jose Ignacio Bernardino, Johannes R. Bogner,
Timing of Antiretroviral Treatment) Trial
Positive Participants in the START (Strategic−Antiretroviral Therapy Initiation Among HIV Changes in Cardiovascular Disease Risk Factors With Immediate Versus Deferred
Online ISSN: 2047-9980
Dallas, TX 75231
is published by the American Heart Association, 7272 Greenville Avenue,Journal of the American Heart AssociationThe doi: 10.1161/JAHA.116.004987
2017;6:e004987; originally published May 22, 2017;J Am Heart Assoc.
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