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Interruption of ART and Risk of Cardiovascular Disease: Findings from SMART
Andrew Phillips*1, A Carr2, J Neuhaus1, F Visnegarwala3, R Prineas4, W Burman5, I Williams6, F Drummond7, D Duprez1, J Lundgren8, and others for the SMART Study Group
1Univ of Minnesota, Minneapolis, US; 2St Vincent's Hosp, Univ New South Wales, Sydney, Australia; 3Baylor Coll of Med, Houston, TX, US; 4Univ of Wake Forest Sch of Med, Winston-Salem, NC, US; 5Denver Publ Hlth, CO, US; 6Royal Free and Univ Coll London Med Sch, UK; 7Natl Ctr for HIV Epidemiology and Clin Res, Sydney, Australia; and 8Hvidovre Hosp, Copenhagen, Denmark
Background: SMART compared strategies of continuous (viral
suppression arm;VS) and CD4-guided
(drug conservation arm; DC; off ART when >350 and (re-)start when <250)
ART. Patients in DC arm deferred/interrupted ART at baseline; those in VS arm
started/continued ART. We compared risk of cardiovascular disease (CVD) events
and lipid changes in the 2 arms.
Methods: We used Cox models to assess the association
between treatment arm and CVD risk and to study this effect in various
subgroups, in particular those relating to specific drugs/classes used at
baseline. Mean changes in lipids were assessed between baseline and year 1.
Results: We randomized 5472 patients, of whom 79 (1.4%)
developed major CVD events. The hazard ratio (HR [DC/VS]) was 1.57 (95%CI 1.00 to
2.46, p = 0.05). For the subset (84%)
on ART at baseline (43% non-nucleoside reverse transcriptase inhibitor [NNRTI]
and not protease inhibitor [PI], 45% on PI) the HR (DC/VS) was 1.37 (0.85 to
2.21, p = 0.20), while for those off
ART at baseline (16%, 5% naïve) it was 4.41 (0.94 to 20.8, p = 0.06) (interaction p =
0.16). There was no evidence that currently being off ART (time-updated covariate)
was associated with increased CVD risk (HR for being on ART vs
off 0.91, 0.57 to 1.47, p = 0.70),
nor was higher current viral load associated with increased CVD risk. Among
those on ART at baseline, the HR (DC/VS) was higher in those on nucleoside-only
(1.78) or NNRTI (2.07) regimens compared with those on a PI (1.00) (interaction
p = 0.37). The HR was most marked in
those on nevirapine at baseline (HR 9.29, 1.19 to
72.6, interaction p = 0.05). The HR
for CVD events per additional year of exposure to the PI was consistent with that
found in the DAD study in the VS arm (HR 1.17, 1.03 to 1.33) but not in the DC
arm (HR 1.02, interaction p = 0.07),
suggesting possibly reduced relevance of cumulative drug use in those who have
interrupted. Total, LDL, and HDL cholesterol were reduced in those DC patients
who interrupted ART, leading to a net unfavorable
change in total/HDL-cholesterol ratio, again particularly in those on
nucleoside-only (mean change in ratio from baseline +0.43) and nevirapine regimens (+0.58).
Conclusions: A borderline significant excess risk of CVD
was observed in DC compared to VS patients in SMART. There was no evidence that
interruption immediately increases risk of CVD, but longer-term consequences cannot
be excluded. On balance, lipid changes
were unfavorable after interruption in DC patients, and the extent of this
differed according to baseline ART regimen.
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