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  Conference on Retroviruses
and Opportunistic Infections (CROI)
February 22-25, 2016, Boston MA
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Early Antiretroviral Therapy Does Not Improve
Vascular Function: A START Substudy
  Reported by Jules Levin
CROI 2016 Feb 22-24 Boston
Jason Baker, Katherine Huppler Hullsiek,
Nicole Wyman Engen & Daniel Duprez
Arterial Elasticity Substudy Team
Early ART in START Trial Does Not Improve Arterial Elasticity
Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston
Mark Mascolini
Immediate antiretroviral therapy (ART) in the START trial did not improve arterial elasticity when compared with deferred ART, according to analysis of 332 START participants through 36 months [1]. The finding is at odds with some other studies of antiretroviral impact on cardiovascular disease signals [2].
Researchers have long measured functional or structural signals of cardiovascular disease to assess the impact of HIV and ART on cardiovascular risk. In the general population,
START researchers pointed out, small artery elasticity predicts coronary heart disease, congestive heart failure, stroke, and other clinical endpoints. START randomized antiretroviral-naive people with a CD4 count above 500 to immediate ART or to defer ART until the CD4 count fell to 350 [3]. The trial ended early when data showed that immediate ART lowered the risk of a serious AIDS event, a serious non-AIDS event, or death. The cardiovascular substudy involved 178 people in the immediate ART group and 154 in the deferred group. Blinded to study arm, START investigators used blood pressure waveform analysis to estimate small and large artery elasticity.
The study group was young and relatively healthy. Median ages of the immediate and deferred groups were 33 and 34, and 30% in each group were women. In the immediate and deferred groups, a median of 1.2 and 1.3 years had passed since HIV diagnosis, median CD4 counts stood at 616 and 634, and median viral load measured 4.2 log10 (about 16,000 copies) in both groups. About 30% in both groups smoked. While 2.6% in the deferred group had prior cardiovascular disease, no one in the immediate group did. Median 10-year Framingham risk score was 1.0 in the immediate group and 1.5 in the deferred group. Two years after randomization, more than 80% in the immediate group and just over 20% in the deferred group had a viral load below 50 copies.
Small artery elasticity did not differ significantly between the immediate and deferred groups at the baseline measure (means about 7.5 and 7.0 mL/mmHg x 100). Elasticity declined slowly in both groups through 36 months but never differed significantly between the immediate and deferred groups. The researchers calculated the treatment effect on change from baseline small-artery elasticity as 0.25 units, a nonsignificant change (P = 0.19). Treatment effect did not reach significance when the START team compared immediate with deferred ART in subgroups defined by age (above or below 30), viral load (above or below 10,000 copies), or systolic blood pressure (above or below 120 mmHg). But among people with a viral load above 10,000 copies, immediate ART did tend to improve small artery elasticity (treatment effect 0.47, P = 0.05). 

Immediate ART had an even smaller impact on large artery elasticity, with an estimated treatment effect of -0.1 units (P = 0.73). Large artery elasticity remained around 16 to 17 mL/mmHg x 100 in both the immediate and deferred arms through 36 months of follow-up. 

Finally, the START team found no evidence of within-participant changes in arterial elasticity in either study group over 3 years.
The researchers cautioned that ART may promote biologically driven cardiovascular benefit or harm that is not reflected in arterial elasticity. They noted that "follow-up duration remains modest for assessing the cumulative effects from ART toxicity, and considering the time frame for development of vascular disease," especially in a young population.
In the initial START analysis, cardiovascular disease incidence was slightly but nonsignificantly lower in the immediate ART arm than in the deferred arm (0.17 versus 0.20 per 100 person-years, hazard ratio 0.84, 95% CI 0.39 to 1.81, P = 0.65) [3]. Another landmark ART strategy trial, SMART, figured that interrupting ART boosted chances of cardiovascular events more than 50% compared with taking continuous ART [4].
IAS/2015: Strategic Timing of AntiRetroviral Treatment (START) Study Primary Results....http://www.natap.org/2015/IAS/IAS_21.htm
1. Baker JV, Huppler Hullsiek K, Wyman N, et al. Early antiretroviral therapy does not improve vascular function: a START substudy. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 41.
2. Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: the ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol. 2008;52:569-576.
3. INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807. http://www.natap.org/2015/IAS/IAS_36.htm 4. Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther. 2008;13:177-187. http://www.ncbi.nlm.nih.gov/pubmed/18505169