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Early antiretroviral therapy has no impact on marker of early cardiovascular disease
Keith Alcorn, 2016-02-23 20:30:00
Starting treatment at a CD4 cell count above 500 does not
lead to improvement in an important early warning sign of cardiovascular
disease, and investigators are still unsure whether people who start treatment at
high CD4 counts will have the same increased risk of cardiovascular disease as
that reported in people with HIV over the past 15 years.
The findings were presented at the Conference on
Retroviruses and Opportunistic Infections (CROI 2016) in Boston on Tuesday.
studies have shown that HIV infection raises the risk of cardiovascular disease,
especially in people who have been infected for more than a decade, but it is
less clear whether or not early antiretroviral therapy reduces the risk of
cardiovascular disease. The SMART
trial of treatment interruption showed a small increase in the risk of
cardiovascular disease in people who stopped taking antiretroviral therapy and
resumed if their CD4 count fell below 250 cells/mm3, leading to a
suspicion that uncontrolled viral load might act as an inflammatory stimulus
for cardiovascular disease.
Subsequently the START trial, which compared starting
antiretroviral therapy at a CD4 cell count of 350 cells/mm3 with
starting treatment early, at a CD4 count above 500, found
no difference in the rate of cardiovascular events (stroke or heart attack)
between early and deferred treatment groups, although the overall number of
events was low.
The study findings presented today came from a sub-study of
the large international trial of immediate versus deferred antiretroviral
treatment, the START study. The sub-study looked at vascular function and in
particular the elasticity of arteries.
A substantial decline in the elasticity of major arteries
can be an important early warning sign of the development of cardiovascular
disease. The walls of arteries may be damaged by oxidative stress, by
inflammation, and in particular by smoking, creating an environment in which
further inflammation is promoted and white blood cells begin to cluster on the
artery wall, leading to the development of plaques of fatty material which
narrow the artery.
Even in the early stages of vascular dysfunction, a loss of
elasticity is detectable. Flexible arteries permit blood to be moved around the
body as the heart beats. A loss of flexibility contributes to the development
of high blood pressure and to cardiovascular disease. Changes in flexibility
are more rapidly and easily detected than other early events in cardiovascular
In order to investigate whether or not early antiretroviral
therapy has an effect on an early stage of cardiovascular disease, START
investigators carried out a sub-study in 322 START study participants randomly
selected at multiple study sites in Europe, Latin America, North America,
Africa and Asia.
The sub-study population was 70% male and 66% non-white.
Although 30% were smokers, other markers of of heart disease risk indicated a
low risk of cardiovascular events: 5%
were taking medication to reduce blood pressure and 3% were taking
lipid-lowering medication, and the 10-year Framingham risk score for
cardiovascular events was 1.2%. The average age was 35 years and study
participants had been diagnosed with HIV for a median of 1.5 years at study
entry. The median CD4 cell count was 625 cells/mm3 on entry to the study.
The investigators looked at vascular function as a measure
of cardiovascular disease, at baseline and at five subsequent follow-up visits
at months 4, 8, 12, 24 and 36 during the trial.
Elasticity in the small artery and large artery was measured
by tonometer. The study found no significant changes in arterial elasticity
over time in either the immediate or deferred treatment groups, even after
controlling for cardiovascular risk factors or duration of follow up. Nor did
they find a significant difference between the treatment groups over time. The
investigators concluded that in younger people with well-preserved immune
function early antiretroviral therapy appears not to have a substantial effect
on vascular function.
The question that still puzzles researchers is whether
cardiovascular disease associated with HIV infection is primarily driven by
immunodeficiency – in which case early treatment, by keeping CD4 cells high and
viral load suppressed, would wipe out any risk associated with having a low CD4
count, or whether immune activation is driving cardiovascular disease. If the
latter is the case, background immune activation that is not quelled by antiretroviral
therapy might still contribute to the development of cardiovascular disease.
And, if there is a beneficial effect of antiretroviral therapy in the
prevention of cardiovascular disease, how can it be detected?
“If ART is beneficial for cardiovascular disease, it’s
happening through a biological mechanism not reflected in arterial elasticity”
said Jason Baker of the University of Minnesota, presenting the results.
“We’re starting to get data back from SMART which suggest
that there isn’t an effect [of early treatment] on cardiovascular disease
[markers]” but “if we intervene early, are these patients just not going to
have the clinical complications that we’ve described over the past 15 years?” he