31 / 67
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 2, March/April 2015
AFRICA
77
It has been hypothesised that atherosclerotic disease in
HIV-infected patients is divided into two distinct phases.
69
The
first includes vessel wall inflammation (Fig. 7A, B), which
cascades towards classic atheromatous features. The second
includes progression of these morphological changes that are
sustained by classic atheromatous risk factors.
The relationship between atherosclerosis and HAART
In the current era of effective HAART, cardiovascular risk has
emerged as a significant marker of morbidity and mortality
among surviving HIV-positive patients. It is questionable
whether HIV itself confers a significant cardiovascular risk, as
some studies show conflicting results.
68
Surrogate markers such
as carotid intimo-medial thickness and endothelial dysfunction
implicate HIV as an independent variable for cardiovascular
risk. The potential mechanisms for coronary artery disease
in HIV-infected patients arise from viral proteins that attract
monocytes to the vessel wall, activation of which stimulates
inflammation and retardation of cholesterol efflux.
68
HAART acts through enzymatic inhibition of HIV. The
currently available agents used to treat HIV-infected patients are
classified into protease inhibitors, nucleoside and non-nucleoside
analogues.
64
The protease inhibitors cause metabolic complica-
tions, including hyperlipidaemia, central fat accumulation and
insulin resistance, while the nucleoside inhibitors cause lipo-atro-
phy and mitochondrial damage. Non-nucleoside analogues cause
lipid elevations. These complications are associated with a 26%
risk of myocardial infarction per year on combination therapy.
66
Newer agents without the risk of lipid elevation, are presently
being studied. It remains to be seen whether this translates into
cardiovascular risk reduction.
It is debatable, however, whether HAART contributes to
endothelial injury. Studies supportive of the concept propose a
triad composed of the virus, immune reconstitution and HAART,
which initiates premature endothelial activation. This collaborative
influence, which may affect the structural composition of arterial
lesions in HIV patients, is borne out by variation in structural
atheromatous changes as opposed to classical atheroma. This
includes the presence of vessel wall inflammation, ultrasonographic
variations and impaired flow-mediated dilatation.
68
The latter
reflects an inverse relation between the viral load and endothelium-
mediated vasodilation in association with some HAART agents.
This produces altered ankle–brachial indices (ABIs) that are
regulated by the magnitude of dyslipidaemia.
The spectrum of atherogenic exposure spans short-term
exposure reflected in acute impairment of brachial artery flow-
mediated dilatation, and long-term intimo-medial thickness in the
carotid vasculature.
67,71
These features are reflective of a metabolic
atheromatous process that is governed by the HIV load.
69
The availability of HAART has dampened the effect of
opportunistic infections and promoted longevity in HIV-infected
patients. As a result, HIV-infected patients have become
increasingly prone to cardiovascular manifestations, particularly
premature atherosclerosis, which is not associated with the
conventional predisposing risk factors that are emphasised in
HIV-naïve patients.
64,65
HIV vasculopathy usually presents in the
advanced stages of the disease.
65,72
Robust data on the cardiovascular implications of viral
infection is largely unknown, as most research has focused
on Caucasians infected with the HIV-B sub-type virus. The
Hypertension in Africa Research Team
73
conducted a prospective
epidemiological study in 300 urban and rural patients and control
subjects. In this study, the preliminary findings in untreated
subjects demonstrated endothelial injury following viral invasion
that resulted in endothelial inflammation and dysfunction, with
elevated molecular markers and accelerated atherosclerosis that
was exacerbated by low levels of HDL cholesterol. In the older
patients there was evidence of rapid vascular aging, suggestive
of diminishing vascular function as determined by pulse-wave
velocity studies.
The treatment group on HAART demonstrated elevated
systolic blood pressure without established systemic hypertension
and stabilised lipid profiles with lipodystrophic changes. Soluble
urokinase plasminogen activator, a soluble protein biomarker
of progressive inflammation in HIV-1 infected patients, is a key
mediator between inflammatory and metabolic derangements.
The levels were significantly elevated in treated, compared to
untreated and control African patients, signifying a correlation
with lipodystrophic changes following HAART over the three-
year follow-up study. The study results seem to suggest a
deteriorating profile irrespective of HAART in the South
African black population. Therefore greater insight into the
adverse cardiovascular influence on the South African HIV
population is necessary.
73,74
Coronary artery calcium scoring, a non-invasive surrogate
marker of atherosclerosis, serves as a predictor of myocardial
infarction and coronary mortality. Studies in this sphere in
HIV-infected patients are lacking. One reported study
demonstrated a 6–8% incidence of coronary calcification.
Although HIV patients on HAART had higher calcium scores,
these levels were, in effect, lower than those in untreated patients.
67
A clinical manifestation of premature atherosclerosis
is peripheral vascular disease (PVD). This is an emerging
HIV-associated disorder with an unknown prevalence that has
assumed prominence following the widespread availability of
HAART. In a Swiss pilot study of 92 HIV-infected patients,
Periard
et al.
75
detected a 20% (
n
=
19) incidence of subclinical
atherosclerosis. Although these patients had normal resting
ABIs, the exercise ankle systolic pressure (ASP) and ABI were
deranged. The possible mechanisms underlying PVD relates
to lifestyle-induced cardiovascular risk factors, combinations
of antiretroviral therapeutic agents and HIV
per se
causing
inflammatory lesions.
Management
The medical management of HIV-associated vasculopathy
includes HAART, control of hyperlipidaemia and eradication of
traditional risk factors.
•
The International AIDS society of USA recommends the
use of HAART in asymptomatic individuals with CD4 cell
counts
<
350 cells/mm
3
. Other indications include a high viral
load of
>
100 000 copies/ml, active hepatitis B or C infections,
and evidence of HIV nephropathy.
67,76
The main objective of
the initial choice of regime relates to viral suppression but
adverse effects of the drug profiles should be considered in
patients at high cardiovascular risk.
•
Current recommendations, including lifestyle modifications
such as dietary and exercise interventions, have demon-