There is only a weak
association between immune suppression and risk of heart attack and coronary
heart disease for people with HIV, results of a large observational study
published in the online edition of AIDS
show. There was a stronger association between a low CD4 cell count and an
increased risk of stroke, but the investigators believe this was in part driven
by misclassifications and other biases.
disease is an increasingly important cause of serious illness and death in people with HIV. This is likely to be due to a number of factors, including
the ageing of the HIV-infected population, lifestyle factors, the side-effects
of some antiretroviral drugs and the inflammatory effects of untreated HIV
the association between low CD4 cell count and the risk of cardiovascular
disease have yielded conflicting results. Investigators from the large D:A:D
study therefore designed a prospective observational study (involving 33,301
participants) to clarify this important question.
Data were gathered
on the incidence of heart attack, coronary heart disease (CHD), stroke and
cardiovascular disease overall. The investigators examined the association
between immune suppression – both a nadir and current CD4 cell count below 200 cells/mm3 –
and these outcomes.
contributed over 223,000 person-years of follow-up. There were 717 heart
attacks (incidence, 3.2 per 1000 person-years), 1056 CHD events (incidence,
4.8 per 1000 person-years), 303 confirmed strokes (incidence, 1.4 per 1000
person-years) and 1284 cardiovascular disease events overall (incidence, 5.8
per 1000 person-years).
All outcomes were
less frequent among people who had never experienced immune suppression.
The first set of
analyses showed that a low CD4 cell count was associated with a higher risk of
all endpoints. However, after controlling for potential confounders, the
association between immune suppression and an increased risk of heart attack
and CHD ceased to be significant. But individuals with a current CD4 cell count
below 100 cells/mm3 had double the risk of stroke compared to people without immune suppression (RR = 2.02; 95% CI, 1.20-3.38).
There were only
modest and largely insignificant associations between longer duration of immune
suppression and risk of cardiovascular events.
analysis to participants taking antiretroviral therapy showed similarly weak
associations between cardiovascular diseases outcomes and immune suppression.
illnesses (such as cytomegalovirus, or CMV) can involve symptoms similar to those of stroke. The
authors were therefore concerned that some cases of stroke had been
misclassified, and that this could have implications for their finding
that a low current CD4 cell count increased the risk of stroke.
Closer analysis of
stroke cases confirmed their suspicions.
They placed stroke
incidents into three categories: confirmed strokes only; confirmed strokes and
stroke-like events; and confirmed strokes, stroke-like events and non-stroke
The strongest risk
factors associated with confirmed cases of stroke were traditional factors such
as hypertension, smoking, older age and a history of cardiovascular disease.
Each doubling of CD4 cell count also reduced the risk of confirmed stroke by
approximately 19% (RR = 0.81; 95% CI, 0.74-0.89, p =0.0001). The association between
traditional risk factors and stroke weakened when the investigators expanded
their analysis to include stroke and stroke-like events and also stroke,
stroke-like events and non-stroke events. As the diagnosis of stroke became
less certain, the association with a low CD4 cell count strengthened.
“A proportion of
strokes that occur in individuals with low CD4 cell counts may be caused by
HIV-associated CNS disorders and not by traditional atherosclerotic patho-physiological
processes,” explain the authors. “Such misclassifications will most likely
occur at low CD4 counts (when these other disorders are most prevalent).”
They conclude: “We
do not find strong evidence that individuals with a low CD4 count are more
likely to experienced a new [heart attack] or CHD event. Although stroke
appears to occur more commonly in those with low CD4 counts, some of this
association may be explained by misclassification of events.”