Only a weak association between immune suppression and increased cardiovascular disease risk for people with HIV

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.

Cardiovascular 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 infection.

Studies examining 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.

The participants 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.

Restricting analysis to participants taking antiretroviral therapy showed similarly weak associations between cardiovascular diseases outcomes and immune suppression.

Some AIDS-defining 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 events.

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.”