A standard test used as a marker for inflammation for 70 years can help identify heart attack risk in patients with HIV as well as in HIV-negative patients, a recent study in the Journal of Acquired Immunodeficiency Syndromes has found.
The study found that HIV infection and levels of C-reactive protein (CRP) are both independently associated with a raised risk of heart attack. This means that CRP levels can be used to independently quantify heart attack risk and are not just passive ‘markers’ for a risk caused by HIV itself.
The researchers found that having an elevated CRP level more than doubled the risk of heart attack while having HIV infection slightly less than doubled it. Not surprisingly, then, having both risk factors raised the risk more than fourfold compared with people who had neither raised CRP nor HIV infection.
Having a raised CRP level was not in itself associated with HIV infection, nor with smoking status, viral load, CD4 count, family history of CVD, or statin use. This is useful to know, because it means CRP levels are not surrogate markers for any of these other factors either.
Discovered in 1930, CRP is produced by cells in the liver in response to a signal from the cytokine (immune-signalling chemical) interleukin-6 (IL-6). It binds to a component of cell and bacterial membranes, and initiates a process whereby bacteria and infected cells are targeted for destruction. CRP levels rise up to 50,000-fold in any infection or injury that causes inflammation and it is used as a standard test for acute inflammation, where its upper limit of normal is defined as 5 to 6 milligrams per litre (mg/l).
A more sensitive CRP test is used to detect subtle but chronic inflammation and as one of the battery of tests that predict an individual’s risk of cardiovascular disease. A CRP level consistently above 1mg/l (i.e. not in response to an acute infection) is associated with a raised risk of a subsequent heart attack.
Researchers from two hospitals in Massachusetts wanted to determine if CRP levels could also be used as a heart-attack predictor in people with HIV. Findings from previous studies had found that inflammatory proteins, including IL-6, rise significantly in people with HIV who are not on treatment, and that this appears to be linked to a raised incidence of heart disease. A recent study found that this process appeared to start very soon after HIV infection.
Researchers sifted through the records from the Massachusetts General and Brigham and Young’s Hospitals taken between 1997 and 2007 to find patients who had had an acute myocardial infarction (AMI: a heart attack) and who had HIV infection and/or a CRP test taken more than a week and less than three years before the heart attack. They found nearly 70,000 patients with a CRP test result, 7100 with HIV, and nearly 500 with both. The average gap between CRP test and having a heart attack was 199 days in people with HIV and 176 in people without.
Patient with HIV were more likely to have raised CRP levels than HIV-negative patients: 59% compared with 39%. In univariate analysis, high CRP multiplied the risk of subsequent heart attack by 2.51 and HIV infection by 2.07.
The researchers then performed various multivariate analyses to see if these risks were surrogate markers for other heart attack risks such as age, gender, high blood pressure, diabetes, dyslipidaemia (high blood fat levels) or race. Adjusting for these factors made very little difference; in a model that adjusted for all of them, high CRP was still associated with 2.13 times the risk of a heart attack and HIV infection with 1.93 times the risk.
Patients with HIV did have other raised risks for a heart attack compared with HIV-negative patients. For instance, 57% smoked compared with 35% of HIV-negative patients. However having high CRP seemed to be remarkably independent of most other factors; for instance, there was absolutely no difference in CRP levels in the HIV-positive patients who smoked and those who did not, and very little difference in the HIV-negative patients.
The only hint that an HIV-related factor might be influencing CRP levels was that the researchers found a somewhat raised risk of high CRP levels in patients taking protease inhibitors: 67% of HIV-positive patients on protease inhibitors had high CRP levels compared with 39% not on protease inhibitors. This difference was not observed with other HIV drug classes. Although this study was too small to establish causation or association with individual drugs, it adds to the evidence that protease inhibitor use appears to be associated with a risk of heart attack that accumulates over time.
The authors comment that their findings "highlight the need for further in-depth evaluation of the prognostic value of CRP for AMI in the HIV population".