CRP Predicts Cardiovascular Events in Patients With HIV Receiving ART

Becky McCall

November 17, 2009

November 17, 2009 (Cologne, Germany) — C-reactive protein (CRP) has been clearly shown to be an independent predictive biomarker associated with cardiovascular (CV) events in patients with HIV who are receiving antiretroviral therapy (ART).

Presenting results here at the 12th European AIDS Conference/European AIDS Clinical Society, Andrea De Luca, MD, from the Catholic University, Rome, Italy, demonstrated that in HIV-positive patients, high-sensitivity CRP results predict CV disease (CVD) risk independently from other established CV risk factors. "The risk was found to increase by almost 20-fold in the group with [CRP levels of] more than 3 mg/L vs those with 1 mg/L or less, and for each log10 higher, the risk is increased by 14-fold," he said.

To date, experience with CVD biomarkers has been shown to relate to inflammation, platelet function, coagulation, or formation of thromboses in the HIV-negative setting. "These biomarkers have previously been shown to play an independent role to traditional CVD risk factors, but until now there has been no specific study to investigate whether these biomarkers play a relevant and independent role in HIV-positive patients," noted Dr. De Luca.

In general, HIV-infected patients are at higher risk for CV events, which in these patients occur earlier in life compared with in HIV-negative patients. HIV infection per se may also lead to inflammation in the blood vessel endothelium, and ART therapies such as some protease inhibitors or nucleoside analogues may also affect outcomes.

The investigation led by Dr. De Luca was case controlled with cases of myocardial infarction and revascularization taken from the Catholic University and the Italian Cohort of Antiretroviral Naive Patients Foundation Study Group cohort. These cohorts had stored and available blood samples that were matched with 2 control patients for diabetes and smoking status. Six biomarkers were assessed: highly sensitive CRP, interleukin 6, tissue plasminogen activator, plasminogen activator inhibitor 1, d-dimer, and p-selectin. All these markers are involved with thrombosis events.

Importantly, the study was powered to detect a significant difference in CRP, which constituted the primary study endpoint. Secondary endpoints were differences in the other biomarkers.

There were 31 patients with CV events and 64 control patients, who were homogeneous except for level of exposure to ART. It was required that control patients had received at least 5 years of ART without any events. Results were adjusted for this. Patients with CV events were found to have significantly higher levels of CRP compared with control patients and significantly higher levels of p-selectin compared with control patients.

Levels of biomarkers were stratified by quartiles, which allowed for a multivariable analysis. "In the univariate analysis, we found that the highest quartile of the CRP biomarker, interleukin 6, and p-selectin were related to a higher probability of CV events, but in the multivariable analysis, in which we adjusted for traditional CV risk factors such as exposure to ART, HIV viral load, and CD4 count, as well as calendar year of sampling, the only significant factor independently associated with the events was CRP," explained Dr. De Luca.

Other factors that remained independently associated with events were calendar year (for which the more recent the year of sample, the lower event risk found), total cholesterol and high-density lipoproteins, and current use of abacavir. "Abacavir was also borderline associated with a higher risk of events. This was an incidental finding," Dr. De Luca added. "The study, though, was not designed to detect associations between specific drug use and CV events," he continued.

"Clearly we now show a marker which is an independent predictor of CV events in HIV-infected patients. It is very cheap, and we can use it to assess risk together with traditional risk factors. The good thing is that we can treat CRP either using statins, which lower CRP, or anti-inflammatory drugs. If I see high CRP in patients, then I would be more tempted to assess coronary function and circulation in more detail."

Dr. De Luca concluded by saying that to demonstrate a significant independent association with other biomarkers, further large-scale studies were needed, but for CRP, these results are final.

Bill Powderly, MD, dean of the Medical School, University College, Dublin, Ireland, believes that this study contributes to a growing surge of interest in the issue that typically non-AIDs events, particularly CVD, have emerged as an important cause of morbidity and mortality in people with HIV.

"A number of studies have shown that stopping treatment is associated with an increased risk of non-AIDs events including heart disease. Other studies have also shown that higher levels of certain biomarkers such as CRP and d-dimers have been associated with that risk.

"The link may be activation of the immune system, and that partially controlled or uncontrolled HIV infection may lead to a greater degree of activation of the immune system, and this inflammation drives non-AIDs mortality. People living with HIV on ART are at much greater risk of non-AIDs events than AIDs events, and this is the predominant reason for illness or death," he concluded.

Dr. De Luca has declared that he has received lecture and consultancy fees from GlaxoSmithKline, Gilead, BMS, Tibotec, Abbott, Boehringer, and Monogram. Dr. Powderly is a member of the data safety monitoring board for a number of trials sponsored by Tibotec.

12th European AIDS Conference/European AIDS Clinical Society: Abstract 9.5. Presented November 13, 2009.

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