HIV/AIDS and Cardiovascular Risk: The C-Reactive Protein Link

March 19, 2013

Elevated levels of the biomarker C-reactive protein in patients with HIV infection increased the risk of MI approximately 2-fold.

Why discuss HIV/AIDS in a series dedicated to cardiovascular (CV) risk factors? Primary care physicians do not typically manage HIV-infected individuals without consultative assistance; however, in the era of antiretroviral therapy (ART), persons with HIV/AIDS are living longer. As a result, they are at higher risk for CV disease as well as other problems commonly seen in primary care practice.

Although the HIV/AIDS cohort is plagued by traditional CV risk factors (smoking, obesity, metabolic syndrome, and diabetes, etc), underlying systemic inflammation associated with the infection per se poses additional CV risk. This physiologic constellation presents an opportunity to review biomarkers as surrogate measures of CV risk in the context of HIV and other diseases.

The conclusion of a 2007 paper that explored the combination of HIV/AIDS and CV risk factors says it all: “Acute myocardial infarction rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.”1 Since this article series has already addressed traditional CV risk factors (for example, LDL and its lowering), this article will discuss one of the nontraditional risk factors, a so-called biomarker, that reflects inflammation levels in the body and may help evaluate CV risk.

The biomarker in question is C-reactive protein (CRP). Studies have implicated an elevated CRP level as a risk factor for CV mortality2,3 and in some circles the CRP value is factored in with traditional risk factors (ie, Framingham) to ehnance risk stratification.3 Primary care physicians are accustomed to CRP measurements, and order them in the setting of inflammatory diseases comprised of infections and multiple rheumatologic disorders.4 CRP is a product of the acute immune response consequent to many triggers that provoke inflammation. More recently, CRP has been implicated as an independent risk factor for CV disease in HIV/AIDS.5 In this study, concurrence of elevated CRP and HIV infection increased the risk of acute myocardial infarction approximately 2-fold.5Early atherosclerosis in the young with HIV
Let’s look at a disturbing recent study that tries to connect the dots of persistent inflammation and a higher risk for CV disease among those with HIV/AIDS.6 HIV-infected children and adolescents were found to have double the odds of increased carotid intima thickness compared with an age-matched HIV-negative cohort. The findings persisted even after controlling for age, sex, body mass index, and smoking. The paper’s authors explained, “Antiretroviral treatment does not cure HIV and since the virus remains in the body, the immune system is constantly activated, [emphasis added] creating a chronic state of inflammation.”6 In the HIV-infected cohort, nearly all (96.7%) subjects had an undetectable viral load.6 The immune system has a role in CV disease. Despite a measurable decline in virus, inflammation persisted and increased the risk of CV disease. 

Although ART can raise LDL-C and lower HDL-C, statins can mitigate the undesirable change just as they do in people without HIV. However, residual risk from inflammation remains a problem.  
 
Another study7 demonstrated that statins retain selected pleiotropic benefits  in persons with HIV/AIDS. In patients treated with ART, statins (rosuvastatin 10 mg/daily, atorvastatin 10 mg/daily, or pravastatin 40 mg/daily), not only lowered cholesterol, but lowered levels of CRP and TNF-α as well.7 It may be that statins, in combination with other agents that further decrease inflammation, will become standard care for reducing CV risk in HIV/AIDS and other diseases characterized by inflammation.

HIV/AIDS is similar to, but at the same time different from other clinical situations associated with elevated CV risk. Traditional risk factors in HIV persons should be treated according to guidelines. However, residual risk consequent to ongoing inflammation is the next frontier in CV prevention. CRP may evolve into a specific marker for these additional risks in HIV, rheumatoid arthritis, lupus, and the general population. 
 

References
1. Triant VA, Lee H, Hadigan C, et al. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with HIV disease. J Clin Endocrinol Metab. 2007;92:2506-2512.
2. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA. 2005; 293:1737-1745.
3. Ridker P. Clinical application of C-reactive protein for cardiovascular disease prevention. Circulation. 2003;107:363-369.
4. Montgomery JE, Brown JR. Metabolic biomarkers for predicting cardiovascular disease. Vasc Health Risk Manag. 2013;3:37-45.
5. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51:268-273.
6. Sainz Costa T.  Increased subclinical atherosclerosis in HIV-infected children and adolescents – the CaroVIH study. EuroEcho 2012; Abstract 50254. Review available at: http://www.medpagetoday.com/Cardiology/Atherosclerosis/36322  
7. Calza L, Trapani F, Bartoletti M, et al. Statin therapy decreases serum levels of high sensitivity C-reactive protein and tumor necrosis factor-alpha in HIV-infected patients treated with ritonavir-boosted protease inhibitors. HIV Clin Trials. 2012;13:153-161.