2009 January 

Reduced inflammation linked to survival

Doctors can easily assess potential cardiovascular risk factors—such as cholesterol levels, blood pressure, age, gender, weight and smoking—to develop an idea of a person’s long-term risk for cardiovascular disease (CVD). However, these risk factors are not very useful when trying to predict events, such as heart attack or stroke, over the short term.
As a result, researchers have been trying to find easy-to-assess proteins in the blood of people that might be more useful at predicting short-term cardiovascular events. A few proteins that might fulfill such a role are described below:

  • CRP (C-reactive protein). This is produced in the liver in response to inflammation. Large studies suggest that increasing CRP levels occur before major CVD events. The test that assesses CRP is called hsCRP (high-sensitivity CRP). CRP rises in people with infections such as HIV.
  • Serum amyloid A. Also produced by the liver in response to inflammation. Elevated blood levels of serum amyloid A may signal an increased risk for uncontrolled blood clotting.
  • D-dimer. Higher-than-normal levels of these proteins suggest an increase in the formation of blood clots.
  • IL-6 (interleukin-6). This is a chemical signal produced by the immune system. High levels of IL-6 have been linked to infection, inflammation and stress. IL-6 can trigger the release of CRP and proteins that help blood to clot.
  • Prothrombin fragment 1+2. These help increase the ability of blood to form clots.

The treatment interruption group in the SMART study, discussed earlier in this issue of TreatmentUpdate, developed a higher-than-expected incidence of heart attacks, stroke and deaths. A Euro-American team of researchers was interested in the investigation of inflammation and its potential role in these cardiovascular events.The team analysed blood samples from the SMART study. Their findings suggest that participants who interrupted therapy had significantly elevated levels of inflammatory markers in their blood compared to people who did not interrupt therapy. This result is consistent with the theory that the immune system activation caused by HIV may play a role in the increased CVD risk seen in some people. The implications of this are discussed in our report below.

Study details

Technicians tested blood samples collected at different points during the SMART study. They particularly sought out the samples collected from 74 people who died before January 11, 2006, and compared them to samples from SMART participants who did not die. Blood samples from people who died as a result of accidents, violence or suicide were not assessed, as researchers felt that these samples would interfere with their analysis.

Technicians matched each blood sample from a person who died in the study with samples from at least two people who did not die. These other samples acted as a comparison, or control. The control samples were selected from people of similar age and gender to those who died.


In general, the following factors were linked to an increased risk of death:

  • older age
  • smoking tobacco
  • prior diagnosis of CVD
  • co-infection with hepatitis B or C virus

Results—focus on inflammation

The researchers found that levels of IL-6 and D-dimer and, to a lesser extent, hsCRP, were significantly increased in people who died compared to controls. On average, having high levels of these proteins increased the risk of death in SMART by a factor of six.

Key findings

  1. In this sub-study of SMART, participants who entered the study with high levels of IL-6 or D-dimer were at high risk of subsequent death.
  2. Elevated levels of these proteins were more common in people who underwent treatment interruption than in people who took HAART continuously.
  3. Increased levels of IL-6 and D-dimer were linked to rising viral load.

These findings suggest that uncontrolled HIV replication activates inflammation and clotting systems in the body. In turn, these reactions reduce a person’s overall health, even in people with relatively well-preserved CD4+ cell counts. Interrupting HAART may increase levels of IL-6 and D-dimer, which could result in death for some people.

Further research on these markers of inflammation and clotting in people with HIV/AIDS is needed, as the number of people studied for this in SMART was relatively small.

Should inflammatory markers be routinely assessed?

Researchers are only just beginning to understand inflammation and its relationship to serious events (such as heart attacks) in viral infections and chronic diseases.

Studies of inflammatory markers have been suggestive of disease in large groups containing hundreds or thousands of HIV negative people. But the SMART team does not encourage the routine use of such markers in individual HIV positive people, because the relationship between these markers and individual health is not yet clear (Jens Lundgren MD, personal communication).

The SMART team prefers that studies be done to confirm its findings in people with HIV/AIDS and to better understand precisely why inflammation in viral infections is sometimes linked to heart attacks and death.

There will also be a need for studies to test the effect of anti-inflammatory compounds in HIV infection to find out if these can reduce the risk of heart attacks and death.

This study is not the final word on SMART, as more analyses are in the works. But what all the analyses of SMART and at least one other treatment interruption study have found is that HIV probably plays a role in speeding up CVD and that treatment interruptions carry new and previously unrecognized dangers.


  1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine. 2005 Apr 21;352(16):1685-95.
  2. Ware JH. The limitations of risk factors as prognostic tools. New England Journal of Medicine. 2006 Dec 21;355(25):2615-7.
  3. Righini M, Perrier A, De Moerloose P, et al. D-dimer for venous thromboembolism diagnosis: 20 years later. Journal of Thrombosis and Haemostasis. 2008 Jul;6(7):1059-71.
  4. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers and the risk of incident hypertension. New England Journal of Medicine. 2006 Dec 21;355(25):2631-9.
  5. Vidula H, Tian L, Liu K, et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Annals of Internal Medicine. 2008 Jan 15;148(2):85-93.
  6. Smith A, Patterson C, Yarnell J, et al. Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study. Circulation. 2005 Nov 15;112(20):3080-7.
  7. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Medicine. 2008 Oct 21;5(10):e203.