HIV viral load linked to inflammatory markers on and off therapy

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Levels of inflammatory, anti-inflammatory and endothelial activation markers of cardiovascular disease are associated with HIV replication, say researchers with the Swiss-Thai-Australian Treatment Interruption Trial (STACCATO) study group. These data, reported in the May 15th issue of AIDS, support the growing links between endothelial dysfunction, cardiovascular disease and HIV disease and treatment, and might help not only explain current discrepancies in trial results, but also provide insight into future treatment options.

The link between cardiovascular disease, HIV and HIV treatment is paradoxical. The D:A:D study group has revealed that long-term use of antiretroviral therapy, particularly protease inhibitors, is associated with an increased risk of heart attack. However, the SMART study found that intermittent use of antiretroviral therapy was associated with an additional 50% increase in risk of heart attack compared with continuous therapy.

While some of the effect of antiretroviral therapy on cardiovascular disease can likely be linked to the impact antiretroviral drugs have on blood lipid levels, researchers are also investigating the impact of HIV and antiretroviral drugs on endothelial inflammation, an early step in atherosclerosis. In 2008, SMART study investigators reported increases in several markers of endothelial inflammation, particularly D-dimer and IL-6 (interleukin-6). In the current report, researchers with the STACCATO trial, which compared continuous antiretroviral therapy with structured treatment interruptions, continue the investigation into this possible mechanistic link.



Relating to the heart and blood vessels.


The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

cardiovascular disease

Disease of the heart or blood vessels, such as heart attack (myocardial infarction) and stroke.

treatment interruption

Taking a planned break from HIV treatment, sometimes known as a ‘drugs holiday’. As this has been shown to lead to worse outcomes, treatment interruptions are not recommended. 


A type of cytokine.

Calmy and colleagues completed a post-hoc analysis on a subset of the STACATTO study data. The 145 participants in the substudy were from the Thailand site and 90 (62%) were women. All were treatment-naive and were relatively healthy, with a median baseline CD4 cell count of 271 cells/mm3, few signs of HIV disease, but a high median viral load of 46,000 copies/ml. Half of participants had a low level of cardiovascular risk based on the Framingham equation, while the risk was unknown for 45% of the group.

In the STACATTO trial, all participants were started on a protease-based regimen for at least six months to achieve an undetectable viral load and a CD4 count about 350 cells/mm3. Participants were then randomised to continuous therapy or interrupted therapy. In the subanalysis, investigators analysed frozen blood samples taken at different times during the trial. The samples were tested for twelve soluble markers associated with cardiovascular disease risk and compared to viral load measures from the same samples.

Investigators first looked at the effect of starting antiretroviral therapy. They noted improvements in several markers of cardiovascular disease risk. In looking at samples before therapy started and after achieving viral suppression, they observed significant decreases in two markers of vascular inflammation, s-VCAM-1 (soluble vascular cell adhesion molecule-1) and P-selectin, and one marker of systemic inflammation, CCL2 (chemokine ligand 2). They also noted significant increases in anti-inflammatory markers IL-10 (interleukin-10) and adiponectin.

Investigators then looked at changes in these markers twelve weeks after randomisation into either the continuous treatment group or the interruption group. In the treatment interruption arm, they observed that levels of inflammatory markers s-VCAM-1, CCL2 and P-selectin rose significantly from the time from first stopping therapy to study end.

Using results from both arms, investigators compared viral load to soluble marker level after randomisation. Increasing viral load was positively correlated with increasing levels of inflammatory markers s-VCAM-1 and CCL2 (adjusted Pearson correlation coefficient, r = 0.27 [p = 0.001] and 0.24 [p = 0.005], respectively). Increases in viral load were also associated with decreases in both IL-10 and adiponectin (adjusted odds ratio, 0.64 p = 0.03) adjusted r = -0.25 (P = 0.002). These associations remained, the investigators noted, even after taking into account the effect of other known cardiovascular disease risk factors.

The investigators noted that all marker values recorded in the study were within normal ranges found within HIV-positive and HIV-negative people, except for s-VCAM-1, which was as high as levels seen in people with type 2 diabetes or end-stage renal failure.

In discussing their results within the context of other studies, the investigators write: “Our work points to possible molecular mechanisms of the proatherosclerotic effect of HIV-RNA in the cascade leading to a cardiovascular event”. They propose that HIV may directly induce monocyte, endothelial and adipocyte activation. These cells can increase endothelial inflammation by increasing inflammatory signals like CCL2 and decreasing anti-inflammatory signals such as adiponectin and IL-10. Damaged endothelial cells release s-VCAM-1, which is a marker of endothelial inflammation.

The investigators urge that medical interventions should be explored for people with HIV with high blood levels of inflammatory markers and ongoing HIV replication and point to data showing a reduction in heart attacks among HIV-negative people who used the lipid-lowering drug rosuvastatin.


Calmy A et al. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS 23:929–939, 2009.