Even with antiretroviral treatment, patients with HIV still have markers indicating increased risk of heart disease and kidney problems

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Key biomarkers associated with an increased risk of serious illnesses such as heart disease and kidney dysfunction are elevated in patients with HIV, even when they are taking HIV treatment, a study published in the June 15th edition of the Journal of Infectious Diseases shows.

Investigators compared levels of C-reactive protein, interleukin 6 (IL-6), D-dimer and cystatin C between US HIV-positive patients in the SMART treatment-interruption study and patients in two large US studies involving the general population.

Even after taking into account the use of antiretroviral therapy and suppression of viral load, the researchers found that levels of these biomarkers, which are indicators of inflammation, coagulation and renal function, were higher in people with HIV.

Glossary

biomarker

Genes, proteins or chemicals that can act as signals for certain diseases.

reactive

Because of the possibility that a positive result from a single HIV test is, in fact, a false positive, the result is described as 'reactive' rather than 'positive'. If the result is reactive, this indicates that the test has reacted to something in the blood and needs to be investigated with follow-up tests.

protein

A substance which forms the structure of most cells and enzymes.

inflammation

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.

D-dimer

D-dimer is one of the protein fragments produced when a blood clot gets dissolved in the body. In case of inflammation (for example, due to HIV) its level in the blood can significantly rise, as inflammation initiates clotting and decreases the activity of natural anticoagulant mechanisms.

Evidence is accumulating that patients with HIV have an increased risk of serious non-AIDS-defining conditions such as cardiovascular disease, kidney dysfunction, liver disease and some cancers. The reasons for this are uncertain, but it has been suggested that infection with HIV causes ongoing inflammation, coagulation and other disturbances.

To test this hypothesis, investigators compared levels of four key biomarkers recorded in 781 HIV-positive patients in the US who participated in the SMART treatment-interruption study to those observed in the large US Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) studies.

The studies involved several thousand patients, and although individuals were not tested for HIV, prevalence of the infection was thought to be very low.

There were significant differences between the patients in the SMART study and those in the MESA and CARDIA studies.

Those with HIV were more likely to smoke, and to take medication to lower their cholesterol or blood pressure. Patients with HIV also had higher cholesterol and a lower body mass index.

Individuals in the SMART study were stratified according to their age (33 to 44 years; and 45 to 76 years). A majority of both younger (51%) and older (62%) patients had a viral load below 400 copies/ml.

The investigators’ first analysis showed that, compared to patients in the CARDIA study, levels of C-reactive protein were 42% higher in patients with HIV, and that IL-6 levels were increased by 59% in those with HIV.

Moreover, levels of C-reactive protein (p = 0.003), IL-6 (p < 0.001), D-dimer (p < 0.001), and cystatin C (p < 0.001) were all significantly higher amongst patients in the SMART study than those in the MESA study.

The investigators then considered the effect of antiretroviral therapy and viral load on these biomarkers.

D-dimer levels were higher in patients who were not taking HIV treatment. This was the case for both younger (62% higher, p < 0.001), and older (63% higher, p < 0.001).

However, regardless of the use of antiretroviral therapy, D-dimer levels were higher for both younger and older HIV-positive patients than individuals in the MESA study.

The investigators then restricted their analysis to patients with a viral load below 400 copies/ml and found that all four biomarkers were higher in both younger (p < 0.001) and older (p < 0.001) patients in the SMART study than those in the other studies.

The type of antiretroviral therapy also appeared to influence biomarker levels.

C-reactive protein levels were higher in patients who took an NNRTI than those who received a protease inhibitor (p < 0.001). Patients who were treated with the NRTI abacavir had higher levels of this biomarker than patients who took other drugs from this class (p = 0.05), and IL-6 levels were also elevated in patients taking abacavir (p = 0.03).

The association between HIV infection and increased levels of biomarkers remained when the investigators took into account potentially confounding factors such as smoking and co-infection with hepatitis C.

“In summary”, write the investigators, “we found that markers of inflammation, coagulation, and renal function were elevated in HIV-infected study participants receiving or not receiving antiretroviral therapy, compared with patients in two large population-based studies. Additional research on the reasons for these elevations and the interventions required to lower them is needed.”

The authors of an editorial that accompanied the study noted that the investigators’ research was “carefully performed”, and that “statistical adjustment for covariates failed to attenuate the relationship between the inflammatory biomarkers and HIV infection.”

Ongoing immune activation and inflammation are suggested as the reasons for these findings, and the authors of the editorial state that it is of critical importance to identify the mechanisms underlying this and to find strategies to prevent it occurring.

References

Neuhaus J et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 201, advance online publication, 2010.

Dube MP et al. Inflammation and complications of HIV disease. J Infect Dis 201, advance online publication, 2010.