HIV / AIDS

Low Level HIV Viral Load May Not Increase Inflammation or Risk of Death

People who maintain very low-level detectable HIV RNA while on antiretroviral therapy (ART) did not have elevated levels of the inflammation or coagulation biomarkers and did not have a increased risk of death, according to study findings published in the November 2, 2011, online edition of PLoS ONE.

A growing body of evidence suggests that inflammation related to chronic HIV infection may contribute to non-AIDS-related conditions such as cardiovascular disease and neurocognitive impairment. A number of studies -- including the large SMART treatment interruption trial -- have found links between ART use, HIV levels, inflammation biomarkers, and risk of AIDS-related illness and death, but the underlying mechanisms are not well understood.

Abigail Eastburn and Phyllis Tien from the University of California at San Francisco and colleagues tested the hypothesis that low-level HIV viremia (detectable HIV RNA in the blood) is associated with inflammation, increased coagulation (blood clotting), and all-cause mortality.

The development of increasingly sensitive tests has enabled measurement of HIV RNA below previous "undetectable" thresholds of 400, 200, and 50 cells/mm³; this analysis used an ultrasensitive test with a limit of detection of 20 copies/mL.

The analysis included 1116 HIV positive participants from the FRAM (Study of Fat Redistribution and Metabolic Change in HIV Infection). HIV RNA levels were categorized as undetectable, 1-19, 20-399, 400-9999, or > 10,000 copies/mL.

The researchers looked at associations between HIV RNA levels and levels of the acute inflammation marker C-reactive protein (CRP), the coagulation marker fibrinogen, and the pro-inflammatory cytokine interleukin 6 (IL-6), as well as their correlations with mortality.

Results

• HIV RNA levels had little association with CRP levels.
• People with HIV RNA < 10,000 copies/mL, however, had IL-6 levels similar to those of people with undetectable viral load.
• Participants with HIV RNA > 10,000 copies/mL, however, had 89% higher IL-6 (an association that was reduced after adjusting for CD4 cell count).
• Higher HIV RNA levels were associated with rising fibrinogen levels (0.6%, 1.9%, 4.5%, 4.6%, and 9.4%, respectively, for the successive viral load categories), reaching statistical significance at the highest level.
• In an unadjusted analysis, mortality progressively increased with higher viral load, but this was reduced after adjusting for CD4 count, and no longer the case after adjusting for inflammation and other cardiovascular risk factors.

Based on these findings, the study authors concluded, "HIV RNA > 10,000 copies/mL was associated with higher IL-6 and fibrinogen, but lower levels of viremia appeared similar, and there was little association with CRP."

"The relationship of HIV RNA with IL-6 was strongly affected by CD4 cell depletion," they continued. "After adjustment for CD4 cell count and inflammation, viremia did not appear to be substantially associated with mortality risk over 5 years."

"Our finding that there was little association of any level of HIV RNA with CRP raises the possibility that CRP may not be a reliable marker of inflammation that is caused by ongoing HIV replication or persistence," they elaborated in their discussion. "However, HIV RNA levels > 10,000 copies/ml were strongly associated with fibrinogen and IL-6."

"Our findings suggest that the mechanisms by which HIV infection induces inflammation, influences coagulation, and causes mortality are complex," they summarized. "Additional study of mechanistic pathways including markers of microbial translocation is needed."

Investigator affiliations: University of California San Francisco, San Francisco, CA; Department of Veterans Affairs Medical Center, San Francisco, CA; Stanford University, Stanford, CA; University of California San Diego, San Diego, CA; University of Vermont, Burlington, VT; Roche Molecular Diagnostics, Pleasanton, CA.

11/22/11

Reference

A Eastburn, R Scherzer, AR Zolopa, et al. Associationof Low Level Viremia with Inflammation and Mortality in HIV-Infected Adults. PLoS ONE 6(11):e26320 (abstract). November 2, 2011 (Epub).