SUMMARY: Individuals with elevated baseline levels of the inflammatory biomarker CRP and the fibrosis biomarker hyaluronic acid were more likely to progress to AIDS, develop immune reconstitution inflammatory syndrome (IRIS), or die within the first month after starting antiretroviral therapy (ART), according to a poster presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco.

By Liz Highleyman

A growing body of evidence indicates that systemic inflammation and immune activation are associated with an increased risk of progression to AIDS, non-AIDS conditions such as cardiovascular disease, and death in people with HIV.

Investigators with the INSIGHT collaboration performed a case-control study to assess the relationship between 3 blood biomarkers -- C-reactive protein (CRP), pro-inflammatory cytokines, D-dimer, and hyaluronic acid -- and risk of AIDS or death occurring during the first year after ART initiation.

Significant illness and mortality can occur during the first year of ART despite good viral suppression, the researchers noted as background. This may be due to IRIS (worsening of symptoms as the recovering immune system begins to react to existing pathogens), new infections, drug-related toxicities, or non-AIDS related events. Biomarkers, they suggested, might help identify high-risk people who require closer monitoring after starting treatment.

This analysis included 189 participants in the FIRST trial, which compared 3 types of first-line ART regimens in people with advanced HIV/AIDS. Out of more than 100 participants who experienced at least a 10-fold drop in HIV RNA during the first month on therapy, the investigators identified 63 patients who experienced AIDS, IRIS, or death within the first year on ART, and selected 126 control patients who did not experience disease progression, matched for demographic characteristics, CD4 cell count, and hepatitis B and C coinfection status if possible.

The researchers compared blood levels of about 20 biomarkers at baseline and after the first month on ART. These included CRP, pro-inflammatory cytokines including tumor necrosis factors (TNF-alpha) and interferon-gamma, interleukin 6 (IL-6, a pro-inflammatory cytokine), IL-8, IL-10 (an anti-inflammatory cytokine), chemokines, the coagulation marker D-dimer, sCD14, intestinal fatty acid binding peptide (IFABP), and hyaluronic acid. Hyaluronic acid is an extracellular matrix component used as a biomarker for liver fibrosis, but it may also signal tissue damage and repair elsewhere in the body.

Results

	Participants in the case group were significantly more likely than those in the control group to have had an AIDS-defining condition before starting ART (73% vs 51%).
	During the month of follow-up, the following endpoints occurred:
	46 patients progressed to AIDS; 28 patients developed IRIS; 22 patients died.
	Looking at all endpoints combined, case patients had higher baseline levels of CRP, IL-6, IL-10, D-dimer, and hyaluronic acid.
	Patients who developed IRIS had higher baseline levels of TNF-alpha, IL-10, and D-dimer.
	After 1 month, case patients still had higher levels of several biomarkers including CRP, TNF-alpha, interferon-gamma, IL-6, IL-8, and D-dimer, than control patients.
	In a multivariate analysis controlling for confounding factors including pre-treatment levels of CRP, IL-6, IL-10, and hyaluronic acid, only CRP and hyaluronic acid remained independent risk factors for AIDS or death.
	Dividing biomarkers levels into quartiles, patients with the highest levels of both CRP and hyaluronic acid relative to those with the lowest levels had:
	More than twice the risk for AIDS or death (odds ratio [OR] 2.6); 5 times the risk of IRIS (OR 5.1).
	However, high CRP plus low hyaluronic acid, or vice versa, were not associated with increased risk of any endpoints.

Based on these finings, the investigators concluded, "Elevated levels of biomarkers associated with inflammation (CRP, IL-6), coagulation (D-dimer) and tissue fibrosis (hyaluronic acid) in ART-naive patients who have good virologic response may be useful in identifying patients at risk for AIDS or death during the first year of ART."

A related study found associations between elevated hyaluronic acid plus inflammation biomarkers and increased risk of death due to non-AIDS causes in HIV/HBV and HIV/HCV coinfected people.

University of Minnesota, Minneapolis, MN; NIAID, NIH, Bethesda, MD; SAIC-Frederick, MD; University of Western Australia, Perth, Australia; University of Illinois, Chicago, IL.

3/12/10

References
D Boulware, K Huppler Hullsiek, C Puronen, and others (INSIGHT Group). Higher Levels of D-dimer, C-reactive Protein, Hyaluronic Acid, and IL-6 before Initiation of ART Are Associated with AIDS, IRIS, or Death among ART-naive Patients with a Good Virologic Response to Initial ART. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 335).