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Inflammation Markers Linked to Disease Progression and Death in People with HIV

Levels of several inflammatory biomarkers were associated with a higher risk of developing AIDS-defining and non-AIDS events among participants in a large clinical trial, researchers reported in the February 1, 2014 Journal of Acquired Immune Deficiency Syndromes. A related study also saw a link between inflammatory markers and mortality in a group of HIV positive adults with alcohol problems.

As effective antiretroviral therapy (ART) has dramatically lowered the risk of oportunistic illnesses and extended survival for people with HIV, a growing body of evidence indicates that persistent inflammation and excessive immune activation play a role in disease progression and non-AIDS conditions such as cardiovascular disease.

Grace McComsey from Case Western Reserve University and fellow investigators with ACTG A5202 substudy A5224s measured inflammatory biomarkers among HIV positive people starting ART for the first time. Most (85%) were men, about half were white, and the median age was 39 years. On average they had advanced immune deficiency, with a median CD4 T-cell count of 240 cells/mm³.

The parent study A5202 randomly assigned 1857 treatment-naive participants to start ART with abacavir/lamivudine (the drugs in Epzicom) or tenofovir/emtricitabine (the drugs in Truvada) plus efavirenz (Sustiva) or boosted atazanavir (Reyataz). The substudy included 244 people with available plasma samples from baseline and week 24 or 96 after treatment initiation.

The researchers measured biomarkers including high-sensitivity C-reactive protein, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), soluble receptors of TNF-alpha (sTNF-RI and sTNF-RII), soluble vascular cellular adhesion molecule 1 (sVCAM-1), and soluble intercellular adhesion molecule 1 (sICAM-1). Then then evaluated asociations between biomarker levels and time to development of AIDS-defining and non-AIDS events.

Results

• Overall, a total of 13 AIDS-defining events (9 opportunistic infections, 3 AIDS-defining cancers, 1 case of recurrent bacterial pneumonia) and 18 non-AIDS events (6 cases of diabetes, 4 cancers, 3 cardiovascular events, 5 cases of pneumonia) occurred during follow-up.
• Higher baseline levels of IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events.
• Adjusting for baseline HIV viral load did not change these results.
• After adjusting for baseline CD4 count, however, only sTNF-RI and sICAM-1 remained significantly associated with increased risk.
• Time-updated levels of IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were also significantly associated with an increased risk.
• Looking at non-AIDS events, higher baseline C-reactive protein was the only biomarker significantly associated with increased risk, while higher IL-6 showed a marginal association.
• Time-updated TNF-alpha level was significantly associated with increased risk, even after adjusting for ART use and CD4 count or viral load.

Based on these findings, the researchers concluded, "Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events."

In a related study described in the January 7, 2014, advance online edition of AIDS, Daniel Fuster from Boston University School of Medicine and colleagues analyzed levels of inflammatory biomarkers in a cohort of 400 HIV positive adults with chronic alcohol problems. About three-quarters were men, the mean age was 42 years, and half had hepatitis C virus (HCV) coinfection.

Participants were recruited during 2001-2003 and prospectively followed through 2010. Mortality data were obtained from the National Death Index. The researchers looked at baseline blood levels of IL-6, IL-10, TNF-alpha, C-reactive protein, serum amyloid A, monocyte chemotactic protein-1, and cystatin-C, categorizing them as high or low. They also develop an "inflammatory burden score", defined as the number of biomarkers in the highest quartile.

By December 2009, a total of 85 participants had died. In a multivariate analysis, high levels of IL-6 and C-reactive protein were significantly associated with increased mortality after adjusting for known risk factors such as smoking (hazard ratio 2.49 and 1.87, respectively). There was also a significant association between higher inflammatory burden score and increased mortality (hazard ratio 2.18, or more than double the risk).

Heavy alcohol use and chronic hepatitis C have been independently associated with higher levels of inflammation in the people with HIV, according to a Boston University Medical Center press release. Although the patients in this study "represent a population already at high risk of mortality from many problems," most deaths were due to either HIV or hepatitis C.

"Current antiretroviral drug regimens may be able to improve mortality in most patients, but are unable to decrease the potentially dangerous burden of a chronic inflammatory state in the body," said Fuster. "Additional research should explore how to better manage chronic inflammation in these patients."

2/14/14

References

GA McComsey, D Kitch, PE Sax, et al. Associations of Inflammatory Markers With AIDS and Non-AIDS Clinical Events After Initiation of Antiretroviral Therapy: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202. Journal of Acquired Immune Deficiency Syndromes65(2):167-174. February 1, 2014.

D Fuster, DM Cheng, EK Quinn, et al. Inflammatory Cytokines and Mortality in a Cohort of HIV-Infected Adults with Alcohol Problems. AIDS. January 7, 2014 (Epub ahead of print).

Other Source

Boston University Medical Center. BUSM Study Associates Pro-inflammatory Molecules with Early Death in HIV Patients. Press release. January 17, 2014.