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Two Inflammation Markers (hsCRP & IL-6) Predict Higher
Risk of Opportunistic Disease in SMART
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16th Conference on Retroviruses and Opportunistic Infections,
February 8-11, 2009, Montreal
Mark Mascolini
Two inflammation markers--high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) measured at study entry and during the trial--independently predicted a new opportunistic disease during the SMART treatment interruption study [1]. Not surprisingly, older age, clinical AIDS before SMART, latest CD4 count, and latest viral load also predicted a new opportunistic disease during the trial.
This case-control comparison involved 91 SMART enrollees diagnosed with a new opportunistic disease during the trial (the cases) and 273 matched SMART participants who did not have a new opportunistic disease during the study (the controls). SMART investigators measured four inflammatory markers (hsCRP, IL-6, amyloid A, and amyloid P) and two coagulation markers (D-dimer and prothrombin fragment 1+2) in samples collected at two points: at study entry and during follow-up (at the time of latest plasma sample before the opportunistic disease in cases and at a matched point in controls).
Among the 91 cases, 72 (79%) had an infectious opportunistic disease, 12 (13%) had a malignancy, and 7 (8%) had a different type of opportunistic diagnosis. Compared with SMART participants who took antiretrovirals without a break, those who interrupted treatment had almost a 4 times higher risk of an opportunistic disease (odds ratio [OR] 3.8, 95% confidence interval [CI] 2.1-.6.9, P < 0.0001). People with clinical AIDS before entering SMART had a tripled risk of a new AIDS diagnosis (OR 3.1, 95% CI 1.6-5.9, P < 0.0001). And every added 5 years of age at SMART entry almost doubled the risk (OR 1.7, 95% CI 1.0-2.9, P = 0.04).
Next the SMART team grouped cases and controls into high, medium, and low categories of entry biomarker levels. After adjustment for other risk factors, only two baseline biomarker variables predicted a higher risk of new opportunistic disease: hsCRP at or above 5 vs under 1 microgram/mL (OR 3.5, 95% CI 1.5-8.1, P = 0.003) and IL-6 at or above 3 vs under 1.5 pg/mL (OR 2.4, 95% CI 1.0 to 5.4, P = 0.02).
A median of 73 days elapsed between last plasma sampling and opportunistic disease diagnosis (interquartile range 39 to 129 days) for cases. After statistical adjustment for study entry variables, four on-treatment factors independently predicted a new opportunistic disease:
• Lower latest CD4 count (over 500 or 350-500 vs under 500, P < 0.0001)
• Higher latest viral load (over 100,000 or 500 to 100,000 vs under 500 copies, P < 0.0001)
• Latest hsCRP at or above 5 vs under 1 microgram/mL (OR 7.6, 95% CI 2.0-28.5, P = 0.002)
• Latest IL-6 at or above 3 vs under 1.5 pg/mL (OR 2.4, 95% CI 0.7-8.8, P = 0.04)
The researchers noted that reverse causality could explain these biomarker correlations; in other words, the opportunistic disease may account for raised biomarker levels. But the correlation between study entry biomarker levels and opportunistic disease diagnosis argues against reverse causality. The investigators also pointed out that previous AIDS, latest CD4 count, and latest viral load were the strongest predictors of opportunistic disease in this analysis. But they suggested that "use of biomarkers could provide additional prognostic information for predicting risk" of opportunistic disease.
The coagulation marker D-dimer proved the strongest predictor of death in SMART [2] but did not predict opportunistic disease, a finding "likely reflecting the contribution of cardiovascular disease to overall mortality."
Finally, the SMART team observed that other biomarkers not assessed in this analysis may also help predict opportunistic disease.
References
1. Rodger A, Fox Z, J Lundgren J, et al. Does activation of inflammatory and coagulation pathways independently predict the development of opportunistic disease in patients with HIV infection? 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 733.
(Poster online at http://www.retroconference.org/2009/PDFs/733.pdf.)
2. Kuller LH, Tracey R, Belloso W, et al. Activation of inflammatory and coagulation pathways is associated with mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
(Article online at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050203.)
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