Risk of Non-AIDS Death in HIV/HCV-Coinfected People in SMART

Risk of Non-AIDS Death in HIV/HCV-Coinfected People in SMART

17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

- The SMART investigators proposed that, among people coinfected with HIV and a hepatitis virus, "those with impaired liver function are particularly in a pro-inflammatory state associated with excess risk of death from causes other than AIDS--and interruption of ART further exacerbates this pro-inflammatory state."


High levels of the liver fibrosis marker hyaluronic acid--coupled above-median readings of high-sensitivity C-reactive protein (hsCRP), IL-6, or D-dimer--raised the risk of non-AIDS death in HIV/(HCV/HBV)-coinfected SMART trial participants 4 to 6 times compared with people whose levels of these markers lay below the medians [1].

The role of inflammation markers (like IL-6 and hsCRP) and coagulation markers (like D-dimer) in the prognosis of HIV-infected people gained attention and credence when SMART researchers demonstrated that higher concentrations of these three markers upon entering SMART (a trial of continuous versus intermittent antiretroviral therapy) independently predicted a higher risk of death from any cause [2]. In this new analysis, SMART investigators probed for predictors of non-AIDS death by evaluating these markers and hyaluronic acid in SMART participants coinfected with HIV and HCV or HBV. They hypothesized that coinfected people with liver impairment signaled by high hyaluronic acid would also have high levels of the other markers and that the ability of biomarkers to predict non-AIDS death would depend on hyaluronic acid concentrations at study entry.

Among 5472 SMART enrollees, 655 (12%) had HCV or HBV infection, hyaluronic acid measured at entry, and samples available for other marker measurements. Most coinfected people had only HCV (82%), while 16% had only HBV and 2% carried both hepatitis viruses. Women accounted for 25% of the study group, which had a median age of 46 years (interquartile range [IQR] 40 to 50), a median CD4 count of 582 (IQR 461 to 737), and a median hyaluronic acid level of 30 ng/mL (IQR 17.5 to 57). But 122 people (18.6%) had hyaluronic acid concentrations above the upper normal range (75 ng/mL). Two thirds of this study group had an HIV load below 400 copies when the study began.

Fifty people died of non-AIDS causes through 6 months of follow-up, 30 in the intermittent-therapy arm and 20 in the continuous arm. There were 7 deaths from infection (14%), 6 from non-AIDS cancers (12%), 6 from substance abuse (12%), 4 from liver complications (8%), 4 form cardiovascular disease (8%), 4 from kidney disease (8%), 4 from violent death including suicide (8%), 1 each (2%) from chronic obstructive pulmonary disease and central nervous system disease, and 13 from unknown causes (26%).

Initial levels of IL-6, hsCRP, and D-dimer were all higher in people with a hyaluronic acid quotient above 75 ng/mL, but the difference was not statistically significantly for hsCRP. People randomized to intermittent antiretroviral therapy gained significantly more D-dimer, but not IL-6 or hsCRP, during follow-up. People in the intermittent arm with elevated baseline hyaluronic acid had a 47% increase in IL-6 through 6 months, while IL-6 dwindled 0.7% in intermittent-arm patients with normal hyaluronic acid.

SMART investigators divided people into four equal groups (quartiles) based on median baseline hyaluronic acid and marker levels. Subgroups with hyaluronic acid and hsCRP, IL-6, or D-dimer above the median at study entry accounted for 52%, 62%, and 48% of non-AIDS deaths. People with hyaluronic acid and each of the other markers below the medians accounted for only 8% of non-AIDS deaths.

To predict risk of non-AIDS death by marker combinations, the SMART team fashioned a model that considered SMART randomization, age, gender, race, prior AIDS, baseline CD4 count and viral load, nadir (lowest-ever) CD4 count, baseline antiretroviral status, alcohol abuse, and HBV status. Compared with paired hyaluronic acid-other biomarker levels below median values, paired levels above the medians independently raised the risk of non-AIDS death:

· High hyaluronic acid/hsCRP: hazard ratio [HR] 6.1, 95% confidence interval [CI] 2.1 to 17.7, P = 0.001

· High hyaluronic acid/IL-6: HR 5.9, 95% CI 2.0 to 17.3, P = 0.001

· High hyaluronic acid/D-dimer: HR 4.4, 95% CI 1.5 to 13.3, P = 0.008

The SMART investigators proposed that, among people coinfected with HIV and a hepatitis virus, "those with impaired liver function are particularly in a pro-inflammatory state associated with excess risk of death from causes other than AIDS--and interruption of ART further exacerbates this pro-inflammatory state."

References
1. Peters L for the INSIGHT SMART Study Group. Biomarkers of inflammation and coagulation and risk of non-AIDS death in HIV/hepatitis co-infected patients in the SMART study. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 660. http://www.retroconference.org/2010/PDFs/660.pdf.
2. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050203.