1. Factors associated with IL-6 levels during HIV infection Álvaro Borges, Jemma O’Connor, Andrew Phillips, Frederikke Rönsholt, Sarah Pett, Michael Vjecha, Martyn French and Jens Lundgren, for the INSIGHT SMART and ESPRIT Study Groups and the SILCAAT Scientific Committee.

2. Background IL-6 is a pro-inflammatory cytokine that regulates various pathophysiological processes. Elevated plasma IL-6 levels have been linked to cardiovascular disease, cancer and death. BMI, older age, smoking, CVD and DM associated with higher IL-6 among HIV-uninfected persons. Compared to the general population, treated HIV+ persons have higher IL-6, but few data on the factors associated with IL-6 levels currently exist. Kuller PloS Med 2008 Neuhaus JID 2010 Duprez PlosOne 2012 Borges AIDS 2013 Tanaka Cancer Immunol 2014

3. Methods Inclusion Criteria: All SMART, ESPRIT and SILCAAT participants whose plasma IL-6 levels were measured at study entry (N=9,864). Statistical analysis: Independent factors associated with IL-6 levels were identified by multivariable linear regression models Log 2 transformed IL-6 levels were used as the dependent variable. Back transformed exponentiated estimates (fold differences in IL-6 levels) with 95% CI were calculated to assess the contribution of baseline variables to the variance of IL-6 levels

4. Methods As some variables of interest were only available for one or two of the three studies, regression models were fitted to three different datasets: SMART, ESPRIT and SILCAAT (N=9,864): Demographics (age, gender, ethnicity, BMI) HIV-specific variables (nadir and baseline CD4 + cell counts, HIV RNA) ART use and ART regimens Markers of inflammation (hsCRP) and activated coagulation (D-dimer) SMART and ESPRIT (N=6,938): Co-morbidities (HBV, HCV, diabetes mellitus, cardiovascular disease) Renal function (eGFR) SMART participants (N=4,498): Smoking Education level Cholesterol levels (LDLc and HDLc)C

10. Results: Renal function, Serum lipids and IL-6 levels Higher eGFR at baseline was associated with lower IL-6 (FD [95% CI]: 0.98 [0.97-1.00] per 10 mL/min/1.73m 2, p= 0.01) There was a negative correlation between serum cholesterol levels and IL-6: Higher LDLc (0.99 [0.99-0.99]/10 mg/dL, p<.0001) and higher HDLc (0.98 [0.96-0.99]/10 mg/dL, p= 0.0003) were both associated with lower IL-6 levels

11. Conclusions Higher IL-6 levels in HIV+ persons were associated with older age and non-black race, higher BMI, lower education, ongoing HIV replication, low nadir CD4 counts, comorbidities, smoking, decreased renal function and lower serum lipids PI-based ART regimens were associated with higher IL-6 levels while nevirapine use was associated with lower IL-6 levels The enhanced inflammation seen during HIV infection is probably determined by a synergistically deleterious interaction of HIV-related and -unrelated morbidity.

12. Acknowledgements Funding: NIH [grant numbers: U01AI46957 and U01AI068641 (ESPRIT); U01AI042170 and U01AI46362 (SMART)] INSIGHT SMART and ESPRIT Study Groups and the SILCAAT Scientific Committee INSIGHT Executive Committee and INSIGHT SSC