Factors Associated With Plasma IL-6 Levels During HIV Infection

Abstract

Background: Elevated interleukin 6 (IL-6) levels have been linked to cardiovascular disease, cancer and death. Persons with human immunodeficiency virus (HIV) infection receiving treatment have higher IL-6 levels, but few data are available on factors associated with circulating IL-6.

Methods: Participants in 3 trials with IL-6 measured at baseline were included (N = 9864). Factors associated with IL-6 were identified by linear regression. Demographic and HIV variables (nadir/entry CD4(+) cell count, HIV RNA level, antiretroviral therapy regimen) were investigated in all 3 trials. In the SMART (Strategies for Management of Anti-Retroviral Therapy) trial, CD4/CD8 ratio, smoking, comorbid conditions, serum lipids, renal function (estimated glomerular filtration rate [eGFR]), and educational level were assessed.

Results: Demographics associated with higher IL-6 levels were older age and lower education, whereas black race was associated with lower IL-6. Higher HIV RNA levels were associated with higher IL-6 levels, and higher nadir CD4(+) cell counts with lower IL-6 levels. Compared with efavirenz, protease inhibitors were associated with higher and nevirapine with lower IL-6 levels. Smoking and all comorbid conditions were related to higher IL-6. IL-6 levels increased with decreasing eGFR and decreasing serum lipids.

Conclusions: Higher levels of IL-6 were associated with older age, nonblack race, higher body mass index, lower serum lipid levels, HIV replication, low nadir CD4(+) cell count, protease inhibitor use, comorbid conditions, and decreased eGFR. Multiple factors affect inflammation in HIV and should be considered in studies of IL-6 as a biomarker of clinical outcomes.

Keywords: HIV; IL-6; cancer; cardiovascular disease; inflammation.

Figure 1.

Fold differences in interleukin 6 (IL-6) levels associated with demographic factors. Fold differences associated with older age are expressed per 10 years older and fold differences associated with higher body mass index (BMI) are expressed per 5 kg/m² higher. ^aSMART (Strategies for Management of Anti-Retroviral Therapy) participants only (n = 4498): adjusted as described in footnote b and also for comorbid conditions (hepatitis B and hepatitis C virus infection, diabetes mellitus, cardiovascular disease), renal function (estimated glomerular filtration rate), smoking status, educational level (less than high school, high school/some college, or bachelor's degree or above), and cholesterol levels (low- and high-density lipoprotein cholesterol); ^bSMART, ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial), and SILCAAT (Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients With Low CD4⁺ Counts Under Active Antiretroviral Therapy) participants (N = 9864): models adjusted for age, sex, ethnicity, BMI, CD4⁺ cell counts (nadir and baseline), markers of inflammation (high-sensitivity C-reactive protein) and activated coagulation (D-dimer), and antiretroviral therapy (ART) use and regimens; ^cSMART, ESPRIT, and SILCAAT participants (N = 9864): univariable analysis. Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus.

Figure 2.

Fold differences in interleukin 6 (IL-6) levels associated with human immunodeficiency virus (HIV)–specific variables. Fold differences associated with the CD4/CD8 ratio are expressed per 1 log₂ higher ratio; fold differences associated with higher baseline and nadir CD4⁺ cell counts are expressed per 100 cells/mm³ higher. ^aSMART (Strategies for Management of Anti-Retroviral Therapy), ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial), and SILCAAT (Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients With Low CD4⁺ Counts Under Active Antiretroviral Therapy) participants receiving antiretroviral therapy (ART) at baseline (n = 9027): models adjusted for age, sex, ethnicity, body mass index (BMI), CD4⁺ cell counts (nadir and baseline), and markers of inflammation (high-sensitivity C-reactive protein [hsCRP]) and activated coagulation (D-dimer). Because of collinearity between ART use and HIV RNA, these variables could not be entered into the same models; ^bSMART, ESPRIT, and SILCAAT participants (N = 9864): models adjusted for age, sex, ethnicity, BMI, CD4⁺ cell counts (nadir and baseline), markers of inflammation (hsCRP) and activated coagulation (D-dimer), and ART use and regimens; ^cSMART, ESPRIT, and SILCAAT participants (N = 9864): univariable; ^dSMART participants with CD8 data (n = 2339): adjusted for age, sex, ethnicity, BMI, CD4⁺ cell counts (nadir and baseline), markers of inflammation (hsCRP) and activated coagulation (D-dimer), ART use and regimens, comorbid conditions (hepatitis B and hepatitis C virus infection, diabetes mellitus, cardiovascular disease), renal function (estimated glomerular filtration rate), smoking, and cholesterol levels (low- and high-density lipoprotein cholesterol); ^eSMART participants with CD8 data (n = 2339): univariable. Abbreviation: CI, confidence interval.

Figure 3.

Fold differences in interleukin 6 (IL-6) levels associated with antiretroviral therapy (ART) and regimens and individual antiretroviral drugs. ^aSMART (Strategies for Management of Anti-Retroviral Therapy), ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial), and SILCAAT (Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients With Low CD4⁺ Counts Under Active Antiretroviral Therapy) participants (N = 9864): models adjusted for age, sex, ethnicity, body mass index (BMI), CD4⁺ cell counts (nadir and baseline), markers of inflammation (high-sensitivity C-reactive protein) and activated coagulation (D-dimer); ART regimens were categorized as off ART, protease inhibitor (PI) based, ritonavir-boosted PI (PI/r) based, nonnucleoside reverse-transcriptase inhibitor (NNRTI) based, or other; ^bAdjusted as described in footnote a but including only participants receiving an NNRTI- or PI-based ART regimen (but not both) (SMART, ESPRIT, and SILCAAT participants; n = 7291); ART regimens were categorized as off ART, PI based (boosted and unboosted), NNRTI based, or other; ^cOther nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs) include adefovir (used in some hepatitis B virus–coinfected participants), zalcitabine, any of the drugs in our chosen NRTI pairs without lamivudine or emtricitabine, or multiple NRTIs, including a pair of NRTIs that are not among our chosen NRTI pairs. Other PIs include tipranavir, darunavir, and multiple PI drugs; other NNRTIs, delavirdine; other ART, ART regimens including NRTI drugs only. Abbreviations: CI, confidence interval; TTC, lamivudine or emtricitabine.

Figure 4.

Fold differences in interleukin 6 (IL-6) levels associated with comorbid conditions and smoking. ^aSMART (Strategies for Management of Anti-Retroviral Therapy) and ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) participants (n = 6938): models adjusted for age, sex, ethnicity, body mass index (BMI), CD4⁺ cell counts (nadir and baseline), markers of inflammation (high-sensitivity C-reactive protein [hsCRP]) and activated coagulation (D-dimer), antiretroviral therapy (ART) use and regimens, comorbid conditions (hepatitis B virus [HBV] and hepatitis C virus [HCV] infection, diabetes mellitus, cardiovascular disease), and renal function (estimated glomerular filtration rate [eGFR]); ^bSMART and ESPRIT participants (n = 6938): univariable; ^cSMART participants (n = 4498): models adjusted for age, sex, ethnicity, BMI, CD4⁺ cell counts (nadir and baseline), markers of inflammation (hsCRP) and activated coagulation (D-dimer), ART use and regimens, comorbid conditions (HBV and HCV infection, diabetes mellitus, cardiovascular disease), renal function (eGFR), smoking, educational level (less than high school, high school/some college and bachelor's degree or above), and cholesterol levels (low- and high-density lipoprotein cholesterol); ^dSMART participants (n = 4498): univariable. Abbreviation: CI, confidence interval.