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Determinants of IL-6 levels during HIV infection
Alvaro H Borges1, Jemma L O'Connor2, Andrew N Phillips2
1Department Infectious Diseases & Rheumatology, CHIP, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Insights
Interleukin-6 (IL-6) levels are higher in people with HIV, influenced by age, BMI, and comorbidities. Factors like HIV-RNA and protease inhibitor use also impact IL-6, highlighting inflammation
Area of Science:
- Immunology
- Infectious Diseases
- Cardiovascular Disease Research
Background:
- Elevated Interleukin-6 (IL-6) is linked to increased risk of cardiovascular disease (CVD), cancer, and mortality.
- Individuals with treated HIV (HIV+) exhibit 50-100% higher IL-6 levels compared to the general population.
- Limited data exists on the determinants of IL-6 levels during HIV infection.
Purpose of the Study:
- To identify factors associated with elevated IL-6 levels in a large cohort of individuals with HIV.
- To investigate the influence of demographics, HIV-specific variables, and comorbidities on IL-6 levels.
Main Methods:
- Analysis of baseline IL-6 plasma levels from 9864 participants across three international HIV trials (SMART, ESPRIT, SILCAAT).
- Multivariate linear regression used to identify factors independently associated with log2-transformed IL-6 levels.
- Assessment included demographics, HIV status (CD4 counts, HIV-RNA, ART regimens), smoking, comorbidities, HDL-cholesterol, renal function, and education.
Main Results:
- Higher IL-6 levels associated with older age, higher BMI, non-black race, not receiving ART, and higher HIV-RNA.
- Protease inhibitor (PI) use, comorbidities (CVD, diabetes, HBV, HCV), lower HDL-cholesterol, decreased eGFR, and lower education were linked to increased IL-6.
- Higher nadir CD4 count was associated with lower IL-6 levels.
Conclusions:
- Multiple factors contribute to inflammation in treated HIV infection, including demographics, HIV replication, and comorbidities.
- Older age, higher BMI, lower HDL-cholesterol, decreased renal function, and specific comorbidities are associated with elevated IL-6.
- The study suggests a potential contribution of PI use to IL-6 levels and calls for investigation into inflammation's role in clinical outcomes.
Introduction:
Elevated IL-6 levels have been linked to increased risk of cardiovascular disease (CVD), cancer and death. Compared to the general population, treated HIV+ persons have 50-100% higher IL-6 levels, but few data on the determinants of IL-6 levels during HIV infection currently exist.
Material And Methods:
Participants in three international HIV trials (SMART, ESPRIT and SILCAAT) with IL-6 plasma levels measured at baseline were included (N=9864). Factors independently associated with log2-transformed IL-6 level were identified by multivariate linear regression; exponentiated estimates corresponding to fold differences (FDs) in IL-6 were calculated. Demographics (age, gender, race, BMI) and HIV-specific variables (nadir and entry CD4 counts, HIV-RNA, use of different ART regimens) were investigated in all three trials. In SMART (N=4498), smoking, comorbidities (CVD, diabetes, hepatitis B/C [HBV/HCV]), HDL-cholesterol, renal function (eGFR) and educational level were also assessed.
Results:
Demographics associated with higher IL-6 were older age (FD [95% CI]: 1.09 [1.08-1.11] per 10 yr) and higher BMI (1.02 [1.01-1.04] per 5 kg/m(2)), whereas black race was associated with reduced IL-6 (0.96 [0.93-0.99]). As for HIV variables, patients not receiving ART (1.36 [1.29-1.43]) and with higher HIV-RNA (1.24 [1.01-1.52] for >100,000 vs. ≤500 copies/mL) had increased IL-6. Participants taking protease inhibitors (PI) had higher IL-6 (1.14[1.09-1.19]). Higher nadir CD4 count (0.98 [0.97-0.99]/100 cells/µL) was related to lower IL-6. All evaluated comorbidities were related to higher IL-6; FDs in IL-6 were 1.08 [1.04-1.12] for smoking, 1.12 [1.02-1.24] for CVD, 1.07 [1.00-1.16] for diabetes and 1.12 [1.02-1.24] for HBV (1.15 [1.02-1.30]) and 1.53 [1.45-1.62] for HCV. IL-6 increased with decreasing eGFR (0.98 [0.97-1.00]/10 mL/min) and HDL-cholesterol (0.98 [0.96-0.99]/10 mg/mL). Lower education was related to higher IL-6 (1.09 [1.03-1.15] for high school vs. bachelor's degree).
Conclusions:
Higher IL-6 levels were associated with older age and non-black race, higher BMI and lower HDL-cholesterol, ongoing HIV replication, low nadir CD4 counts, comorbidities and decreased renal function. This suggests that there are multiple causes of inflammation in treated HIV infection. A possible contribution from PI use was also observed. Contribution from inflammation to explain variation in clinical outcomes for these factors should be investigated.
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