Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort

Abstract

Background. We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings.Methods. We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4+ T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis.Results. Among 99 cases and 234 controls, median baseline CD4+ T-cell count was 181 cells/µL, and HIV RNA was 5.05 log10 cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27–7.20), sCD14 (IRR, 2.17; 95% CI, 1.02–4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01–0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated.Conclusions. Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.

Common Variation in NLRP3 Is Associated With Early Death and Elevated Inflammasome Biomarkers Among Advanced HIV/TB Co-infected Patients in Botswana

“…We found that elevated IL-18 levels at week 4 post-ART were associated with early mortality. This is consistent with a recent study demonstrating that persistently high levels of IL-18 are associated with clinical failure despite ART initiation in HIV-infected patients (20% of whom also had active TB) [ 35 ]. Notably, the NLRP3 rs10754558-G allele was also linked to elevated IL-18 levels at week 4 post–ART initiation in our cohort.…”

Elevated Spontaneous Interferon-γ Secretion in Human Immunodeficiency Virus-Infected Persons

“…It is interesting to compare our results to a recent multi-national study by [ 12 ] that examined plasma concentrations of IFN-γ in a cohort of treatment-naïve HIV-positive subjects in low- and middle-income countries before and after ART therapy [ 12 ]. In that study, subjects with higher VL and lower CD4 count at baseline were more likely to have persistent elevation of IFN-γ after 24 weeks of ART therapy.…”

“…Given the cross-sectional nature of our study, we were unable to evaluate the temporal relationship between the nil QFT value and ART use or clinical outcomes. The two studies are also difficult to directly compare given differences in subject demographics and the lack of an HIV-negative control group in the study by Balagopal et al However, their study suggests that persistently elevated IFN-γ levels in patients on ART may portend better long-term clinical outcomes in the setting studied by [ 12 ].…”

The impact of antiretroviral therapy on iron homeostasis and inflammation markers in HIV-infected patients with mild anemia

“…This chronic state of inflammation/immune activation, that it is established during HIV-infection as a result of the complex interactions between viral and host factors, may be associated to clinical consequences despite of efficient cART. Increased values of IL-18 have been associated with clinical cART failure in HIV-infected patients [ 35 ] and high level of IL-8 has been associated with lower number of CD4 + cell count and HIV disease progression in children [ 36 ]. Patients of group B in our study, who did not recover from anemia, had indeed higher levels of IL-8 and IL-18.…”