Background
A rare subset of people with HIV (PWH) on antiretroviral therapy (ART), known as post-treatment controllers (PTCs), can maintain viral suppression for extended periods after treatment interruption (TI). The mechanisms underlying this clinically valuable phenotype remain unclear and are likely multifactorial, necessitating further comprehensive analysis.
Methods
Pre-TI levels of 247 inflammation and immunomodulatory markers were measured in the plasma of 14 PTCs and 27 matched post-treatment non-controllers (PTNCs) using a multiplex Nucleic acid Linked Immuno-Sandwich Assay (NULISA). PTCs sustained virologic control for ≥24 weeks, maintained plasma viral loads ≤400 copies/ml for at least two-thirds of time points, underwent plasma drug level testing, and had no evidence of spontaneous control before ART initiation. The two groups were matched for sex (p=0.41), age (p=0.75), ethnicity (p=0.74), ART initiation timing (p=0.69), ART duration (p=0.5), and pre-TI CD4 count (p=0.92).
Results
A distinct set of pre-TI markers correlated with the likelihood of achieving the PTC phenotype. Notably, pre-TI levels of FGF21, a hormone regulating sugar and lipid metabolism with anti-inflammatory and anti-metabolic stress effects, was significantly higher in PTCs than PTNCs (p=0.004). FGF21 exhibited a significant odds ratio (OR=1.64; p=0.04) for predicting the PTC phenotype in a logistic model. A predictive model using FGF21 alone demonstrated 78% accuracy, 79% sensitivity, 78% specificity, and an area under the curve (AUC) of 0.77. In addition, CCL4, a chemokine promoting immune surveillance (OR=3.5; p=0.03); erythropoietin (EPO), which exhibits anti-inflammatory properties (OR=2.4; p=0.04), and CNTF, which supports neuronal health and maintains gut barrier integrity (OR=1.7; p=0.048), all predicted a higher likelihood of achieving the PTC phenotype. Conversely, markers associated with a lower OR (p<0.05) for PTCs included IL-27 (OR=0.5), a cytokine promoting chronic inflammation; IL-17A/F (OR=0.4), which drives intestinal inflammation via Th17 activation; PD1 (OR=0.24), a contributor to immune exhaustion; and AGRP (OR=0.16), linked to metabolic stress.
Conclusions
PTCs exhibit a distinct profile of host factors associated with balanced immune regulation and reduced metabolic stress. Future studies are warranted to investigate the mechanistic contributions of these factors to the PTC phenotype and to explore their predictive value in multi-marker models for accurate identification of potential PTCs.