Brain 18F-FDG PET of SIV-infected macaques after treatment interruption or initiation

William Schreiber-Stainthorp,Lori Dodd,Jing Wang,Swati Shah,Michele Di Mascio,Sanhita Sinharay,Sharat Srinivasula,H Clifford Lane,Dima A Hammoud

doi:10.1186/s12974-018-1244-z

Abstract

BackgroundAlthough rates of severe HIV-associated neurocognitive disorders have declined in the post-antiretroviral treatment (ART) era, subtle deficits persist, possibly exacerbated by treatment non-adherence. The actual effects of ART interruption/initiation on brain glucose metabolism as a reflection of viral replication and neuroinflammation remain unclear. Our study investigates how treatment initiation and interruption alter brain glucose metabolism in SIV-infected macaques, using 18F-FDG PET in correlation with plasma and CSF viral loads (VL) and cytokine levels.MethodsSIV-infected macaques (n = 7) underwent ART initiation only, ART interruption only, or both. Five uninfected animals served as controls. 18F-FDG PET imaging was performed at baseline and 1, 3, and 6 months after treatment modification. Mean and maximum standardized uptake values (SUV) for the whole-brain and subregions were calculated. Plasma and CSF VL and cytokine levels were measured. Paired t tests evaluated acute changes in whole-brain SUV from baseline to 1 month, while mixed-effect linear regression models evaluated changes over multiple timepoints and correlated SUV values with disease markers.ResultsART interruption was associated with increased SUVmean and SUVmax acutely, after 1 month (SUVmean 95% CI [0.044–0.786 g/ml], p = 0.037; SUVmax 95% CI [0.122–3.167 g/ml], p = 0.041). The correlation between SUV and time, however, was not significant when evaluated across all timepoints. Increased SUVmean and SUVmax correlated with decreased CD4+ and CD8+ T-cell counts and increased plasma VL. SUVmax was positively associated with increases in CSF VL, and there were borderline positive associations between SUVmax and IL-2, and between SUVmean and IL-15. The treatment initiation group showed no associations between imaging and disease biomarkers despite viral suppression, reduced cytokine levels, and increased CD4+ and CD8+ T-cell counts.ConclusionsART interruption is associated with increased brain glucose metabolism within 1 month of treatment cessation, which, in concert with increased levels of pro-inflammatory cytokines in the CSF, may reflect neuroinflammation in the setting of viral rebound. Although we cannot assert neurologic damage in association with cerebral hypermetabolism, it is a concerning outcome of ART non-adherence. Treatment initiation, meanwhile, did not result in significant changes in brain metabolism. HIV-induced neuroinflammation may require a longer period to abate than our follow-up period allowed.

Highlights

Rates of severe Human immunodeficiency virus (HIV)-associated neurocognitive disorders have declined in the postantiretroviral treatment (ART) era, subtle deficits persist, possibly exacerbated by treatment non-adherence
Treatment initiation Treatment initiation did not result in statistically significant changes in SUVmean or SUVmax at 1, 3, or 6 months post-treatment modification (TM) (Fig. 2)
The current study has clearly demonstrated that discontinuation of antiretroviral therapy (ART) is associated with increased metabolic activity in the brain as measured by FDG uptake, as early as 1 month after interruption

Summary

Introduction

Rates of severe HIV-associated neurocognitive disorders have declined in the postantiretroviral treatment (ART) era, subtle deficits persist, possibly exacerbated by treatment non-adherence. While ART is increasingly accessible, adherence to drug regimens depends on a number of factors and can be disrupted by phenomena including poverty, stigma, lack of social support, comorbid psychiatric disorders, and adverse drug effects including GI discomfort, lipodystrophy, renal dysfunction, and sensory neuropathy [4,5,6,7,8,9,10] Due to these and other factors, ART adherence rates are estimated to be between 56 and 72%, with discipline declining over time, especially for populations with HIV-associated neurocognitive disorders (HAND) [7, 11,12,13,14]. Despite the extensive evidence of benefit from ART, several studies have shown improvements in neuropsychological outcomes of PLWH after the interruption of ART treatment for periods as long as 96 weeks, adding nuance to our understanding of the effects of ART [16, 20, 21] and the balance between effects of HIV and side-effects of ART

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