Association of antiretroviral therapy with brain aging changes among HIV-infected adults

Abstract

Objective: Antiretroviral therapy (ART) is currently recommended for all persons living with HIV (PLWH), regardless of their CD4 T-cell count, and should be continued throughout life. Nonetheless, vigilance of the safety of ART, including its neurotoxicity, must continue. We hypothesized that use of certain ART drugs might be associated with aging-related cerebral degenerative changes among PLWH.

Design: Clinicopathological study of PLWH who were using ART drugs at the last clinical assessment.

Methods: Using multivariable logistic regression, we tested associations between use of each specific ART drug (with reference to use of other ART drugs) and cerebral degenerative changes including neuronal phospho-tau lesions, β-amyloid plaque deposition, microgliosis, and astrogliosis in the frontal cortex and putamen (immunohistochemistry), as well as cerebral small vessel disease (CSVD) in the forebrain white matter (standard histopathology), with relevant covariates being taken into account. The Bonferroni adjustment was applied.

Results: Darunavir use was associated with higher likelihood of neuronal phospho-tau lesions in the putamen [odds ratio (OR) 15.33, n = 93, P = 0.005]. Ritonavir use was associated with marked microgliosis in the putamen (OR 4.96, n = 101, P = 0.023). On the other hand, use of tenofovir disoproxil fumarate was associated with lower likelihood of β-amyloid plaque deposition in the frontal cortex (OR 0.13, n = 102, P = 0.012). There was a trend toward an association between emtricitabine use and CSVD (OR 13.64, n = 75, P = 0.099).

Conclusion: Our findings suggest that PLWH treated with darunavir and ritonavir may be at increased risk of aging-related cerebral degenerative changes.

Figures

Fig. 1.. Immunohistopathologic changes in the frontal cortex and putamen of HIV-infected adults.

Double-label immunofluorescence staining for phospho-tau (p-tau, a) and microtubule-associated protein-2 (MAP2, a’) shows p-tau-immunoreactive neurofibrillary tangles within MAP2-immunoreactive neurons (merge, a”) in the frontal cortex of a 44-year-old black man; scale bars 40 μm. Immunohistochemical staining for p-tau (b−d) shows neuropil threads of grade-1 density in the frontal cortex of 43-year-old white man (b, scale bar 100 μm; arrow and upper inset showing a neuron, arrowheads and lower inset showing neuropil threads), grade-2 density in the putamen of 44-year-old white man (c, scale bar 150 μm; arrow and inset showing an area involved by neuronal p-tau pathology), and grade-3 density in the frontal cortex of a 44-year-old black man (d, scale bar 1000 μm; arrow and inset showing an area involved by neuronal p-tau pathology; the same case as in a−a”). Immunohistochemical staining for β-amyloid (Aβ, e) shows diffuse plaques of widespread density in the frontal cortex of 57-year-old Hispanic woman; scale bar 600 μm. Immunohistochemical staining for ionized calcium-binding adapter molecule-1 (Iba1, f) shows ramified microglia scattered in the frontal cortex of 44-year-old black man (the same case as in a−a”); scale bar 100 μm. Immunohistochemical staining for glial fibrillary acidic protein (GFAP, g) shows astroglia scattered in the putamen of 35-year-old white man; scale bar 100 μm.