Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years

Abstract

Background Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared to that of healthy aging. Methods We examined longitudinal structural brain MRI atrophy rates employing region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants over age 60 years (n=38) compared to age-matched HIV-uninfected healthy and cognitively normal controls (n=24). Results The mean age of participants was 63 years, the mean estimated duration of infection was 21 years and the median of duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, p=0.016), caudate (0.74% vs. 0.03%, p=0.012), frontal lobe (0.48% vs. 0.01%, p=0.034), total cortical gray matter (0.65% vs. 0.16%, p=0.027), brain stem (0.31% vs. 0.01%, p=0.026), and pallidum (0.73% vs. 0.39%, p=0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. Conclusion Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared to healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.

Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

“…The presumably ongoing viral replication in the caudate nuclei, along with the associated neurotoxicity due to neuroinflammation (and/or neurotoxic side effects of antiretroviral agents), might result in growing neuronal injury in the caudate (Chang et al, ; Wang et al, ), which may eventually lead to detectable reduction in caudate volume and neurocognitive performance. Our hypothesis of this ongoing caudate injury model is also supported by findings from other studies: (a) Studies with postmortem brains and SIV models have suggested a high concentration of virus in the caudate nuclei (Kumar, Borodowsky, Fernandez, Gonzalez, & Kumar, ; Perez et al, ) and the basal ganglia in general, and the viral load in the caudate (along with the frontal cortex and the globus pallidus) correlates with neurocognitive impairment (Kumar et al, ); (b) Studies have found that the viral load in plasma and/or CSF correlates with caudate volume or neuronal injury in the caudate (Dewey et al, ; Krivine et al, ; Wang et al, ); (c) Studies have suggested a correlation between caudate volume and the estimated duration of HIV‐disease (Ances et al, ; Becker et al, ), implicating a gradual and ongoing decline in caudate volume after seroconversion, despite being on cART; (d) A recent longitudinal study with HIV+ older adults have found that not only the annualized rate of atrophy is higher in the caudate (0.74%) than any other brain regions in HIV (including the frontal lobe (0.48%) and the globus pallidus (0.73%)), but also the difference in the annualized rates of atrophy between HIV+ older adults and age‐matched controls is the largest in the caudate (ln [(1–0.0003)/(1–0.0074)] = ln (0.9997)−ln [0.9926] = 0.0071), followed by total cortical GM (0.0049) and the frontal lobe (0.0047), and is “twice” more than the globus pallidus (0.0034) (Clifford et al, ), suggesting that the caudate remains one of the most vulnerable and affected brain regions in HIV in the cART era; (e) Another longitudinal study also found that HIV+ adults with chronic infection have smaller caudate, putamen, and other subcortical regions than HIV+ adults with acute infection (Sanford et al, ), suggesting an ongoing neural injury to the caudate/striatum.…”

“…the frontal lobe (0.0047), and is "twice" more than the globus pallidus (0.0034) (Clifford et al, 2017), suggesting that the caudate remains one of the most vulnerable and affected brain regions in HIV in the cART era; (e) Another longitudinal study also found that HIV+ adults with chronic infection have smaller caudate, putamen, and other subcortical regions than HIV+ adults with acute infection (Sanford et al, 2018), suggesting an ongoing neural injury to the caudate/striatum.…”

Longitudinal Trajectories of Brain Volume and Cortical Thickness in Treated and Untreated Primary Human Immunodeficiency Virus Infection

“…The brain regions affected during untreated infection correspond with previous studies that examined people living with HIV. These studies reported volume reductions throughout the subcortical regions [2,3,[33][34][35][36] and cerebellum [37,38], and cortical thickness reductions in the frontal and temporal lobes, and cingulate cortex [2,3,17,39]. The data in aggregate add to the growing body of evidence that demonstrate the brain is not spared in early infection.…”

The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity

“…Although HIV and aging appear to contribute independently to heighten brain structural vulnerability (Ances et al, 2012 ), HIV may accelerate brain aging (Cysique et al, 2013 ; Cole et al, 2017 ). Consequently, despite persistent control of plasma viremia, older HIV infected patients demonstrate more rapid progressive brain compromise when compared to healthy aging (Clifford et al, 2017 ).…”