Cognitive change trajectories in virally suppressed HIV-infected individuals indicate high prevalence of disease activity

Abstract

BackgroundThe longitudinal rate and profile of cognitive decline in persons with stable, treated, and virally suppressed HIV infection is not established. To address this question, the current study quantifies the rate of cognitive decline in a cohort of virally suppressed HIV+ persons using clinically relevant definitions of decline, and determine cognitive trajectories taking into account historical and baseline HAND status.MethodsNinety-six HIV+ (clinically stable and virally undetectable) and 44 demographically comparable HIV- participants underwent standard neuropsychological testing at baseline and 18-months follow-up. We described clinically relevant cognitive trajectories based on standard definitions of historical and baseline HAND status and cognitive decline. Historical, moderate to severe HAND was formally diagnosed at the start of the cART era in 15/96 participants based on clinical neurological and neuropsychological assessment. The same standard of care has been applied to all participants at St. Vincent’s Hospital Infectious Disease Department for the duration of their HIV infection (median of 20 years).ResultsRelative to HIV- controls (4.5%), 14% of HIV+ participants declined (p = .11), they also scored significantly lower on the global change score (p = .03), processing speed (p = .02), and mental flexibility/inhibition (p = .02) domains. Having HAND at baseline significantly predicted cognitive decline at follow up (p = .005). We determined seven clinically relevant cognitive trajectories taking into account whether participant has a history of HAND prior to study entry (yes/no); their results on the baseline assessment (baseline impairment: yes/no) and their results on the 18-month follow up (decline or stable) which in order of prevalence were: 1) No HAND history, no baseline impairment, 18-month follow-up stable (39%), 2) No HAND history, baseline impairment, 18-month follow-up stable (35%), 3) History of HAND; baseline impairment, 18-month follow-up stable (9%) 4) No history of HAND, baseline impairment, 18-month follow-up decline (7%), 5) History of HAND, no baseline impairment, 18-month follow-up stable (3%), 6) No HAND history, no baseline impairment, 18-month follow-up decline (3%) 7) History of HAND, baseline impairment, 18-month follow-up decline (3%). There was no relationship between cognitive decline (taking into account historical and baseline HAND) and traditional HIV disease biomarkers.ConclusionsDespite long-term viral suppression, we found mostly subclinical levels of decline in psychomotor speed and executive functioning (mental flexibility and cognitive inhibition); well-established markers of HAND progression. Moreover, 57% of our cohort is undergoing slow evolution of their disease, challenging the notion of prevalent neurocognitive stability in virally suppressed HIV infection.

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection

“…Clinically meaningful cognitive change (improve and decline) vs stability was defined using published norms for change (see reference 3 for further details). To determine the neurocognitive trajectories, we combined the participants' baseline impairment classification with their neurocognitive change status at follow-up.…”

“…To determine whether baseline HIV disease markers and treatment factors were predictive and/or associated with brain metabolite changes over time in the HIV+ group, we conducted linear regression analyses with the metabolites that were found to be significantly different between the overall HIV+ and HIV− groups as the outcomes to reduce the number of experiment-wise comparisons and concentrate on clinically meaningful effects. The following predictors were assessed for their correlations (if r ≥ 0.30, a redundant predictor was removed to reduce the number of relevant variables in the final regression model): baseline HIV duration (years), nadir CD4 T-cell count (copies/mL), total number of AIDS-defining illnesses (other than HAND), history of HAND (yes/no; dummy coded, see reference 3 for further details), baseline combination antiretroviral (cART) duration (months), baseline CNS penetration effectiveness rank score, 16 difference in CD4 T-cell count between baseline and follow-up, cART change during the study period (yes/no; dummy coded), and viral blip during the study period (<50 copies/mL, undetectable; yes/no; dummy coded). Nadir CD4 count and total number of AIDS-defining illnesses were associated ( r = −0.45; p < 0.0001); thus, nadir CD4 was retained.…”

“…Indeed the long-term study of neurochemical abnormalities by 1 H-MRS may have several prognostic benefits: (1) It may inform whether virally suppressed HIV+ persons with stable cognition or stable HIV-associated neurocognitive disorder (HAND) across several years (the most prevalent neurocognitive trajectories in chronic treated HIV infection 3 , 4 ) demonstrate active HIV-related brain injury rather than a “burnt out” form of injury reflecting irreversible historical damage. (2) It may assist in the early detection of HAND incidence and progression, despite viral suppression.…”

Selective Estrogen Receptor β Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders

“…In the post-cART era, HAND has been defined as a progressive, neurode-generative disease (Cohen et al 2015;McLaurin et al 2019a) characterized by alterations in speed of information processing, attention, working memory, and executive function (e.g., Cysique et al 2004;Garvey et al 2009;Heaton et al 2011). Due to the prevalence of HAND in the post-cART era, and its progressive nature (Heaton et al 2015;Gott et al 2017;McLaurin et al 2019a), there is a critical need to develop additional neuroprotective and/or neurorestorative therapeutics.…”

HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment

“…The “natural history” of HAND in the context of viral suppression has also been clarified recently. Most patients who continue to be virally suppressed remain stable, but some improve and a small number deteriorate 23 . This is best termed as the activity of HAND.…”