Neurocognitive performance among HIV-positive people improved with longer time on antiretroviral therapy (ART) in a new U.S. study of adults taking virally suppressive regimens. But, overall odds of neurocognitive impairment still rose almost 20% with every 10 years of age.
HIV-associated neurocognitive disorder (HAND) can persist in people with well-controlled HIV infection, or it may arise de novo in antiretroviral-treated individuals. Older age is an established risk factor for HAND, but studies exploring the impact of age on neurocognitive impairment have been cross-sectional, small or reliant on limited neurocognitive measures. This new study aimed to evaluate neurocognitive impairment in an aging HIV-positive population with viral suppression for at least two years.
Researchers analyzed prospectively collected data on members of the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study, whose participants agreed to long-term follow-up after completing one of seven ACTG parent trials. This analysis included people starting their first ART in the parent trial who had a neuropsychological 4 test battery z-score (NPZ4) result when entering ALLRT and a result at least two years after starting ART. The researchers standardized the raw score for each test using normative means adjusted for age, sex, years of education and race/ethnicity. They used univariable and multivariable generalized estimating equation (GEE) models to identify risk factors for neurocognitive impairment, defined as -2.0 standard deviation (SD) or less on one test or -1.0 SD or less on two tests.
Of the 3,313 study participants, 42% were non-Hispanic white and 20% were women. Median baseline age stood at 38 years and 12% were more than 50 years old. Participants had a viral load below 200 copies/mL on 91% of HIV RNA measures and a median of three NPZ4 results after two years of ART.The univariable GEE regression model determined that every 10 years older age at parent study entry conferred 17% higher odds of neurocognitive impairment (odds ratio 1.17, 95% confidence interval [CI] 1.10 to 1.25, P < .001). This association held in the multivariable model adjusted for the effects of aging using norms from HIV-negative people (adjusted odds ratio [aOR] 1.18, 95% CI 1.11 to 1.36, P < .001). This age-related rise in neurocognitive impairment began at age 41 to 50. Yet, the multivariable model also determined that, in the whole cohort, every additional year since ART began independently lowered odds of impairment by 6% (aOR 0.94, 95% CI 0.92 to 0.96, P < .001).
Other independent predictors of neurocognitive impairment in the multivariate model were female sex (OR 1.35, 95% CI 1.15 to 1.59, P < .001), Hispanic ethnicity (aOR 2.61, 95% CI 2.22 to 3.07, P < .001), hepatitis C infection (OR 1.40, 95% CI 1.08 to 1.82, P = .01), less education (OR 1.37, 95% CI 1.20 to 1.57, P < .001), time-varying CD4 count less than 350 cells/mm3 during follow-up versus above 500 cells/mm3 (OR 1.21, 95% CI 1.05 to 1.40, P = .008) and time-varying CD4 count 351 to 500 cells/mL during follow-up versus above 500 cells/mm3 (OR 1.12, 95% CI 1.01 to 1.24, P = .03).
The ACTG team stresses that the link between advancing age and higher risk of neurocognitive impairment in this cohort, which consisted of people with well-controlled HIV replication after two years of ART, held true “despite normative adjustment of neurocognitive scores for age from HIV-negative individuals, and after adjusting for a variety of covariates in multivariable models.” But, across all ages in the ALLRT cohort, longer time on ART independently lowered chances of neurocognitive impairment.
The authors suggest three mechanisms that might explain increasing risk of neurocognitive impairment with age in people with HIV: (1) ART may magnify the impact on neurocognition of age-related comorbidities, including diabetes, hypertension and abdominal obesity. (2) Older people may have a greater need for antiretrovirals that penetrate the central nervous system. (3) Antiretroviral-related central nervous system toxicities may have a greater impact in older people.