AIDS patients who respond to antiretroviral therapy over prolonged periods have stable or improving cognitive function, according to the findings of an observational study published in the May 31st edition of AIDS. The study found that improved performance on neuropsychological tests was marginally associated with viral suppression but that these patients were more likely to be cognitively impaired than the general population.
HIV infection may result in central nervous system (CNS) disorders ranging from severe HIV-associated dementia to sub-clinical but functionally important cognitive abnormalities.
The role of antiretroviral therapy (ART) in CNS disorders is controversial. ART appears to reduce HIV-associated dementia and HIV-induced cognitive impairment. Some antiretroviral drugs do not reach therapeutic levels in the CNS resulting in lack of CNS protection. Some antiretroviral drugs also cause peripheral nerve mitochondrial dysfunction and might be toxic to brain mitochondria. CNS dysfunction in AIDS patients on ART might therefore be due to failure of therapy in the CNS, CNS neurotoxicity, or both.
However, cognition in treatment-experienced, immune-reconstituted advanced AIDS patients is not known. A team of US investigators have addressed this issue in an observational study based on the original AIDS Clinical Trials Group (ACTG) 362 study.
The ACTG 362 study took place in 29 US university-based out-patient clinics between 1997 and 1999 to assess the efficacy of prophylaxis for Mycobacterium avium complex after immune reconstitution on ART. ACTG 362 was converted into an observational cohort for assessing cognitive function in advanced AIDS patients who had responded to ART.
Patients were assessed every four months with medical histories, plasma HIV RNA determinations, and CD4 counts. At week 16 and on every third visit, three cognition tests were administered. Of 433 advanced AIDS patients with documented immune reconstitution on ART, (CD4 lymphocyte counts <50 before and >100 cells/mm3 after ART), 286 had cognition tests at least once with no confounding neurological conditions.
Raw scores of neuropsychological impairment (NPI) were converted to standardized t-scores which were adjusted for relevant demographic factors from normative databases. Impairment points were assigned for each of the three tests as 0, 1, or 2 if the scores were above or within 1 SD of the norms, 1-2 SD below norms, or ³ 2 SD below norms, respectively.
Total impairment points were summed for the three tests. NPI was defined as 2 impairment points or greater. The expected rate of NPI in the normal population was estimated by a simulation exercise.
Three demographically corrected t scores (from each of the tests) were averaged to obtain the summary neuropsychological z-score from the three tests (NPZ-3). Whereas NPI is relevant to clinical diagnosis, NPZ-3 scores have greater power to detect association with factors such as ART and plasma viral load.
The study participants (n = 286) were predominantly male (90 %), white (80 %), mature (median age 40 years), well-educated (median 14 years of schooling), and had remained on antiretroviral treatment since their initial visit (median exposure of 161 weeks).
At the initial neuropsychological assessment, median CD4 cell count was 326 cells/mm3 and 73% had undetectable viral load (< 500 copies/ml). ART included a protease inhibitor (PI) in 85%, non-nucleoside reverse transcriptase inhibitor (NNRTI) and no PI in 7%, and neither a PI nor NNRTI in one patient. The remaining 19 subjects (6.6 %) were not on any antiretroviral treatment.
Out of 286 participants, 27% exhibited neuropsychological impairment at their initial study assessment. This rate was nearly twice that expected in a normal (HIV-uninfected) reference population (14%). These impaired participants did not differ from the unimpaired group with respect to demographic factors, CD4 cell counts, or HIV-RNA levels.
The baseline NPI (27 %) decreased to significantly lower levels at 16 and 14 % at 48 and 96 weeks, respectively (P < 0.001 for each). Among the 210 patients who were tested at all three visits, the prevalence of NPI was similar at each assessment (24, 16, 14 %, at weeks 0, 48, and 96), indicating that the improvement in cognitive function was not due to the attrition of the more impaired participants.
Substantial shifts among the NPI categories in both directions occurred during the study. At 48 weeks, a repeated NPI diagnosis was seen in only 27 % of patients who had NPI at baseline while 6% of those without NPI at baseline progressed to NPI. From 48-96 weeks, 21 out of 33 (64 %) retained the NPI diagnosis and 8/177 newly acquired NPI. Only 21 participants remained impaired at all three assessments, 19 became impaired at one follow up visit, and 42 were unimpaired at the next assessment.
Practice is an important confounder of longitudinal neuropsychological tests. When the effect of practice was adjusted for, there was a 9-13 % real improvement in two test scores; less improvement was seen in the third test score.
The average norm-adjusted NPZ-3 scores, consistent with the decreasing prevalence of NPI, improved over three years of observation.
The relationship between neuropsychological functioning and HIV plasma suppression was explored using statistical models. Non-impairment (absence of NPI diagnosis) across visits was marginally associated with viral suppression. By contrast, continuous NPZ-3 scores were not significantly associated with plasma HIV suppression.
CD4 counts did not correlate with NPZ-3 scores and nor did adherence at entry to ACTG 362 and to this substudy.
The findings demonstrate an improved performance on neuropsychological tests over a two year period three to five years after initiating potent HIV treatment. However, the mechanisms underlying the improvement are not clear since there was no association with CD4 counts and the association with viral suppression was not unequivocal.
The detection of sub-clinical HIV-1 induced cognitive impairment opens up novel possibilities for averting the deterioration of cognitive functions through medical intervention. The development of standardized protocols for neuropsychological assessments would be a significant advance for both developed and developing countries. In the latter, HIV-1 related dementia has been reported but sub-clinical neurocognitive impairment has not been extensively investigated.