Central nervous system penetration-effectiveness rank does not reliably predict neurocognitive impairment in HIV-infected individuals.
BACKGROUND
Central nervous system (CNS) penetration-effectiveness (CPE) rank was proposed in 2008 as an estimate of penetration of ARV regimen into the CNS, and validated as predictor of CSF HIV-1 replication. RESULTS on predictive role of CPE on neurocognitive and clinical outcome were conflicting.


METHODS
Retrospective, cross-sectional analysis of neurocognitive profile in HIV-infected cART-treated patients. All patients underwent neuropsychological (NP) assessment by standardized battery of 14 tests on 5 different domains. People were classified as having NCI if they scored >1 standard deviation (SD) below the normal mean in at least two tests, or >2 SD below in one test. Linear and logistic regression analyses were fitted using as outcome Npz8 and impaired/not impaired respectively.


RESULTS
A total of 660 HIV-infected cART-treated individuals from 2009 to 2014, contributing a total of 1003 tests (mean age 49 (IQR 43-56), male 82%; median current CD4 586/mm(3); 18% HCV infected; HIV-RNA <40 cp/mL in 84%). Current ARV regimen was 2NRTIs+1NNRTI 50.3%, 2NRTI+1PI/r in 32.6%, NRTI sparing in 11.1%. Mean CPE of current regimens was 6.6 (95% CI 6.5-6.7). As per test multivariable analysis, higher CPE values were associated to poor NP tasks (Beta=-0,09; 95% CI -0,14 -0,03; p=0.002 at multivariable linear regression). The association between higher CPE and increased NCI risk was confirmed at multivariable logistic regression, with a 1.24-fold risk of NCI occurrence for each point increase of CPE of current regimen at the time of NP testing (see Table 1). In a sensitivity analysis performed only on patients at the first NP test, the association between higher CPE and poor NP tasks and enhanced NCI risk was only marginally confirmed (Beta=-0,05; [-0,12-0,02]; p=0,19; OR 1,13 [0,95-1,34]; p=0.17). Older age, longer time from HIV diagnosis, current CD4 count <350 cell/mm(3) and lower education level were all associated to an increased risk of NCI.


CONCLUSIONS
In our analysis, higher CPE rank is associated to poorly performing at NP tasking. Even if selection bias could not be excluded due to retrospective cross-sectional design, these results fitted with the direct correlation between high CPE and HIV dementia recently recorded in a large observational database. We think that CPE use to guide ART in patients neurocognitively impaired should be revised.
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Raffaella
R
Libertone
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Patrizia
P
Lorenzini
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Pietro
P
Balestra
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Carmela
C
Pinnetti
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Martina
M
Ricottini
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Maria Maddalena
MM
Plazzi
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Samanta
S
Menichetti
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Mauro
M
Zaccarelli
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Emanuele
E
Nicastri
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Rita
R
Bellagamba
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Adriana
A
Ammassari
Clinical Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
Andrea
A
Antinori