Background

1. Factors Associated with Persistent Neurocognitive Impairment Despite Long-term HAART in Patients with HIV-Dementia Abstract E-119 V Tozzi, P Balestra, MF Salvatori, C Vlassi, A Corpolongo, R Bellagamba, P Lorenzini, S Galgani, M Zaccarelli, G Liuzzi, L Giancola, U Visco-Comandini, E Boumis, A Antinori, P Narciso. National Institute for Infectious Diseases "L. Spallanzani", Via Portuense 292, 00149 Rome, Italy. *Contact e-mail: tozzi@inmi.it 1 • Background • The optimal treatment for HIV-D has not been established, but there are strong evidences that the highly active antiretroviral therapy (HAART) is effective in treating the neurocognitive impairment (NCI). However, although potent antiretroviral treatment can reverse HIV-D, the benefits vary substantially between individuals. In the era of HAART, the course of HIV-D has changed, and several distinct patters of evolution of cognitive functions have been proposed. Although these patterns have not been fully characterized, they include: • 1) improvement of cognitive functions with full reversal of the cognitive deficit (“reversible NCI”), • 2a) initial improvement after the initiation of HAART but with significant persistent neurological deficit, or 2b) slow continued decline in neurocognitive functions with or without effective peripheral virological control (“persistent NCI”). • Thus, although HAART improves NCI, predictors of reversible NCI are unknown. Therefore, we have conducted a prospective observational study to examine the clinical course of HIV associated NCI in patients with HIV-D treated with HAART. • Aims • To describe prevalence of persistent neurocognitive impairment despite long-term HAART in patients with HIV-D. • To assess and risk factors for persistent neurocognitive impairment despite long-term HAART in patients with HIV-D. • Methods • Design. Prospective observational study. • Setting. National Institute for Infectious Diseases, L Spallanzani, Rome, Italy. • Patients. All patients with HIV-related NCI (as defined below) seen in our Institute since 1995. • Exclusion criteria. Opportunistic infections or tumors of the CNS, any confounding neurological illness, major neurological or psychiatric disorders, current drug abuse, use of sedative-hypnotics. • Neuropsychological testing.A battery of 17 standardized tests sensitive to a wide spectrum of different cognitive domains. Administered by one of us (P.B.). Requiring approximately 90 minutes to complete. • Neuropsychological (NP) testing z-scores. The NPl scores from each test was transformed into a z-scores using a reference population. Each z-score was adjusted so that negative values indicated below-average performance. Summary global NPZ8 and NPZ4 scores were also ogtained. • Neurological diagnosis. HIV-related neurocognitive impairment (NCI) was defined as performing below one standard deviation for the normative mean on at least two NP tests or two standard deviations below the mean on at least one test. The diagnosis of NCI also required the exclusion of other conditions that could explain the finding. • HAART regimens. As best judged by the treating physician. • Criteria for the diagnosis of either reversible or persistent neurocognitive impairment (NCI).According to the results of serial NP assessments, patients were considered having either reversible or persistent NCI. • End points. Neuropsychological test results. • Statistics. The Kaplan-Meier method was used to estimate the probability of reversible neurocognitive impairment over time. The association between reversible NCI and selected characteristics was assessed by means of the chi-square test, or, when appropriate, by means of the student’s t-test. A multivariable analysis using a multiple logistic regression model was performed in order to assess statistically significant associations between reversible neurocognitive impairment and main demographic (age, gender, years of education), clinical (HIV disease stage at enrollment, virological response to HAART, antiretroviral treatment, exposure to CSF penetrating drugs), laboratory (CD4 cell count at enrollment and during follow-up, plasma HIV RNA at enrollment and during follow-up), and neuropsychological (NPZ4 and NPZ8 scores at enrollment and follow-up) variables. Moreover, a multiple logistic regression was also used to assess the probability of reversible neurocognitive impairment adjusted by the same variables. 5 • Baseline characteristics in the 116 study patients, by HAART exposure • All patients naive experienced p • (n=116) (n=68) (n=48) • Clinical • Age in years, mean (±SD) 41.5 (±8.4) 40.4 (±8.8) 43.1 (±7.4) .096 • Education in years, mean (±SD) 10.9 (±4.0) 10.7 (±4.3) 10.9 (±3.6) .079 • Gender, n. (%) male 94 (81.0) 56 (82.3) 38 (79.2) .666 • HIV transmission modality, n. (%): • Intravenous drug use 47 (40.5) 27 (39.7) 20 (41.7) • MSM 27 (23.3) 22 (32.3) 5 (10.4) .030 • Heterosexuality 40 (34.4) 18 (26.4) 22 (45.8) • Other / unknown 2 (1.7) 1 (1.5 ) 1 (2.1) • HIV clinical stage, n. (%): • - CDC group A or B 56 (48.3) 38 (55.9) 18 (37.5) .051 • - CDC group C 60 (51.7) 30 (44.1) 30(62.5) • Positive HCV serology, n. (%) 56 (47.9) 30 (44.1) 26 (53.0) .244 • CD4 cell count/ml, mean (±SD) 259 (±224) 194 (±167) 350.8 (±259) <.001 • HIV RNA, log cp/ml, mean (±SD), 3.9 (±1.4) 4.6 (±1.1) 3.1 (±1.4) <.001 • Months of HIV infect., mean (±SD) 75.5 (±62.1) 58.1 (±56.1) 99.4 (±62.7) <.001 • Neuropsychological Test Battery ° • Global NPZ4 score* (±SD) -2.4 (±2.5) -2.1 (±1.6) -2.9 (±3.3) .128 • Global NPZ8 score* (±SD) -2.0 (±1.6) -1.7 (±1.2) -2.3 (±1.9) .100 • Trail Making A (±SD) -3.5 (±5.3) -3.1 (±3.7) -3.9 (±6.9) .410 • WAIS-R Digit Span (forward) *(±SD) -0.76 (±1.2) -0.71 (±1.1) -0.83 (±1.3) .656 • WAIS-R Digit Span (back.) *(±SD) -1.22 (±1.2) -1.3 (±1.0) -1.11 (±1.3) .436 • WAIS-R Digit Symbol * (±SD) -1.49 (±1.0) -1.47 (±0.9) -1.5 (±1.1) .848 • Stroop Word and Colour * (±SD) -1.05 (±2.1) -0.88 (±1.6) -1.3 (±2.5) .300 • Corsi Cube test * (±SD) -1.08 (±1.4) -1.11 (±1.2) -1.03 (±1.7) .757 • Trail Making B * (±SD) -4.05 (±4.2) -3.7 (±3.6) -4.46 (±4.9) .395 • Stroop Colour-Word *(±SD) -2.04 (±2.3) -1.85 (±2.0) -2.29 (±2.7) .373 • Controlled Oral Word *(±SD) -1.40 (±1.8) -1.21 (±1.2) -1.67 (±2.4) .283 • Rey Auditory Verbal Learning * (±SD) -1.91 (±1.4) -1.70 (±1.3) -2.18 (±1.4) 078 • Rey Audit. Verb. Learn. at 15’ * (±SD) -2.26 (±1.6) -1.98 (±1.6) -2.61 (±1.5) .049 • Rey Complex Figure (delayed)* (±SD) -1.52 (±1.4) -1.40 (±1.4) -1.65 (±1.4) .469 • L. Grooved (dominant hand) * (±SD) -2.3 (±3.3) -2.17 (±3.2) -2.47 (±3.4) .648 • L. Grooved (non dom. hand) * (±SD) -2.13 (±4.1) -2.01 (±3.1) -2.3 (±5.3) .722 • Rey Complex Figure (copy)* (±SD) -0.76 (±1.6) -0.70 (±1.6) -0.81 (±1.6) .817 • ° All neuropsychological test battery results are given as normalized z-scores • p student’s t-test • * greater negative z-scores reflect greater neurocognitive impairment Factors associated with reversible neurocognitive impairment (NCI) Reversible NCI All patients No Yes p (n=116) (n=81) (n=35) Age in years, mean (±SD) 41.5 (8.4) 40.7 (8.0) 43.4 (9.0) .110 Education in years, mean (±SD) 10.8 (3.9) 10.1 (3.6) 12.4 (4.4).004 Gender, n. (%) female 21 (18.1) 20 (24.7) 2 (5.7) .017 Months of follow-up, mean (±SD) 36.2 (27.7) 35.6 (26.7) 37.6 (30.0) .725 HIV transmission modality, n. (%): - Intravenous drug use 47 (40.2) 37 (45.7) 10 (28.6) - MSM 27 (23.1) 17 (20.9) 10 (28.6) .408 - Heterosexuality 40 (35.0) 25 (30.9) 15 (42.3) - unknown 2 (1.7) 2 (2.5) 0 HIV clinical stage, n. (%): - CDC group A or B 56 (48.7) 35 (43.2) 21 (60.0) .148 - CDC group C 60 (51.3) 46 (56.8) 14 (40.0) Positive HCV serology, n. (%) 56 (47.) 44 (54.3) 12 (34.3) .231 Baseline CD4 cell/ml, mean (±SD) 259 (±224) 268 (±228) 238 (±219) .514 Nadir CD4 cell/ml, mean (±SD) 153 (±137) 142 (±116) 178 (±174) .205 Bas viral load log cp/ml, mean (±SD) 3.93 (±1.4) 3.8 (±1.5) 4.3 (±1.3) .097 Virological suppression (<50 cpml) 66 (60)49 (62.8) 17 (53.1) .346 during HAART n.(%) NPZ4 score, mean (±SD)at baseline -2.42 (±2.5) -2.8 (± 2.7) -1.8 (± 2.1) .078 NPZ8 score (±SD) at baseline -1.97 (±1.6) -2.3 (±1.6) -1.5 (±1.3) .026 Delta NPZ4 score, mean (±SD) 0.86 (±1.8) 0.61(±1.8) 1.24 (±1.9) .178 (first follow-up vs baseline) Delta NPZ8 score, mean (±SD) 0.45 (±1.3) 0.18 (±1.2) 0.84 (±1.3) .044 (first follow-up vs baseline) “Neuroactive HAART”, %* (±SD) 57.4 (±49.2) 59.9 (±54.0) 51.7(±44.5) .369 * % of months of treatment with 2-3 neuroactive drugs (d4T, AZT, ABC, EFV, NVP, IDV) containing HAART 6 4 2 4 1 5 1 Factors associated with reversible NCI in the 116 impaired HIV-positive patients. Results of the logistic regression model Univariate analysisMultivariate analysis Factor OR 95% CI p OR 95% CI p Sex Female 1.00 Male 5.41 1.19-24.58 .029 3.62 0.51-25.5 .196 Education 1.15 1.15-1.04 .006 1.17 0.98-1.38 .070 (for 1 degree increase) CD4 at last visit 1.00 0.99-1.00 .128 1.00 0.99-1.00 .241 (for 1 degree increase) Baseline NPZ8 score 1.63 1.02-2.59 .037 5.53 2.03-5.06 .001 (for 1 degree increase) Delta NPZ8 visit 0-1 1.56 0.99-2.46 .055 6.94 2.39-20.09 <.001 (for 1 degree increase) 7 2 4 3 Main Findings Changes in Neuropsychological Test Battery during HAART. HAART was associated with significant improvements in neuropsychological performances at months 6, 12, 18, 24, 36, 48 of treatment, but no longer beyond the 48th month. The improvement was more prominent in neurocognitive measures exploring mental flexibility and fine motor functioning, and less prominent in neurocognitive measures exploring memory and concentration and speed of mental processing. Prevalence of persistent neurocognitive impairment (NCI). A persistent NCI was observed in 69% of patients, despite 9 years of HAART. Factors associated with persistent neurocognitive impairment. Patients with persistent NCI were less educated (10.1 vs 12.4 years; p=.004), predominantly female (75.3% vs 94.3; p=.017), had a worse baseline mean NPZ8 global score (-2.29 vs -1.47; p=.026), and a lower improvement in mean NPZ8 score between baseline and first follow-up visit ( +0.18 vs +0.84; p=.044). In multivariable analyses, only baseline NPZ8 scores (OR 5.5; 95% CI 2.0-5.0; p=.001) and changes between baseline and first follow-up NPZ8 scores (OR 6.9; 95% CI 2.4-20.1; p<.001) remained significantly associated with persistent NCI. 4 4 Results Patient’s characteristics at enrollment. 116 neurocognitively impaired patients were included. 68 (58.6%) patients were antiretroviral naïve, while 48 (41.4%) were HAART-experienced. HAART-naïve and HAART-experienced patients did not differ in terms of age, education, gender, clinical stage, positive HCV serology, nadir CD4 cell count, peak plasma viral load. As expected, HAART-experienced patients had higher CD4 cell count, lower plasma viral load, longer time since first documented positive HIV test. Finally, the neuropsychological profile did not differ between the two groups. Changes in Neuropsychological (NP) Test Battery during HAART. The changes in NP test results were assessed among the 68 naïve patients only. NP z-scores showed significant (p<.05) improvements after 6, 12, 18, 24, 36, 48 months of HAART, but no longer beyond the 48th month. The improvement was more prominent in neurocognitive measures exploring mental flexibility (71.4% of measures) and fine motor functioning (64.3% of measures) and less prominent in neurocognitive measures exploring memory (28.6% of measures) and concentration and speed of mental processing (21.4% of measures). Prevalence of persistent neurocognitive impairment. Overall, a reversible NCI was observed in 35/116 (30.2%) patients, while a persistent NCI was observed in 81 (69.8%) of patients. After 9 years of HAART the estimated probability of remaining neurocognitively impaired was 69% , by Kaplan-Meier. Factors associated with persistent neurocognitive impairment. Age, CDC stage, risk category, baseline CD4+ count and viral load, virological response to HAART, changes in viral load and CD4+ count, use of CNS penetrating drugs did not differ between patients with persistent or reversible NCI. By contrast, patients with persistent NCI were less educated (10.1 vs 12.4 years; p=.004), predominantly female (24.7% vs 5.7; p=.017), had a worse baseline mean NPZ8 global score (-2.29 vs -1.47; p=.026), and a lower improvement in mean NPZ8 score between baseline and first follow-up ( +0.18 vs +0.84; p=.044). In multivariable analyses, only baseline NPZ8 scores (OR 5.5; 95% CI 2.0-5.0; p=.001) and changes between baseline and first follow-up NPZ8 scores (OR 6.9; 95% CI 2.4-20.1; p<.001) remained significantly associated with persistent NCI. Conclusions Although HAART was associated with a reversal of neurocognitive abnormalities, the impairment persisted in nearly 2/3 of cases despite 9 years of HAART. Less severe impairment and prompt improvement in cognitive performance were both independently associated with reversible NCI. Our data indicate that HAART should be initiated as soon as NCI is diagnosed to avoid a potentially irreversible neurological damage. Additional treatment strategies are needed in patients with persistent NCI despite HAART. 4 3 5 6 4 2 3 7 6 4 7