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Use of efavirenz is not associated to an increased risk of neurocognitive impairment in HIV-infected patients. Pinnetti C 1 , Balestra P 1 , Libertone R 1 , Lorenzini P 1 , Cozzi-Lepri A 2 , Ammassari A 1 , Ricottini M 1 , Menichetti S 1 , Tozzi V 1 , Antinori A 1.

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  1. Use of efavirenz is not associated to an increased risk of neurocognitive impairment in HIV-infected patients Pinnetti C1, Balestra P1, Libertone R1, Lorenzini P1, Cozzi-Lepri A2, Ammassari A1, Ricottini M1, Menichetti S1, Tozzi V1, Antinori A1 1Clinical Department, National Institute for InfectiousDiseases Lazzaro Spallanzani IRCCS, Roma, Italy; 2Research Department of Infection & PopulationHealth, University College London, London, United Kingdom.

  2. Disclosures Personal fees for consultancy and lectures from Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck, ViiV. Travel grants from Abbvie. Research grants from Bristol Myers Squibb, Gilead, Janssen, ViiV.

  3. Background • Efavirenz (EFV) iscurrentlyrecommendedas a preferred component of ARV regimens for treatment-naïve patients in most of ART guidelines. • Due to patentexpiry in 2013, EFV isnowavailableas a genericdrug. • EFV has been associated to a well recognized neuropsychiatric side effect pattern1, but an association with neurocognitive impairment (NCI) was not originally confirmed in a randomized trial in ARV naive2. • More recently, EFV has been related to a worse neurocognitive function3-4, but this association remains controversial. 1Mills A, et al. HIV Med 2013;14:391-400; Clifford DB, et al. AnnInternMed 2005;143:714-721; 3Ciccarelli N, et al. Neurology, 2011;76:1403-1409; 4Letendre S, et al. 20th CROI, Atlanta, GA, 2013; Poster #407.

  4. Objectives • Aim of the study was: • to evaluate if patients receiving an EFV-based regimen had a worse neurocognitive performance compared to patients currently receiving an ARV regimen not including EFV; • to estimate the risk of NCI independently associated to EFV current use. • The prevalence and severity of HIV-associated neurocognitive disorders (HAND) according to EFV current use was also investigated.

  5. Methods • Single-centre, retrospective, cross-sectional analysis of cART-treated HIV-infected patients undergoing neuropsychological assessment (NPA). • NPA was carried out by a set of 14 standardized and comprehensive tests on 5 different domains. • People wereclassifiedashaving NCI iftheyscored>1 standard deviation (SD) below the normalmean in atleast 2 tests, or >2 SD below in 1 test. • Asadditionalbinaryoutcome, HIV-associated neurocognitive disorders (HAND) were classified according to Frascati’s criteria (Neurology, 2007).Clinicaldepression and otherpsychiatricdisordershasbeencontrolledasconfounders. • Z-Scores (negvaluesif performance wasbelow the mean) wereusedascontinuousoutcome: • Global NPZ-8 Deficit Score • Z-Scores for each Cognitive Domain

  6. NP Battery and Domains • Memory • Rey Auditory Verbal Learning (immediate recall) • Rey Auditory Verbal Learning (delayed recall) • Rey Complex Figure (delayed recall) • Fine Motor Functioning • Lafayette Grooved Pegboard (dominant hand) • Lafayette Grooved Pegboard (non dominant hand) • Visuospatial and Constructional Abilities • Rey Complex Figure (copy) • Concentration and Speed of Mental Processing • Trail Making A • WAIS-R Digit Span (forward) • WAIS-R Digit Span (backward) • WAIS –R Digit Symbol • Stroop Test (word and color) • Corsi's Block-Tapping Test • Mental Flexibility • Trail Making B • Stroop test (color and word) • Controlled Oral Association Test

  7. Statistical analyses • Comparisonsbetweencurrently EFV-exposed and currently EFV-notexposed • Mann-Whitneytest and Spearman’s Rho for continuousvariables • Chi-square test for categoricalvariables • Univariable and multivariable logistic and linear regression models were fitted. • Variables were retained in multivariable analysis if they had a p-value <0.05.

  8. Patientscharacteristics(1020 consecutive NPA over 859 patients)

  9. NCI impairment by EFV current use(NPZ-8) NPZ-8 by months of drugexposure for EFV currentregimen Spearman'srho=-0.029; P=0.525 P=0.291 at univariableanalysis (Mann-Whitney test) Median (IQR) exposureto current EFV regimen: 30 months (12-40). Difference in slope for NPZ-8 from fitting multivariable linear regression models for patients receiving EFV vs those not receiving the drug [Beta -0.04 (95%CI -0.18; 0.09) p=0.514]

  10. EFV currentuse and NCI risk(Unadjusted and adjustedrisk by logisticregression) * Subjects are definedasneurocognitivellyimpairediftheyscored>1 standard deviation (SD) below the normalmean in atleast 2 tests, or >2 SD below in 1 test. ^ Sensitivityanalysisincludingonly the 859 subjectsat the first NP assessment. # Risk of neurocognitiveimpairment for EFV currentuse. § Adjusted for age, mode of HIV transmission, years of education, CDC C stage, HCV-Ab positivity, nadir CD4, HIV-RNA and CD4 at NPA, haemoglobinand BMI at NPA, NRTI combination in the currentregimen, calendaryear of NPA) Olderage, IVDU, HCV-Ab+, CDC-C stage, wererelated to an increasedrisk of NCI; current CD4 >500 and years of schooling to a decreasedrisk. Gender, CD4 nadir, HIV-RNA undetectableat NPA, anemia, BMI and CPE 2010 notassociated.

  11. Factorslikely to haveconfounded the association(crude and adjusted OR of NCI by EFV exposure) Current EFV use was associated with a significantly decreased risk of NCI at univariable analysis (OR: 0.71 vs. no EFV; 95%CI 0.54-0.94), but no longer significant after controlling for potential confounding (OR: 1.02; 95%CI 0.74-1.41).

  12. EFV currentexposure and HAND occurrence *EFV-exposedindividualshada significantlowerrisk to have a symptomatic HAND (MND/HAD) by univariateanalysis.

  13. Beta and 95%CI of Z-score for cognitive areas from fitting multivariable linear regression models for patients receiving EFV vs those not receiving the drug Fullymodelswereadjusted for gender, age, years of education, mode of HIV transmission, CDC-C stage, HCVAbpositivity, nadir CD4, CD4 cellcount/mmc and HIV-RNA cp/mLat NPA, haemoglobinevalue, BMI, NRTI backbone in the currentregimen.

  14. Limitations • Observationalnature of design • channelingbias (if EFV preferablyallocated in individualsatlow-risk of developing NCI); • unmeasuredconfounders (e.g. drugadherence). • Cross-sectionalanalysis • reverse causality (if EFV wasavoided in patients with NCI); • notconsideredthe effectsof previousregimensexposures. • Major depressioncontrolledas a confounder, but a systematicalassessment of depression (e.g. BDI-II, PHQ-9 or CES-D) wasnotperformed in allsubjects.

  15. Conclusions • In this large case series, EFV exposure was not associated with an increased risk of NCI. • Current EFV use was associated with a 30% decreased risk of NCI at univariable analysis, but no longer significant after controlling for schooling and other potential confounding. • In subjects receiving EFV, no increased risk of HAND occurred. • The duration of EFV exposure was not related to worse neurocognitive performance. • No increased risk of impairment according to specific domains was observed in EFV-exposed. • Eventhoughconfounding by indicationmay play a role, and reverse causalitycannot be ruledout, ourresultssuggestthatpresenceof NCI amongpersonstreated with EFV-based cART isnot more common than in peoplenottreated with EFV

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