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Examining the impact of CNS penetration effectiveness (CPE) of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living.

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Presentation on theme: "Examining the impact of CNS penetration effectiveness (CPE) of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living."— Presentation transcript:

1 Examining the impact of CNS penetration effectiveness (CPE) of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: Findings from the Ontario HIV Treatment Network (OHTN) Cohort Study Sean B. Rourke, Ph.D. University of Toronto, Toronto, Canada Ontario HIV Treatment Network St. Michael’s Hospital

2 I have the following potential conflicts of interest: Advisory Board/ Publications/ Honoraria: Abbott Laboratories Research Funding: Canadian Institute for Health Research Public Health Agency of Canada The Ontario HIV Treatment Network CONFLICT OF INTEREST DISCLOSURE

3 Co-Principal Investigators: Dr. Sean B. Rourke OHTN, St. Michael’s Hospital, University of Toronto Dr. Adriana Carvalhal McMaster University, Psychiatry and Behavioral Neurosciences Co-Investigators: Amy R. ZipurskyOHTN, St. Michael’s Hospital Tsegaye BekeleOHTN Dr. Jen McCombeUniv Alberta, Univ Calgary, Department of Medicine Dr. Anita Rachlis University of Toronto, Sunnybrook Health Sciences Center Dr. Evan CollinsUniversity of Toronto, Psychiatry Dr. M. John GillUniversity of Calgary, Department of Medicine Dr. Janet RaboudUniversity Health Network, University of Toronto Dr. Ann BurchellOHTN, McGill University, Oncology INVESTIGATOR TEAM

4 BACKGROUND

5 HIV enters CNS shortly after infection HIV Associated Neurocognitive Disorder (HAND): Antinori et al.  Asymptomatic neurocognitive impairment (ANI)  HIV-associated mild neurocognitive disorder (MND)  HIV-associated dementia (HAD) Introduction of cART has decreased incidence of HAD, but there is evidence of an increased prevalence of MND and ANI Detrimental effect of mild neuropsychological deficits in HIV  Can affect job functioning and decreased performance in those working  Can affect ability to carry out complex tasks  Shown to affect medication adherence  Associated with increased mortality rates THE ISSUE

6  cART can improve NP functioning (but not complete recovery)  Different ARVs have different abilities to penetrate the CNS  Letendre et al., (2006, 2010) developed a system to evaluate the CNS penetration of antiretroviral drugs with respect to neurological outcomes  What we know so far: (1) Increased CNS penetration of ARVs is associated with decreased CNS viral load (most consistent in prospective studies); (2) the relationship between CPE of ARVs and neuropsychological outcomes is more equivocal (potentially because further downstream in effect) THE ISSUE

7 CURRENT LITERATURE REVIEW Author, YearSample SizeDesignNeurocognitive Effects (green-direct association NP, grey- no association NP, blue- CSF viral load) Garvey et al., 2011N=22,356Cross-SectionalCNS disease more frequent with CPE ≤4 and less frequent with CPE ≥10 Smurzyinski et al., 2011N=2,636Cross-Sectional Better NPZ3 scores among individuals with higher CPE taking more than 3 drugs but not in participants with higher CPE taking 3 or fewer drugs Starace et al., 2010 (Conference)N=45Cross-Sectional Higher CPE correlated with neurocognitive performance on measures of working memory, verbal fluency, and executive functions Cysique et al., 2009N=37Longitudinal Higher CPE rank (greater than or equal to 2) was associated with neuropsychological improvement Patel et al., 2009N=2,398Longitudinal ARV regimens with higher CNS penetration were correlated with a 41% reduced incidence of HIV encephalopathy compared to regimens with lower CNS penetration Tozzi et al., 2009N=185Longitudinal Higher CPE scores correlated with greater improvements in NPZ-4, NPZ-8, concentration, and speed of mental processing Sacktor et al., 2001N=73Longitudinal Regimens with CSF penetrating drug improved psychomotor speed but no difference was found between single and multiple CSF penetrating drugs Garvey et al., 2011 (Conference)N=101Cross-SectionalNo association between neurocognitive performance and CPE in an asymptomatic sample Ciccarelli, et al., 2011N=146Cross-SectionalNo association between CPE rank and cognitive impairment in an asymptomatic sample Picchi et al., 2011 (Conference)N=219Cross-Sectional Higher CPE 2010 associated with lower HIV-RNA in CSF in patients with supressed viral load but not in patients with detectable viral load Letendre et al., 2010 (Conference)N=1,221Cross-SectionalHigher CPE (modified system) were correlated with lower CSF viral load Marra et al., 2009N=79LongitudinalOdds of suppression of CSF HIV RNA were higher when CPE was 2 or greater Letendre et al., 2008N=467Cross-SectionalLower CPE rank (less than 2) correlated with higher CSF viral load Letendre et al., 2006 (Conference)N=374Cross-SectionalHigher CNS penetration scores were correlated with lower CSF viral load, with and without adjusting for total number of ART

8 To assess the association of CNS penetration of ARV regimen and neuropsychological functioning in people living with HIV in Ontario Hypothesis: Individuals on antiretroviral regimens with higher CPE rankings will perform better overall on measures of neuropsychological functioning (global, domains) MAJOR OBJECTIVE

9 METHODS

10 PARTICIPANTS AND TESTING  834 participants were recruited from two hospital-based clinics in Toronto, Canada that are part of the Ontario HIV Treatment Network Cohort Study (OCS), a longitudinal cohort of 5,000 people living with HIV collected at 10 sites across the province  Neuropsychological tests were administered as part of the annual data collection of the OCS  Medical information retrieved by chart abstraction  Sample is restricted to participants with both neuropsychological and medical information available. Frequency of neuropsychological assessments:  Time 1: 338  Time 2: 271  Time 3: 218  Time 4: 007

11 SAMPLE Completed Neuropsychological Tests Sample Size=834 Observations=1,562 Final Sample Sample=529 Observations=864 Excluded ARV Naïve, N=211 Suboptimal ARV, N=94

12 CharacteristicsOn >=3 ARVs (Included) N=529 On suboptimal ARVs N=94 Not on ARVs N=211 P value Age in years (mean, SD)48.6 (10.1)47.9 (9.9)48.5 (10.2)<0.001 b,c Male (n,%)439 (83%)69 (73%)156 (74%)0.006 a,b Caucasian (n,%)323 (61%)63 (67%)113 (54%)0.055 Born in Canada (n,%)299 (57%)59 (63%)118 (56%)0.491 Speak English at home (n,%)445 (84%)79 (84%)176 (83%)0.972 Years of education (mean, SD)13.8 (2.7)13.8 (2.3)13.3 (3.0)0.056 Currently employed (n,%)248 (47%)43 (46%)84 (40%)0.215 Personal annual income < $30K (n,%)280 (53%)57 (61%)146 (69%)<0.001 b Recent CD4 count < 500 cells/ml (n,%)242 (46%)45 (48%)111 (53%)0.241 Nadir CD4 < 200 cells/ml (n,%)353 (67%)65 (69%)67 (32%)<0.001 b,c Log viral load (mean, SD)4.1 (1.0)4.3 (1.3)2.6 (1.2)<0.001 c Diagnosed with HCV (n,%)49 (9%)10 (11%)28 (13%)0.273 Years since HIV diagnosis (mean, SD)13.1 (6.8)14.0 (6.7)9.2 (7.4)<0.001 b,c Used substances in the past 6 months (n,%)68 (13%)9 (10%)43 (20%)0.012 b,c Depressive symptoms - CES-D score (Mean, SD)12.0 ( 11.7)11.4 (11.1)14.2 (12.5)0.049 b Alcohol use - AUDIT-10 score (Mean, SD)3.4 (4.3)3.7 (4.8)7.0 (2.8)<0.001 b SAMPLE – COMPARISON INCLUDED AND EXCLUDED a – difference between those on >=3 ARVs and on suboptimal ARVs is significant (p<0.05) b - difference between those on >=3 ARVs and Not on ARVs is significant (p<0.05) c - difference between those on suboptimal ARVs and Not on ARVs is significant (p<0.05)

13 COMPUTATION OF NEUROPSYCHOLOGICAL SCORES  Raw scores were converted into demographically corrected T-scores (corrected for Age, gender, education, race/ethnicity). 6 NP tests were categorized into 3 domains  T-scores were converted below into deficit scores for each test using Carey et al (2004) algorithm  NP Deficit Scores: 5 Impairment levels were collapsed into 2 categories (i.e., NP normal v NP impaired) Neuropsychological TestMeasurementDomain Evaluated Digit SymbolDigit Symbol Score Motor Efficiency Grooved PegboardDominant Hand Score Non-dominant Hand Score Spatial SpanSpatial Span ScoreSpatial Working Memory Hopkins Verbal LearningTotal Learning Score Delayed Recall Score Memory T scoresDeficit ScoresImpairment Descriptor ≥400Normal Mild Mild-to-Moderate Moderate Moderate-to-Severe ≤195Severe Carey, C.L., Woods, S.P., Gonzalez, R., Conover, E., Marcotte, T.D., Grant, I., Heaton, R.K., & the HNRC Group (2004). Predictive Validity of Global Deficit Scores in Detecting Neuropsychological Impairment in HIV Infection. Journal of Clinical and Experiment Neuropsychology, 26,

14 Two major ways to evaluate neurocognitive impairment: 1.Global Neuropsychological (NP) Impairment Rating, Heaton et al (1991): at least mild neuropsychological impairment on 2 or more ability domains 2.Global NP Deficit Score, Carey et al (2004): total sum of deficits scores for all tests were ≥0.50 cut-off METHODS TO CALCULATE IMPAIRMENT

15 Letendre S, et al. 13th CROI, Denver 2006, Abstract #74 CPE RANKING SYSTEM NRTIs Abacavir Zidovudine Emtricitabine Lamivudine Stavudine Didanosine Tenofovir Zalcitabine NNRTIs Delavirdine Nevirapine Efavirenz PIs Amprenavir-r Indinavir-r Lopinavir-r Amprenavir Atazanavir Atanzanavir-r Indinavir Nelfinavir Ritonavir Saquinavir Saquinavir-r Tipranavir-r Fusion Enfuvirtide

16 Letendre S, et al. 17th CROI, San Francisco CA 2010, Oral #172 CPE RANKING SYSTEM NRTIs Zidovudine Abacavir Emtricitabine Lamavudine Stadudine Didanosine Tenofovir Zalcitabine NNRTIs Nevirapine Delavirdine Efavirenz Etravirine PIs Indinavir-r Duranavir-r Fosamprenivir-r Indinavir Lopinavir-r Atazanavir-r Atazanavir Fosamprenavir Nelfinavir Ritonavir Saquinavir-r Tipranavir-r Entry Inhs MaravirocEnfuvirtide Integrase Inhs Raltegravir

17 COMPARISON OF CPE RANKING SYSTEMS 2006 AND 2010 Letendre S, et al. 17th CROI, San Francisco CA 2010, Oral #172

18 Letendre, S., Marquie-Beck, J., Capparelli, E., Best, B., Clifford, D., Collier, A. C. et al. (2008). Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch.Neurol., 65, DICHOTOMIZED CPE SCORES 2006

19 For the Present Investigation: Breakdown of sample: 1) CPE rank 2006  Mean CPE= 1.57, Median=1.50  Group 1 (CPE <=1.5:52.9%)  Group 2 (CPE>1.5:47.1%) * Same as Letendre et al., 2008 dichotomized scores 2) CPE rank 2010  Mean CPE= 7.08, Median=7.00  Group 1 (CPE <=7:40.0%)  Group 2 (CPE>7:60.0 %) DICHOTOMIZED CPE SCORES - PRESENT

20 RESULTS

21 BASELINE CHARACTERISTICS OF PARTICIPANTS (N=834) CharacteristicsGlobal Deficit Scores: < 0.5 (n=364) Global Deficit Scores: ≥ 0.5 (n=470) p Age in years (mean, SD)46.6 (9.8)47.2 (10.9)0.395 Male (n,%)356 (85%)308 (76%)0.002 Caucasian (n,%)231 (64%)268 (57%)0.060 Years of education (mean, SD)13.5 (2.7)13.8 (2.7)0.153 Born in Canada (n,%)232 (64%)244 (52%)0.006 Speak English at home (n,%)317 (87%)383 (81%)0.029 Currently employed (n,%)193 (53%)182 (39%)<0.001 Personal Annual income < $30K (n,%)197 (54%)286 (61%)0.051 Recent CD4 count < 500 cells/ml (n,%)169 (46%)229 (49%)0.511 Nadir CD4 < 200 cells/ml (n,%)291 (53%)194 (62%)0.012 Recent viral load (Log 10) (mean, SD)4.9 (2.1)4.8 (2.0)0.673 Diagnosed with HCV829 (%)58 (12%)0.040 Years since HIV diagnosis (mean, SD)12.3 (7.3)12.2 (7.0)0.935 Used substances in the past 6 months (n,%)55 (15%)65 (14%)0.601 Alcohol use - AUDIT-10 score (Mean, SD)4.3 (5.1)3.3 (4.8)0.004 Depressive symptoms - CES-D score (Mean, SD)11.8 (11.6)13.0 (12.0)0.134 Global deficit score is computed as the average of Spatial Span, Digit Symbol, Grooved Pegboard, and HVLT tests deficit scores following Carey et al’s (2004) algorithm

22 Global Deficit Score ≥ 0.5 by CPE 2006 (N=834, p=0.06)

23 Global Deficit Score ≥ 0.5 by CPE 2010 (N=834, p=0.41)

24 NEUROPSYCHOLOGICAL IMPAIRMENT BY CPE 2006 (N=529)

25 NEUROPSYCHOLOGICAL IMPAIRMENT BY DOMAIN (N=529) – CPE 2006

26 NEUROPSYCHOLOGICAL IMPAIRMENT CLASSIFICATIONS (N=529) – CPE 2006

27 Dependent Variable  Neuropsychological Outcomes Covariates  Age at interview (Years)  Race (White / Black/ Other)  Gender (Male / Female)  Education (Years)  HCV Diagnosis (Yes/No)  Current CD4 count ( = 500)  Dichotomized ARV CPE (High/Low)  Time HIV positive (Years)  Closest viral load value from interview date (log)  CD4 nadir ( =200)  Drug Use Last Six Months (Yes/No)  Depressive Symptoms (CES-D total score) GENERALIZED ESTIMATING EQUATION (GEE)

28 GENERALIZED ESTIMATING EQUATION RESULTS Neuropsychological Impairment Measure (Impaired or Not) CPE 2010*CPE 2006** Global Impairment Rating1.08 (0.78, 1.50)1.05 (0.77, 1.43) Global Deficit Score (>0.5)1.08 (0.77, 1.52)1.32 (0.96,1.80) Global Deficit Score (>1.0)1.07 (0.76, 1.52)1.15 (0.83, 1.60) NOTE: Numbers reported are Odds Ratio (95% CI) from GEE models * CPE > 7 vs. CPE <=7 ** CPE > 1.5 vs. CPE <= 1.5

29 GENERALIZED ESTIMATING EQUATION Neuropsychological Test (T-Scores) CPE 2010*CPE 2006** Spatial Span Pegboard Dominant Hand Pegboard ND Hand Hopkins Recall Hopkins Delayed Recall Digit Symbol Motor Efficiency Domain Working Memory Domain Memory Domain NOTE: Numbers reported are unstandardized regression coefficients from linear GEE models * CPE > 7 vs. CPE <=7 ** CPE > 1.5 vs. CPE <= 1.5 Observations=864

30 SIGNIFICANT COVARIATES – FULL SAMPLE (OBS=864) CPE ranking Spatial Span Peg DH Peg NDH HVLT Recall HVLT DRecall Digit Symbol MEFFSWMMEM Age2006XXX 2010XXX Race2006XXXXXXX 2010XXXXXXX Gender2006XXXX 2010XXXX Education2006XX 2010XXX History of HCV Diagnosis 2006XXXXXX 2010XXXXXX CD4 Nadir2006XX 2010XX Time since HIV Diagnosis Current Viral Load2006XX 2010XX Current CD4 Count Drug use in the Past 6 Months 2006XXXXX 2010XXXXX Depressive Symptoms 2006XXXXXXX 2010XXXXXXX

31 Neuropsychological Impairment among participants who completed two NP evaluations (N=218)

32 Neuropsychological Impairment among participants who completed two NP evaluations and were on >=3 ARVs at baseline (N=127) NOTE: 2006 CPE ranking was used.

33 CONCLUSIONS

34  No effect of CPE scores on overall neuropsychological (NP) outcomes but specific effect were seen on individual domains using Letendre 2006 criteria (but not using the 2010 criteria): (1) negative effect on motor functioning (2) positive effect on spatial working memory  Our results are consistent with other neuropsychological studies of CPE (Smurzyinski et al., 2011; Starace et al., 2010, Cysique et al., 2009; and Tozzi et al., 2009; however, our results need to be replicated prospectively, and we need to identify why our results were not consistent across both criteria  NP outcomes are downstream effects – we will need to explore other ARV effects (timing / length), methodological issues (better matching) and confounding comorbidities (e.g., HCV)CONCLUSIONS

35 Igor G, Canada Presentation, 2011,

36 Thank You Examining the impact of CNS penetration effectiveness (CPE) of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: Findings from the Ontario HIV Treatment Network (OHTN) Cohort Study Sean B. Rourke, Ph.D. University of Toronto, Toronto, Canada St. Michael’s Hospital Ontario HIV Treatment Network

37 EXTRA: Sample Info Region of BirthN(%) Africa131(37%) Caribbean65(18%) South Asia10(3%) Asia21(6%) Europe56(16%) North America28(8%) South America31(9%) Central America8(2%) Other9(3%) Total358100% Geographic region of birth of Foreign-born participants (N=358)

38 BASELINE CHARACTERISTICS OF PARTICIPANTS BY PLACE OF BIRTH (N=834) CharacteristicsBorn in Canada (n=476) Born in other countries (n=358) p Age in years (mean, SD)48.2 (10.1)45.3 (10.7)<0.001 Male (n,%)423 (88%)241 (67%)<0.001 Caucasian (n,%)421 (88%)78 (22%)<0.001 Years of education (mean, SD)13.7 (2.7)13.5 (2.8)0.395 Speak English at home (n,%)460 (97%)240 (67%)<0.001 Currently employed (n,%)213 (45%)162 (45%)0.885 Personal annual income < $30K (n,%)246 (52%)237 (66%)<0.001 Recent CD4 count < 500 cells/ml (n,%)222 (47%)176 (49%)0.470 Nadir CD4 < 200 cells/ml (n,%)281 (59%)204 (57%)0.552 Recent viral load (Log 10) (mean, SD)4.8 (2.0)4.9 (2.1)0.383 Diagnosed with HCV (n,%)63 (13%)24 (7%)<0.001 Years since HIV diagnosis (mean, SD)13.8 (7.3)10.1 (6.3)<0.001 Used substances in the past 6 months (n,%)94 (20%)26 (7%)<0.001 Alcohol use - AUDIT-10 score (Mean, SD)4.5 (5.3)2.6 (4.2)<0.001 Depressive symptoms - CES-D score (Mean, SD)13.1 (12.4)12.0 (11.4)0.195

39 BASELINE CHARACTERISTICS OF NP IMPAIRED (GDS > 0.5) PARTICIPANTS BY PLACE OF BIRTH (N=470) CharacteristicsBorn in Canada (n=244) Born in other countries (n=226) p Age in years (mean, SD)49.4 (10.6)44.8 (10.8)<0.001 Male (n,%)208 (85%)148 (65%)<0.001 Caucasian (n,%)214 (88%)54 (24%)<0.001 Years of education (mean, SD)13.9 (2.6)13.6 (2.9)0.279 Speak English at home (n,%)236 (97%)147 (65%)<0.001 Currently employed (n,%)89 (36%)93(41%)0.299 Personal annual income < $30K (n,%)137 (56%)149 (66%)<0.030 Recent CD4 count < 500 cells/ml (n,%)119 (49%)110 (49%)0.983 Nadir CD4 < 200 cells/ml (n,%)158(65%)133 (59%)0.188 Recent viral load (Log 10) (mean, SD)4.7 (2.0)4.9 (2.1)0.189 Diagnosed with HCV (n,%)38 (16%)20 (9%)<0.027 Years since HIV diagnosis (mean, SD)14.3 (7.1)10.0 (6.3)<0.001 Used substances in the past 6 months (n,%)47 (19%)18 (8%)<0.001 Alcohol use - AUDIT-10 score (Mean, SD)4.0 (5.2)2.5 (4.3)<0.001 Depressive symptoms - CES-D score (Mean, SD)12.7 (11.5)13.3 (12.5)0.573

40 GENERALIZED ESTIMATING EQUATION- GDS >=0.5 ONLY Neuropsychological Test (T-Scores) CPE 2010CPE 2006 Spatial Span Pegboard Dominant Hand Pegboard Non-dominant Hand Hopkins Recall Hopkins Delayed Recall Digit Symbol Motor Efficiency Domain Spatial Working Memory Domain Memory Domain NOTE: Numbers reported are unstandardized regression coefficients from linear GEE models * CPE > 7 vs. CPE <=7 ** CPE > 1.5 vs. CPE <= 1.5 Observations=483

41 GENERALIZED ESTIMATING EQUATION Neuropsychological Test (T-Scores) CPE 2010CPE 2006 Foreign- Born (obs=349) Canadian- Born (obs=515) Foreign- Born (obs=349) Canadian-Born (obs=515) Spatial Span Pegboard Dominant Hand Pegboard Non-dominant Hand Hopkins Recall Hopkins Delayed Recall Digit Symbol Motor Efficiency Domain Spatial Working Memory Domain Memory Domain NOTE: Numbers reported are unstandardized regression coefficients from linear GEE models * CPE > 7 vs. CPE <=7 ** CPE > 1.5 vs. CPE <= 1.5

42 GENERALIZED ESTIMATING EQUATION Neuropsychological Impairment Measure (Impaired or Not) CPE 2010CPE 2006 Foreign- Born (obs=349) Canadian- Born (obs=515)* Foreign- Born (obs=349) Canadian- Born (obs=515)** Global Impairment Rating1.38 (0.84, 2.26) 0.86 (0.55, 1.35) 1.04 (0.64, 1.70) 1.07 (0.70,1.63) Global Deficit Score (>0.5)1.50 (0.91, 2.49) 0.91 (0.57,1.46) 1.42 (0.88, 2.32) 1.40 (0.90, 2.17) Global Deficit Score (>1.0)0.98 (0.58, 1.67) 1.11 (0.69, 1.79) 0.78 (0.46, 1.32) 1.70 (1.07,2.67) NOTE: Numbers reported are Odds Ratio (95% CI) from GEE models * CPE > 7 vs. CPE <=7 ** CPE > 1.5 vs. CPE <= 1.5

43 GENERALIZED ESTIMATING EQUATION Neuropsychological Impairment Measure (Impaired or Not) CPE 2010CPE 2006 Foreign- Born (obs=349) Canadian- Born (obs=515)* Foreign- Born (obs=349) Canadian- Born (obs=515)** Global Impairment Rating 1.38 (0.84, 2.26) 0.86 (0.55, 1.35) 1.04 (0.64, 1.70) 1.07 (0.70,1.63) Global Deficit Score (>0.5) 1.50 (0.91, 2.49) 0.91 (0.57,1.46) 1.42 (0.88, 2.32) 1.40 (0.90, 2.17) Global Deficit Score (>1.0) 0.98 (0.58, 1.67) 1.11 (0.69, 1.79) 0.78 (0.46, 1.32) 1.70 (1.07,2.67) NOTE: Numbers reported are Odds Ratio (95% CI) from GEE models * CPE > 7 vs. CPE <=7 ** CPE > 1.5 vs. CPE <= 1.5


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