examining the impact of cns penetration effectiveness (cpe) of combination antiretroviral treatment...

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, CanadaOntario HIV Treatment NetworkSt. Michael’s Hospital

I have the following potential conflicts of interest:

Advisory Board/ Publications/ Honoraria: Abbott Laboratories

Research Funding:Canadian Institute for Health ResearchPublic Health Agency of Canada The Ontario HIV Treatment Network

CONFLICT OF INTEREST DISCLOSURE

Co-Principal Investigators:

Dr. Sean B. RourkeOHTN, St. Michael’s Hospital, University of Toronto

Dr. Adriana CarvalhalMcMaster University, Psychiatry and Behavioral Neurosciences

Co-Investigators: Amy R. Zipursky OHTN, St. Michael’s HospitalTsegaye Bekele OHTNDr. Jen McCombe Univ Alberta, Univ Calgary, Department of MedicineDr. Anita Rachlis University of Toronto, Sunnybrook Health Sciences CenterDr. Evan Collins University of Toronto, PsychiatryDr. M. John Gill University of Calgary, Department of MedicineDr. Janet Raboud University Health Network, University of TorontoDr. Ann Burchell OHTN, McGill University, Oncology

INVESTIGATOR TEAM

BACKGROUND

• 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

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

CURRENT LITERATURE REVIEW

Author, Year Sample Size Design Neurocognitive Effects (green-direct association NP, grey- no association NP, blue- CSF viral load)

Garvey et al., 2011 N=22,356 Cross-Sectional CNS disease more frequent with CPE ≤4 and less frequent with CPE ≥10

Smurzyinski et al., 2011 N=2,636 Cross-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=45 Cross-Sectional Higher CPE correlated with neurocognitive performance on measures of working memory, verbal fluency, and executive functions

Cysique et al., 2009 N=37 Longitudinal Higher CPE rank (greater than or equal to 2) was associated with neuropsychological improvement

Patel et al., 2009 N=2,398 Longitudinal 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., 2009 N=185 Longitudinal Higher CPE scores correlated with greater improvements in NPZ-4, NPZ-8, concentration, and speed of mental processing

Sacktor et al., 2001 N=73 Longitudinal 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=101 Cross-Sectional No association between neurocognitive performance and CPE in an asymptomatic sample

Ciccarelli, et al., 2011 N=146 Cross-Sectional No association between CPE rank and cognitive impairment in an asymptomatic sample

Picchi et al., 2011 (Conference) N=219 Cross-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=1,221 Cross-Sectional Higher CPE (modified system) were correlated with lower CSF viral load

Marra et al., 2009 N=79 Longitudinal Odds of suppression of CSF HIV RNA were higher when CPE was 2 or greater

Letendre et al., 2008 N=467 Cross-Sectional Lower CPE rank (less than 2) correlated with higher CSF viral load

Letendre et al., 2006 (Conference) N=374 Cross-Sectional Higher CNS penetration scores were correlated with lower CSF viral load, with and without adjusting for total number of ART

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

METHODS

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

SAMPLE

Completed Neuropsychological Tests

Sample Size=834Observations=1,562

Final SampleSample=529

Observations=864

ExcludedARV Naïve, N=211

Suboptimal ARV, N=94

Characteristics On >=3 ARVs(Included)

N=529

On suboptimal ARVsN=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)

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 Test Measurement Domain Evaluated

Digit Symbol Digit Symbol ScoreMotor Efficiency

Grooved Pegboard Dominant Hand ScoreNon-dominant Hand Score

Spatial Span Spatial Span Score Spatial Working Memory

Hopkins Verbal Learning Total Learning ScoreDelayed Recall Score

Memory

T scores Deficit Scores Impairment Descriptor

≥40 0 Normal

39-35 1 Mild

34-30 2 Mild-to-Moderate

29-25 3 Moderate

24-20 4 Moderate-to-Severe

≤19 5 Severe

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, 307-319.

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

Letendre S, et al. 13th CROI, Denver 2006, Abstract #74

CPE RANKING SYSTEM 2006

1 0.5 0

NRTIs AbacavirZidovudine

EmtricitabineLamivudineStavudine

DidanosineTenofovirZalcitabine

NNRTIs DelavirdineNevirapine Efavirenz

PIsAmprenavir-rIndinavir-rLopinavir-r

AmprenavirAtazanavirAtanzanavir-rIndinavir

NelfinavirRitonavirSaquinavirSaquinavir-rTipranavir-r

Fusion Enfuvirtide

Letendre S, et al. 17th CROI, San Francisco CA 2010, Oral #172

CPE RANKING SYSTEM 2010

4 3 2 1

NRTIs Zidovudine AbacavirEmtricitabine

LamavudineStadudine

DidanosineTenofovirZalcitabine

NNRTIs Nevirapine DelavirdineEfavirenz Etravirine

PIs Indinavir-rDuranavir-rFosamprenivir-rIndinavirLopinavir-r

Atazanavir-rAtazanavirFosamprenavir

NelfinavirRitonavirSaquinavir-rTipranavir-r

Entry Inhs Maraviroc Enfuvirtide

Integrase Inhs Raltegravir

COMPARISON OF CPE RANKING SYSTEMS 2006 AND 2010

Letendre S, et al. 17th CROI, San Francisco CA 2010, Oral #172

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, 65-70.

DICHOTOMIZED CPE SCORES 2006

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

RESULTS

BASELINE CHARACTERISTICS OF PARTICIPANTS (N=834)

Characteristics Global 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 HCV 829 (%) 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

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

Not on ARV N=175

CPE<=0.5 N=53

CPE=1

N=225

CPE=1.5

N=117

CPE=2 N=151

CPE>2.5

N=113

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

CPE Ranking 2006

Prev

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

Not on ARV

N=175

CPE <=5

N=103

CPE=6

N=83

CPE=7 N=251

CPE=8 N=111

CPE>=9 N=111

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

CPE Ranking 2010

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NEUROPSYCHOLOGICAL IMPAIRMENT BY CPE 2006 (N=529)

Spatial Span Peg Dom Peg Ndom Digit Symbol HVLT Recall HVLT Drecall0

10

20

30

40

50

60

CPE≤1.5

CPE>1.5

Neuropsychological Measure

Mea

n T-

Scor

e

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

Spatial Working Memory Motor Efficiency Memory0

10

20

30

40

50

60

CPE≤1.5

CPE>1.5

Neuropsychological Domain

Mea

n-Ts

core

NEUROPSYCHOLOGICAL IMPAIRMENT CLASSIFICATIONS (N=529) – CPE 2006

Global Deficit Score ≤0.5 Global Impairment Rating0

10

20

30

40

50

60

70

CPE≤1.5

CPE>1.5

Impairment Measure

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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 / >= 500) Dichotomized ARV CPE (High/Low) Time HIV positive (Years) Closest viral load value from interview date (log) CD4 nadir (< 200/ >=200) Drug Use Last Six Months (Yes/No) Depressive Symptoms (CES-D total score)

GENERALIZED ESTIMATING EQUATION (GEE)

GENERALIZED ESTIMATING EQUATION RESULTS

Neuropsychological Impairment Measure

(Impaired or Not)

CPE 2010* CPE 2006**

Global Impairment Rating 1.08 (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

GENERALIZED ESTIMATING EQUATION

Neuropsychological Test (T-Scores)

CPE 2010* CPE 2006**

Spatial Span 1.60 1.66Pegboard Dominant Hand -0.72 -1.15Pegboard ND Hand -0.77 -1.01Hopkins Recall 0.17 -0.99Hopkins Delayed Recall 0.54 -0.74

Digit Symbol -1.47 -1.77Motor Efficiency Domain -1.46 -1.61Working Memory Domain 1.60 1.66Memory Domain 0.33 -0.89

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

SIGNIFICANT COVARIATES – FULL SAMPLE (OBS=864)

CPE ranking

Spatial Span

Peg DH

Peg NDH

HVLT Recall

HVLT DRecall

Digit Symbol

MEFF SWM MEM

Age 2006 X X X

2010 X X X

Race 2006 X X X X X X X

2010 X X X X X X X

Gender 2006 X X X X

2010 X X X X

Education 2006 X X

2010 X X X

History of HCV Diagnosis

2006 X X X X X X

2010 X X X X X X

CD4 Nadir 2006 X X

2010 X X

Time since HIV Diagnosis

2006

2010

Current Viral Load 2006 X X

2010 X X

Current CD4 Count 2006

2010

Drug use in the Past 6 Months

2006 X X X X X

2010 X X X X X

Depressive Symptoms

2006 X X X X X X X

2010 X X X X X X X

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

On >=3 ARVs (n=127) On suboptimal ARV (n=52) Not on ARV (n=92)0.4

0.45

0.5

0.55

0.6

0.65

0.7

0.59

0.63

0.57

0.54

0.63

0.58

Baseline Follow-up

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Neuropsychological Impairment among participants who completed two NP evaluations and were on >=3 ARVs at baseline (N=127)

High CPE (n=79) Low CPE (n=48)0.4

0.45

0.5

0.55

0.6

0.65

0.7

0.62

0.560.54 0.54

Baseline Follow-up

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NOTE: 2006 CPE ranking was used.

CONCLUSIONS

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

Igor G, Canada Presentation, 2011, http://hnrc.hivresearch.ucsd.edu/

NEUROTOXICITY

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. ([email protected])University of Toronto, Toronto, CanadaSt. Michael’s HospitalOntario HIV Treatment Network

EXTRA: Sample Info

Region of Birth N (%)

Africa 131 (37%)

Caribbean 65 (18%)South Asia 10 (3%)

Asia 21 (6%)

Europe 56 (16%)

North America 28 (8%)

South America 31 (9%)

Central America 8 (2%)Other 9 (3%)Total 358 100%

Geographic region of birth of Foreign-born participants (N=358)

BASELINE CHARACTERISTICS OF PARTICIPANTS BY PLACE OF BIRTH (N=834)

Characteristics Born 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


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


Nadir CD4 < 200 cells/ml (n,%) 281 (59%) 204 (57%) 0.552


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


BASELINE CHARACTERISTICS OF NP IMPAIRED (GDS > 0.5) PARTICIPANTS BY PLACE OF BIRTH (N=470)

Characteristics Born 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


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


Nadir CD4 < 200 cells/ml (n,%) 158(65%) 133 (59%) 0.188


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


GENERALIZED ESTIMATING EQUATION- GDS >=0.5 ONLY


CPE 2010 CPE 2006

Spatial Span 1.76 3.07Pegboard Dominant Hand 5.53 0.59Pegboard Non-dominant Hand

-6.02 0.09

Hopkins Recall 0.32 0.58Hopkins Delayed Recall 0.45 0.23

Digit Symbol -2.23 -2.05Motor Efficiency Domain -0.84 -2.21Spatial Working Memory Domain

1.76 3.07

Memory Domain 0.38 0.40


Observations=483



CPE 2010 CPE 2006

Foreign-Born (obs=349)

Canadian-Born (obs=515)


Canadian-Born (obs=515)

Spatial Span 1.99 1.59 2.76 0.85Pegboard Dominant Hand -1.40 -0.07 -2.21 -0.35Pegboard Non-dominant Hand -2.22 0.33 -2.56 0.20

Hopkins Recall -0.38 0.86 -0.04 1.73

Hopkins Delayed Recall -0.79 1.56 -1.36 -0.45

Digit Symbol -1.44 -1.03 -0.35 -2.65Motor Efficiency Domain -1.77 -0.78 -1.78 -1.30Spatial Working Memory Domain

-0.67 1.59 -0.79 0.85

Memory Domain 1.99 1.20 2.76 -1.13



Neuropsychological Impairment Measure (Impaired or Not)

CPE 2010 CPE 2006


Canadian-Born (obs=515)*


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)


1.11(0.69, 1.79)

0.78(0.46, 1.32)

1.70 (1.07,2.67)



Neuropsychological Impairment Measure (Impaired or Not)

CPE 2010 CPE 2006


Canadian-Born (obs=515)*


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)


0.91 (0.57,1.46)

1.42(0.88, 2.32)

1.40(0.90, 2.17)


1.11(0.69, 1.79)

0.78(0.46, 1.32)

1.70(1.07,2.67)


examining the impact of cns penetration effectiveness (cpe) of combination antiretroviral treatment...

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