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Table 1 Review of studies that have assessed the effect of CNS penetrating ARTs on NP performance and/or on CSF HIV RNA

From: Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research

Author & date What Samples HIV
Disease
Design Findings Quality scoring > 80% * < 80% Quality scoring
Main factors
POWER > 80%
Antinori et al., 2002 [25] CSF
39% detectable viral load at baseline
75 advanced HIV+ individuals
37% naive
29 advanced HIV+ individuals
39% AIDS
Median current CD4: 131
Cross-sectional
Longitudinal
Initiating cART or new cART/retest mean: 11 weeks
Indinavir associated with greater HIV RNA suppression in the CSF
Greater CSF HIV RNA suppression with 3 or more CNS penetrant ARTs
No Clinical groups heterogeneous with multiple types of CNS HIV-related disorders
IVDU risk factor in 40%
-
Chang et al., 2003 [26] NP tests
CSF
97% detectable viral load
MRS
33 HIV+ individuals all ART naïve
19 with HAD
Mean current CD4: 182 Longitudinal
3 months follow-up
NP tests
MRS
Better NP performance in individuals on 2 CNS penetrant drugs on 2 NP tests
No correlation between number of CNS penetrant ARTs and reduction in MRS abnormalities.
Yes - No
Cysique et al., 2004 [27] NP tests 97 advanced HIV+ individuals
on long-term CART (average 5 years)
100% AIDS
Mean Nadir CD4: 73
Mean current CD4: 369
Cross sectional Better performance in Learning and memory when on a CART regimen with = > 3 neuroactive agents in NP impaired (N = 26) Yes - No
Cysique et al, 2006 [28] NP tests 81 advanced HIV+ individuals
on long-term CART (average 5 years)
100% AIDS
Mean Nadir CD4: 73
Mean current CD4: 385
Longitudinal
Yearly for an average of 27 months
Improvement on Psychomotor speed
on a CART regimen with = > 3 neuroactive agents
No Inclusion/exclusion criteria not readily available; NeuroHAART definition not readily available -
Author & date What Samples HIV
Disease
Design Findings Quality scoring > 80% * < 80% Quality scoring
Main factors
POWER > 80%
Cysique et al. 2009 [29] NP tests
CSF
85% detectable at baseline
37 HIV+ individuals with mild to moderate HAND
Initiated on CART
38% ART naïve
Means Nadir CD4 = 106
Baseline CD4 = 195
AIDS 77%
Longitudinal
Every 12 weeks for 48 weeks
Overall improvement in cognitive functions with higher CPE Yes - No
De Luca et al., 2002 [30] CSF
Median log 10 CSF HIV RNA: 2.9
95 HIV+ individuals
On cART
50 HIV+ individuals On cART
Median current CD4: 110
Median current CD4: 59
Cross-sectional
Longitudinal
Follow-up median of 7 weeks
Higher number of CNS penetrant ARTs correlated with lower CSF HIV RNA (trend only).
Greater longitudinal decrease in CSF HIV RNA associated higher number of CNS penetrant
No Clinical groups heterogeneous with multiple types of CNS HIV-related disorders
IVDU risk factor in 30-40%
-
Eggers et al., 2003 [31] CSF
80% detectable
at baseline
40 HIV+ individuals
10 with HIVE
8 with HAD
Median current CD4: 60
29% CDC stage C
Longitudinal
LP prior and after cART initiation
Unclear time-frame
No correlation between the number of CNS penetrant drugs and slope of CSF viral decay. No Definition of HAND using brief screens
Clinical groups heterogeneous
-
Marra et al., 2003 [32] NP tests
CSF
75% detectable at baseline
25 HIV+ individuals
HAND baseline rate?
Mean current CD4: 259 Longitudinal
Testing before CART initiation at 4 & 8 weeks after
Comparison of regimen containing AZT & IDV to other regimen
Improved on 4 NP tests associated with VL suppression in the CSF in ART naïve (but not 8 weeks)
No significant change in CSF viral load.
No Small test battery
Unclear inclusion/exclusion criteria
Unclear baseline level of NP-impairment
No adequate normative data
No practice effect correction
-
Author & date What Samples HIV
Disease
Design Findings Quality scoring > 80% * < 80% Quality scoring
Main factors
 
Marra et al., 2009 [33] NP tests
CSF
Median log 10 CSF HIV RNA at baseline: 3.3
101 HIV+ individuals initiating or changing cART Median CD4: 111 Longitudinal
Follow-up at 24 and 52 weeks
ACTG 736
Odds of suppression of CSF HIV RNA were higher when CPE rank was = > 2 (N = 79)
Impaired HIV+ individuals on a cART with a CPE = > 2 had worse NP performance over time (N = 26) on NP 4 tests, but not 8 NP tests.
No Unclear inclusion/exclusion criteria
Short NP testing battery
Lack of education and racial correction in NP tests relevant to the study population
-
Letendre et al., 2004 [34] CSF
Mean log 10 CSF HIV RNA at baseline: 4.1
31 HIV+ with mild to moderate HAND 81% AIDS
Means nadir Cd4: 30
Current CD4: 111
Longitudinal
Testing before & 15 months after CART initiation
Greater CSF HIV RNA reduction with higher number of CNS penetrant ARTs No Unclear study time points
No control for practice effect
Correlational analyses only
No practice effect correction
-
Letendre et al., 2008 [35] CPE
CSF
17% detectable at baseline
467 HIV+ individuals on cART
389 Undetectable and 78 Detectable
77% AIDS
Medians nadir CD4: 116 current CD4: 406
Cross-sectional
Validation of the CPE index
CPE < 2 associated with an 88%
increase in the odds of detectable CSF viral load
CPE ranks were associated with detectable CSF viral loads with and without treatment and disease adjustments
Yes - No
Patel et al., 2009 [36] Survival time 2398 HIV+ children
77 incident HIVE
[incidence rate 5.1 cases per 1000 person-years.
CD4% ≤ 15%: 19% Longitudinal
Median 6.4 years
AACT219/219C
High CNS-penetrating regimens associated with a survival benefit (74% reduction in the risk of death, 95% CI 39-89%) after HIVE diagnosis compared with low CNS-penetrating regimens No Clinical groups heterogeneity
Clinical diagnoses as outcome
No NP assessment
-
Author & date What Samples HIV
Disease
Design Findings Quality scoring > 80% * < 80% Quality scoring
Main factors
 
Sacktor et al., 2001 [37] NP tests 18 in single in CSF penetrant group
55 in multiple CSF penetrant group
With psychomotor slowing
6-7% HAD
11%-31% AIDS
Mean current CD4: 339-255
Longitudinal
Six annual study visit
cART initiation
No difference in NP improvement between 2 groups. No Unclear inclusion/exclusion criteria
NeuroHAART definition not readily available
Short NP battery
-
Sevigny et al., 2004 [38] Incident HAD 203 advanced non-demented HIV+ individuals
73% on cART
Median current CD4: 127 Longitudinal
Median follow-up of 21 months
36% with incident HAD
Regimens containing = > CNS penetrant ARTs was not associated with time to HAD No Clinical groups heterogeneity
Ad hoc analyses of time to HAD
Time to HAD not a validated measure of NP change
-
Smurzynski et al., 2011 [39] NP tests 2636 HIV+ individuals at least 6 weeks on cART Median current CD4: 243
Nadir CD4: 182
Longitudinal
Median follow-up of 4.7 years
CPE rank score & ARTs in cART
Neuroscreen: 3 NP tests
When cART was composed of more than 3 ARTs there was a positive association between CPE and better NP performance in unadjusted and adjusted models. Yes   Yes
Tozzi et al., 2009 [40] NP tests Patients with (n = 93) or at risk for (n = 92) HIV-associated neurocognitive disorders 37% stage CDC C
Mean current CD4: 292
Nadir CD4: 181
Cross-sectional
Longitudinal
NP testing before and after cART initiation (20 months mean interval)
Comparison of 2 "neuropenetration" scores (CPE vs. numbers)
Higher CPE correlated with better NP performance at baseline and follow-up, but not using the number of CNS penetrant drugs Yes - Yes
  1. NB: italicized font: beneficial effect of NeuroHAART on NP performance and or CSF HIV RNA reduction
  2. Regular font: neutral effect of the NeuroHAART,
  3. Bold front: negative effect of NeuroHAART.
  4. ARTs: Antiretrovirals
  5. LP: lumbar puncture
  6. HIVE: HIV encephalopathy
  7. MRS: Magnetic Resonance Spectroscopy
  8. MND: Minor motor Deficits
  9. MSK: Memorial Sloan Kettering
  10. NP: neuropsychological
  11. A score less than or equal to 80% meant that a study presented at least three or more methodological limitations.