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 Infectious Diseases
Lazzaro Spallanzani IRCCS, Roma, Italy; 2Research Department of
Infection & Population Health, University College London,
London, United Kingdom.
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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.
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Background
• Efavirenz (EFV) is currently recommended as a preferred
component of ARV regimens for treatment-naïve patients in
most of ART guidelines.
• Due to patent expiry in 2013, EFV is now available as a generic
drug.
• 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. Ann Intern Med 2005;143:714-721; 3Ciccarelli N, et al.
Neurology, 2011;76:1403-1409; 4Letendre S, et al. 20th CROI, Atlanta, GA, 2013; Poster #407.
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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.
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Methods
• Single-centre, retrospective, cross-sectional analysis of cART-treated HIVinfected patients undergoing neuropsychological assessment (NPA).
• NPA was carried out by a set of 14 standardized and comprehensive tests
on 5 different domains.
• People were classified as having NCI if they scored >1 standard deviation
(SD) below the normal mean in at least 2 tests, or >2 SD below in 1 test.
• As additional binary outcome, HIV-associated neurocognitive disorders
(HAND) were classified according to Frascati’s criteria (Neurology, 2007).
Clinical depression and other psychiatric disorders has been controlled as
confounders.
• Z-Scores (neg values if performance was below the mean) were used as
continuous outcome:
– Global NPZ-8 Deficit Score
– Z-Scores for each Cognitive Domain
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NP Battery and Domains
•
•
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
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•
•
•
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)
Statistical analyses
• Comparisons between currently EFV-exposed and
currently EFV-not exposed
– Mann-Whitney test and Spearman’s Rho for continuous
variables
– Chi-square test for categorical variables
• Univariable and multivariable logistic and linear
regression models were fitted.
• Variables were retained in multivariable analysis if
they had a p-value <0.05.
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Patients characteristics
(1020 consecutive NPA over 859 patients)
Male gender, n (%)
Age, yrs, median (IQR)
Mode of HIV transmission, n (%)
MSM
IVDU
heterosexual
other/unkown
Years of education, median (IQR)
CDC C stage, n (%)
HCV-Ab positivity, n (%)
Nadir CD4 cell/mm3, median (IQR)
Current CD4 cell/mm3, median (IQR)
HIV-RNA cp/mL at NPA, n (%)
undetectable
detectable <40
>=40
Haemoglobin <=12 mg/dL, n (%)
Calendar year of NPA
2000-2004
2005-2009
2010-2013
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overall
795 (77.9%)
46 (40-53)
EFV (n=324)
265 (81.8%)
46 (40-53)
no EFV (n=696)
530 (76.1%)
46 (39-54)
400 (39.2%)
182 (17.8%)
393 (38.5%)
45 (4.4%)
13 (8-13)
245 (24.0%)
285 (27.9%)
190 (82-300)
483 (287-689)
154 (47.5)
44 (13.6)
112 (34.6)
14 (4.3)
13 (8-17)
55 (17.0)
64 (19.7)
225 (112-323)
532 (354-714)
246 (35.3)
138 (19.8)
281 (40.4)
31 (4.4)
13 (8-13)
190 (27.3)
221 (31.8)
165 (73-282)
470 (261-671)
279 (27.5%)
423 (41.6%)
314 (30.9%)
99 (9.7%)
120 (37.1%)
133 (41.2%)
70 (21.7%)
22 (6.8%)
159 (22.9%)
290 (41.8%%)
244 (35.2%)
77 (11.1%)
256 (26.0%)
338 (33.1%)
417 (40.9%)
80 (24.7%)
86 (26.5%)
158 (48.8%)
185 (26.6%)
252 (36.2%)
259 (37.2%)
p
0.043
0.874
0.002
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.023
0.001
NCI impairment by EFV current use
(NPZ-8)
0
-2
NPZ 8 score
0
-1
-4
-2
NPZ 8 score
1
2
2
NPZ-8 by months of drug exposure for
EFV current regimen
-3
Spearman's rho=-0.029; P=0.525
EFV
-6
No EFV
P=0.291 at univariable analysis
(Mann-Whitney test)
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]
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0
20
40
60
80
Months of exposure to EFV containing regimen
Median (IQR) exposure to current EFV
regimen: 30 months (12-40).
100
EFV current use and NCI risk
(Unadjusted and adjusted risk by logistic regression)
Unadjusted
Impaired*
(n=382)
Not impaired*
(n=638)
On EFV
(n=324)
104 (32.1%)
220 (67.9%)
Not on EFV
(n=696)
278 (39.9%)
418 (60.1%)
Impaired*
(n=322)
Not impaired*
(n=537)
On EFV^
(n=292)
89 (30.5%)
203 (69.5%)
Not on EFV^
(n=567)
233 (41.1%)
Adjusted§
OR#
95%CI
p
OR#
95%CI
p
0.71
0.54-0.94
0.016
1.02
0.74-1.41
0.89
0.65
0.46-0.85
0.002
0.98
0.67-1.41
0.90
334 (58.9%)
* Subjects are defined as neurocognitivelly impaired if they scored >1 standard deviation (SD) below the normal
mean in at least 2 tests, or >2 SD below in 1 test.
^ Sensitivity analysis including only the 859 subjects at the first NP assessment.
# Risk of neurocognitive impairment for EFV current use.
§ Adjusted for age, mode of HIV transmission, years of education, CDC C stage, HCV-Ab positivity, nadir CD4,
HIV-RNA and CD4 at NPA, haemoglobin and BMI at NPA, NRTI combination in the current regimen, calendar year
of NPA)
Older age, IVDU, HCV-Ab+, CDC-C stage, were related to an increased risk of NCI; current CD4 >500 and years
of schooling to a decreased risk.
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Gender, CD4 nadir, HIV-RNA undetectable at NPA, anemia, BMI and CPE 2010 not associated.
Factors likely to have confounded 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).
0.95
1.0
1.02
0.71
0.1
crude OR
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OR adjusted for yrs of schooling
and for nadir<200 cell/mmc
OR adjusted in fully model*
EFV current exposure and HAND occurrence
Not impaired
ANI
MND/HAD
On EFV
(n=324)
220 (67.9%)
51 (15.7%)
53 (16.4%)
Not on EFV
(n=696)
418 (60.1%)
116 (16.7%)
162 (23.2%)
Overall population
(n=1020)
638 (62.5%)
167 (16.4%)
215 (21.1%)
p
0.026*
*EFV-exposed individuals had a significant lower risk to have a symptomatic HAND
(MND/HAD) by univariate analysis.
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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
0.3
0.2
0.1
0.0
0.02; p=0.729
0.03; p=0.541
-0.09; p=0.358
-0.1
-0.12; p=0.315
-0.2
-0.3
-0.4
concentration and
mental speed
mental flexibility
memory
fine motor
functioning
Fully models were adjusted for gender, age, years of education, mode of HIV transmission, CDC-C stage,
HCVAb positivity, nadir CD4, CD4 cell count/mmc and HIV-RNA cp/mL at NPA, haemoglobine value, BMI,
NRTI backbone in the current regimen.
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Limitations
• Observational nature of design
– channeling bias (if EFV preferably allocated in individuals at lowrisk of developing NCI);
– unmeasured confounders (e.g. drug adherence).
• Cross-sectional analysis
– reverse causality (if EFV was avoided in patients with NCI);
– not considered the effects of previous regimens exposures.
• Major depression controlled as a confounder, but a
systematical assessment of depression (e.g. BDI-II, PHQ-9
or CES-D) was not performed in all subjects.
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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.
• Even though confounding by indication may play a role, and reverse
causality cannot be ruled out, our results suggest that presence of
NCI among persons treated with EFV-based cART is not more
common than in people not treated with EFV
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