Survival after neuroAIDS - CHU de Clermont

Transcription

balt4/znl-neurol/znl-neurol/znl00711/znl8509-11z xppws Sⴝ1 12/24/10 10:31 Art: WNL202244 Input-mm
Survival after neuroAIDS
Association with antiretroviral CNS Penetration-Effectiveness score
See
E. Lanoy, PhD
M. Guiguet, PhD
M. Bentata, MD
E. Rouveix, MD
C. Dhiver, MD
I. Poizot-Martin, MD
D. Costagliola, PhD
J. Gasnault, MD
On behalf of the
FHDH-ANRS CO4
Address correspondence and
reprint requests to Dr. Emilie
Lanoy, INSERM U943, 56 Bd V.
Auriol, BP 335, 75 625 Paris
Cedex 13, France
[email protected]
ABSTRACT
Objective: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs
was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis.
Methods: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIVinfected patients diagnosed with a first neurologic AIDS-defining event in the pre–combination
antiretroviral therapy (cART) (1992–1995), early cART (1996–1998), or late cART (1999–
2004) periods. Follow-up was subdivided (CPE ⬍ 1.5 and CPE ⱖ 1.5), and relative rates (RR) of
death were estimated using multivariable Poisson regression models.
Results: In the pre-cART and early cART periods, regimens with CPE ⱖ 1.5 were associated with
lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47–
0.86 and RR 0.45; 95% CI 0.35–0.58) and after PML (RR 0.79; 95% CI 0.55–1.12 and RR
0.45; 95% CI 0.31–0.65), compared to regimens with CPE ⬍ 1.5, while in the late cART period
there was no association between the CPE score and the mortality. A higher CPE score was also
associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI
0.56–0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34–0.74). Whatever the neurologic
event, these associations were not maintained after adjustment on updated plasma HIV-RNA
(missing, ⬍500, ⱖ500 copies/mL) with RR ranging from 0.82 (95% CI 0.36–1.91) to 1.02
(0.69–1.52).
Conclusion: At the beginning of the cART era, the CPE score was of importance for survival after
severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.
Neurology® 2011;76:1–1
GLOSSARY
cART ⫽ combination antiretroviral therapy; CI ⫽ confidence interval; CPE ⫽ CNS Penetration-Effectiveness; ICD ⫽ International Classification of Disease; JCV ⫽ JC virus; PML ⫽ progressive multifocal leukoencephalopathy; RR ⫽ relative rate.
Since the introduction of combination antiretroviral therapy (cART), the incidence of neurologic AIDS-defining events (HIV-related encephalopathy, progressive multifocal leukoencephalopathy [PML], cerebral toxoplasmosis, and cryptococcal meningitis) has fallen.1-3 However,
these disorders remain frequent in patients with advanced stage HIV infection4 and account for
a large proportion of AIDS diagnoses.5,6 Moreover, while survival after neurologic AIDSdefining events has improved in the cART era, it is shorter than after other AIDS-defining
events, especially among patients who develop PML.7,8
HIV RNA can remain detectable in CSF even when it is rendered undetectable in plasma by
cART.9,10 Pharmacodynamic models and in vivo evidence show that antiretroviral drugs have
different degrees of effectiveness on HIV replication in the CNS.11,12 An antiretroviral CNS
Supplemental data at
www.neurology.org
e-Pub ahead of print at www.neurology.org.
From INSERM (E.L., M.G., D.C.), U943, Paris; UPMC Univ Paris 06 (E.L., M.G., D.C.), UMR S943, Paris; Service de Médecine Interne (M.B.),
Hôpital Avicenne, Bobigny; Service de Médecine Interne 2 (E.R.), Hôpital Ambroise-Paré, Boulogne; Service de Maladies Infectieuses (C.D.), Hôpital
Conception, Marseille; Service d’Immuno-Hématologie Clinique (I.P.-M.), Centre d’Informations et de Soins de l’Immunodéficience Humaine et des
Hépatites Virales, Hôpital Sainte-Marguerite, Marseille; AP-HP (D.C.), Groupe Hospitalier Pitié-Salpêtrière, Service de Maladies Infectieuses et
Tropicales, Paris; and Service de Médecine Interne (J.G.), Hôpital Bicêtre, le Kremlin-Bicêtre, France.
Disclosure: Author disclosures are provided at the end of the article.
Copyright © 2011 by AAN Enterprises, Inc.
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1
Penetration-Effectiveness (CPE) score has
been proposed and higher CPE scores are associated with lower CSF viral load.13 In a recent study, CPE score was not associated with
suppression of plasma HIV RNA and a higher
CPE score was associated with lower neurocognitive performance.14 Correlation of CPE
score with clinical progression remained to be
evaluated.
Here we examined if CPE score was associated with patient survival after a diagnosis of
HIV-related encephalopathy or a diagnosis of
severe neurologic complication. We first studied the association of CPE score with survival
according to the calendar period of diagnosis,
pre-cART (1992–1995), early cART (1996 –
1998), or late cART (1999 –2004). Then the
respective influence of CPE score and undetectable plasma HIV-RNA were analyzed for
patients diagnosed after 1997.
each antiretroviral drug based on the impact of treatment on
CSF viral load, as reported by Letendre et al.13,16 A score of 0 was
assigned to didanosine, tenofovir, zalcitabine, amprenavir,
nelfinavir, ritonavir, saquinavir, saquinavir/ritonavir, tipranavir/ritonavir, and enfuvirtide, a score 0.5 to lamivudine,
stavudine, efavirenz, amprenavir/ritonavir, fosamprenavir/
ritonavir, atazanavir, and atazanavir/ritonavir, and a score of
1 to abacavir, emtricitabine, zidovudine, delavirdine, nevirapine, indinavir, indinavir/ritonavir, and lopinavir/ritonavir.
For each antiretroviral regimen, the individual CNS penetration scores were summed to yield a CPE score. A CPE score of
1.5 was used as the cutoff for good CNS penetration as lower
CPE ranks were associated with an increased probability of
detectable CSF viral load.13
For each patient, the first 12 months of follow-up after diagnosis of the neurologic AIDS-defining event were subdivided
into periods according to CPE score of antiretroviral therapy.
Three categories were distinguished: no antiretroviral treatment,
treatment with CPE ⬍ 1.5, and treatment with CPE ⱖ 1.5.
Patients could participate in more than one of these periods during their follow-up but, in an intent-to-continue-treatment conservative approach, only changes toward a higher category were
taken into account. This approach was chosen to limit overestimation bias in assessing the CPE score effect. Time was expressed in months, and a time lag of 1 month was added after
cART initiation or intensification.
METHODS Patients. The FHDH-ANRS CO4 database is
described in detail elsewhere.15 Briefly, FHDH is a clinical epidemiologic network implemented since 1992 in 62 French teaching hospitals belonging to 29 HIV Treatment and Information
Centers (CISIH) located in both mainland France and French
overseas territories. Patients are eligible if they have documented
HIV-1 or HIV-2 infection. Data are recorded prospectively by
trained research assistants. In the database used for the analysis,
the follow-up was up to June 2006. The standardized FHDHANRS CO4 data collection form includes baseline characteristics, standard biological markers such as the CD4⫹ cell count
and plasma HIV RNA level, clinical manifestations, treatments,
clinical trials in which the patients are enrolled, deaths, and
causes of death, as reported in the medical records. By mid-2006,
more than 107,000 HIV-infected subjects who had attended at
least one follow-up visit between 1992 and June 2006 were included in the database, with a mean follow-up of 64 months.
Patients who had a first neurologic AIDS-defining event between 1992 and 2004 were included in this analysis.
Statistical analysis. Survival after each neurologic AIDS-
Standard protocol approvals, registrations, and patient
consents. Patients give their written informed consent to participate to the FHDH-ANRS CO4 database. The database has
been approved by the French computer watchdog commission
(CNIL) according to the French legislation at the time.
Definition of neurologic AIDS-defining events. In the
FHDH, clinical events were recorded with the International
Classification of Disease version 9 (ICD-9) until the end of
1996, and with version 10 (ICD-10) thereafter. The following 4
neurologic AIDS-defining events were studied (ICD-9/ICD-10
codes in parentheses): HIV-related encephalopathy (3239/
G051-B220, F024-B220, B220), progressive multifocal leukoencephalopathy (PML, 0463, 3316, 0463-3316/A812),
cerebral toxoplasmosis (3234-130/G052-B582), and cryptococcal meningitis (3210-1175/B451).
Scoring system for CNS penetration effectiveness. A
CNS penetration score of 0 (low) to 1 (high) was assigned to
2
Neurology 76
February 15, 2011
defining event was evaluated by using Kaplan-Meier estimates in
the 3 calendar periods (1992–1995, 1996 –1998, 1999 –2004).
Patients were followed up from the diagnosis of a neurologic
AIDS-defining event until death, end of follow-up, or 1 year
after the diagnosis, whichever occurred first. Only the first 12
months after diagnosis of the neurologic event were considered
in order to limit competing causes of death. Every patient’s
follow-up was divided into consecutive 1-month periods, and
time-varying covariables were updated at the beginning of every
month. A Poisson regression modeling was used to quantify the
effect of the CPE score of treatment on mortality rates within the
first 12 months after diagnosis of the neurologic event among
patients receiving antiretroviral therapy. Only patients receiving
antiretroviral therapy were selected in order to avoid potential
indication bias in assessing the effect of CPE score on survival.
Association between mortality and variables measured at neurologic event diagnosis, namely age (⬍30, 30 – 40, 40 –50, 50 – 60,
and ⬎60 years), AIDS status, migration for sub-Saharan Africa,
gender, and the HIV exposure group (men who have sex with
men, other men, and women), were investigated using a backward procedure, retaining variables with a p value ⬍0.05. For
each neurologic event, only the variables significantly associated
with the mortality rate were retained in the Poisson regression
model. A first multivariable model was fitted on the 3 calendar
periods (1992–1995, 1996 –1998, 1999 –2004), and the CPE
score effect was estimated after adjustment for updated CD4 cell
count per mm3 (missing, ⬍100, 100 –199, 200 –349, ⱖ350) in
addition to the previously retained variables. In order to detect
some effect modification according to the calendar period, the
interactions between CPE score and periods were systematically
assessed. When interaction term was nonsignificant, the relative
rate (RR) of mortality associated with CPE score above 1.5 compared to treatment with CPE score ⬍ 1.5 was estimated over all
the studied period. When interaction term was significant ( p ⬍
0.05), RR was estimated within each calendar period. Restricting
to patients diagnosed since 1997, when viral load measurement
Table 1
Baseline and follow-up characteristics
HIV-related
encephalopathy
Cerebral
toxoplasmosis
PML
Cryptococcal
meningitis
No.
%
No.
%
No.
%
No.
%
3,127
100.0
1,427
100.0
4,358
100.0
1,020
100.0
357
11.4
124
8.7
748
17.2
165
16.2
30–40
1,419
45.4
758
53.1
2,118
48.6
507
49.7
40–50
784
25.1
369
25.9
998
22.8
240
23.5
50–60
351
11.2
126
8.8
356
8.2
85
8.3
>60
216
6.9
50
3.5
138
3.2
23
2.3
MSM
1,136
36.3
504
35.3
1,440
33.0
407
39.9
Non-MSM men
1,365
43.7
673
47.2
1,800
41.3
445
43.6
626
20.0
250
17.5
1,118
25.7
168
16.5
3,026
96.8
1,383
96.9
4,082
93.7
925
90.7
101
3.2
44
3.1
276
6.3
95
9.3
No
1,144
36.6
650
45.6
2,489
57.1
564
55.3
Yes
1,983
63.4
777
54.4
1,869
42.9
456
44.7
130
4.2
60
4.2
278
6.4
66
6.5
All diagnoses
Age at diagnosis, y
<30
Sex and exposure group
Women
Migration from sub-Saharan Africa
No
Yes
History of AIDS before diagnosis
CD4 nadir at diagnosis
Missing values
2,537
81.1
1,086
76.1
3,539
81.2
869
85.1
100–200
271
8.7
207
14.5
375
8.6
61
6.0
200–350
137
4.3
63
4.4
120
2.8
14
1.4
52
1.7
11
0.8
46
1.0
10
1.0
1992–1995
1,789
57.2
712
49.9
2,421
55.6
545
53.4
1996–1998
746
23.9
345
24.1
875
20.1
237
23.2
1999–2004
592
18.9
370
26.0
1,062
24.3
238
23.4
<100
>350
Period of diagnosis
Abbreviations: MSM ⫽ men who have sex with men; PML ⫽ progressive multifocal leukoencephalopathy.
T2
T3
T1
T4
became routinely available, a second model was fitted adjusting
for updated CD4 cell count and updated plasma HIV-RNA in
copies/mL (missing, ⬍500, ⱖ500). Sensitivity analyses were
performed using a different cutoff for CPE score with the following 2 categories: treatment with CPE ⬍ 2.0, and treatment with
CPE ⱖ 2.0. All analyses were done with the SAS software package version 9 (SAS Institute, Cary, NC).
RESULTS Between 1992 and 2004, 3,127 patients
were diagnosed with HIV-related encephalopathy,
1,427 patients with PML, 4,358 patients with cerebral toxoplasmosis, and 1,020 patients with cryptococcal meningitis (table 1). Over 50% of these
diagnoses were made during the pre-cART period
(1992–1995). At diagnosis, fewer than 5% of patients were receiving antiretroviral therapy with high
CPE score in the pre-cART era, while in 1999 –
2004, over 80% of patients diagnosed with HIVrelated encephalopathy, or PML, and over 60% of
patients diagnosed with cerebral toxoplasmosis, or
cryptococcal meningitis, were receiving regimens
with CPE score ⱖ1.5 (table 2). After diagnosis,
nearly all patients received antiretroviral therapy either with CPE score ⬍1.5 or with CPE score ⱖ1.5
(table 3, table e-1 on the Neurology® Web site at
www.neurology.org). Within 12 months of diagnosis, 1,769 deaths occurred in patients diagnosed with
HIV-related encephalopathy, 807 in patients diagnosed with PML, 1,681 in patients diagnosed with
cerebral toxoplasmosis, and 342 in patients diagnosed with cryptococcal meningitis (table 4). Overall, 12.5% of patients were censored and the mean
(SD) duration of follow-up in patients who did not
die was 10.8 (2.9) months. Survival after diagnosis of
each of the 4 neurologic AIDS-defining events improved after 1996 compared to the pre-cART period.
Neurology 76
February 15, 2011
3
Table 2
CPE score of antiretroviral regimen at diagnosis of neurologic AIDS-defining events
HIV-related
encephalopathy
Progressive multifocal
leukoencephalopathy
Cerebral toxoplasmosis
Cryptococcal meningitis
Period of
diagnosis
No. (%)
Untreated,
n (%)
CPE score
<1.5, n (%)
1992–1995
1789 (100)
355 (20)
1371 (77)
1996–1998
746 (100)
83 (11)
281 (38)
382 (51)
1999–2004
592 (100)
61 (10)
52 (9)
479 (81)
1992–1995
712 (100)
155 (22)
521 (73)
36 (5)
1996–1998
345 (100)
37 (11)
115 (33)
193 (56)
29 (8)
310 (84)
1999–2004
370 (100)
1992–1995
2,421 (100)
31 (8)
869 (36)
1,500 (62)
CPE score
>1.5, n (%)
63 (3)
52 (2)
1996–1998
875 (100)
268 (31)
307 (35)
300 (34)
1999–2004
1,062 (100)
311 (29)
111 (11)
640 (60)
1992–1995
545 (100)
156 (29)
358 (66)
31 (5)
1996–1998
237 (100)
54 (23)
89 (37)
94 (40)
1999–2004
238 (100)
49 (20)
30 (13)
159 (67)
Abbreviation: CPE ⫽ CNS Penetration-Effectiveness.
After a diagnosis of HIV encephalopathy, the 1-year
survival rate increased from 25% in 1992–1995, and
55% in 1996 –1998, to 65% in 1999 –2004. For cerebral toxoplasmosis, the survival rates in the 3 periods were 40% in 1992–1995, 73% in 1996 –1998,
and 82% in 1999 –2004. A gradual improvement of
survival was also observed for cryptococcal meningitis. Conversely, the 1-year survival after a diagnosis of
PML increased from 20% in 1992–1995 to 56% in
1996 –1998 but remained unchanged after.
When the relationship between the CPE score
and survival of treated patients was investigated,
there were interactions between CPE score and calendar periods for HIV encephalopathy ( p ⫽ 0.02),
and PML ( p ⫽ 0.02), indicating that the association
between the CPE score and survival varied according
to the time period. In a first analysis adjusting for
baseline characteristics and current CD4 cell count, a
higher CPE score was associated with a better sur-
T5
Table 3
Number of patient-years (%) of time of follow-up spent in the
different categories of treatment after diagnosis of a neurologic
AIDS-defining event
vival after a diagnosis of HIV-related encephalopathy, or PML, associated with a higher CPE score, was
observed only during the pre-cART era and the early
cART era period, while the risk of mortality was not
associated with the CPE score in the most recent period (1999 –2004) (table 5, model 1). In a second
model restricted to patients diagnosed since 1997, no
evidence remained of this association after adjustment on undetectability of plasma HIV RNA (table
5, model 2). Controlling for CD4 cell count, a better
survival after a diagnosis of cerebral toxoplasmosis
and cryptococcal meningitis was observed under antiretroviral therapy with CPE score ⱖ1.5, compared
to a regimen with CPE score ⬍1.5, and the association was of similar magnitude over the 3 calendar
periods (interaction terms: p ⫽ 0.28 in model for
cerebral toxoplasmosis and p ⫽ 0.63 in model for
cryptococcal meningitis) (table 5, model 1). The association of survival with higher CPE score vanished
after adjustment on plasma HIV RNA (table 5,
model 2). For all the 4 diagnoses, results of model 1
and model 2 were similar when the cutoff for the
CPE score was fixed at 2 instead of 1.5.
Patient-years of follow-up (%)
Total
HIV-related
encephalopathy
leukoencephalopathy
Untreated
Under
antiretroviral
treatment with
CPE score <1.5
1,459 (100)
79 (5)
669 (46)
711 (49)
615 (100)
38 (6)
234 (38)
343 (56)
2,861 (100)
425 (15)
1,314 (46)
1,122 (39)
707 (100)
72 (10)
315 (45)
320 (45)
4
Under
antiretroviral
treatment with
CPE score >1.5
Neurology 76
February 15, 2011
In this study of almost 10,000 patients
participating in a large prospective hospital cohort, we
showed that survival after diagnosis of HIV-related encephalopathy, PML, cerebral toxoplasmosis, or cryptococcal meningitis improved markedly with the advent
of cART and continued to improve gradually in the
cART era, except among patients who developed PML.
When antiretroviral therapy regimens were categorized
according to their CNS penetration effectiveness score,
the association of CPE score with survival after HIV-
DISCUSSION
Table 4
Kaplan-Meier estimates of 1-year survival after diagnosis of
neurologic AIDS-defining events
HIV-related
encephalopathy
leukoencephalopathy
Period
No.
Deaths
12-month
survival,
% (95% CI)
1992–1995
1,789
1,278
23 (21–25)
1996–1998
746
316
55 (51–59)
1999–2004
592
195
65 (61–69)
1992–1995
712
511
20 (17–23)
1996–1998
345
138
56 (50–62)
1999–2004
370
158
52 (47–58)
1992–1995
2,421
1,275
42 (40–44)
1996–1998
875
219
73 (70–76)
1999–2004
1,062
187
82 (79–84)
1992–1995
545
251
50 (46–55)
1996–1998
237
53
76 (71–82)
1999–2004
238
38
83 (78–88)
Abbreviation: CI ⫽ confidence interval.
related encephalopathy, or PML, was observed only
during the pre-cART era and the first cART era period
(1996–1998). Regimens with high CPE scores were associated with a longer survival after cerebral toxoplasmosis, or cryptococcal meningitis. However, after
accounting for plasma HIV-RNA, there were no associations of survival with CPE score.
Strengths of our study include its large size and
relatively long follow-up. We included 3 calendar periods in pre- and post-cART eras. The numbers of
person-years of follow-up were sufficient for meaningful comparisons of antiretroviral regimens according to their CPE scores by specific neurologic
Table 5
endpoints. In order to prevent chance finding in
multiple comparisons, we dichotomized CPE score
such as above and below the cutoff of 1.5, which has
been previously proposed.13 However, a sensitivity
analysis classifying CPE ranks of at least 2 as high
CPE score lead to similar results. As nearly 10,000
patients with a diagnosis of severe neurologic event
are included, this large size prevented us from verifying diagnostic criteria, and we relied on ICD codes
which are routinely used in the participating clinical
centers. The good reporting of AIDS-defining events
in the FHDH cohort is supported by previous analyses with diagnosis validation on very different pathologies such as PML15 or Kaposi sarcoma.17 We did not
investigate causes of death, which were less systematically reported, and we focused on mortality in the
first year to limit competing events. We cannot exclude some underreporting of deaths among patients
who were lost to follow-up in the FHDH-ANRS
CO4 cohort. During the 12 months following their
first neurologic AIDS-defining events, 12.5% of patients were censored, possibly leading to an overestimation of survival.18 To have adequate power, we did
not consider primary cerebral lymphoma, another
AIDS-defining neurologic manifestation, which was
diagnosed in 318 patients in the pre-cART era, but
only 87 patients in 1999 –2004. We could not study
the association of antiretroviral penetration on less
severe cognitive disorders than HIV encephalopathy,
because these are not routinely screened for in HIVinfected patients. Among the other limitations of our
study, we ended it in 2005 to prevent exposure to
new antiretroviral classes such as fusion inhibitors,
integrase inhibitors, and CCR5 entry inhibitors, for
Adjusted relative rate of death (95% confidence interval) in treated patients receiving
antiretroviral regimen with high CPE score (CPE >1.5) compared to patients receiving regimen
with lower CPE score during the period 1992–2004 (model 1) or during the period 1997–2004
when plasma HIV-RNA viral load measurement was routinely available (model 2)
1992–1995b
1996–1998b
1999–2004b
Model 2 adjusted on
variables at diagnosisa
and current CD4 cell
count and plasma HIV-RNA,
1997–2004b
HIV-related
encephalopathy
0.64 (0.47–0.86)
0.45 (0.35–0.58)
1.11 (0.58–2.11)
0.98 (0.65–1.49)
leukoencephalopathy
0.79 (0.55–1.12)
0.45 (0.31–0.65)
1.30 (0.61–2.39)
0.85 (0.53–1.58)
Model 1 adjusted on variables at diagnosisa and
current CD4 cell count
Period of diagnosis
1992–2004
1997–2004
0.68 (0.56–0.84)
1.02 (0.69–1.52)
0.50 (0.34–0.74)
0.82 (0.36–1.91)
a
All multivariate Poisson regressions were adjusted for age, AIDS status before diagnosis, and updated CD4 cell count
(missing, ⬍100, 100–199, 200–349, ⱖ350); in addition, model 2 was adjusted on current plasma HIV-RNA (missing, ⬍500,
ⱖ500 copies/mL). Models were also adjusted on gender and exposure group (HIV-related encephalopathy, progressive
multifocal leukoencephalopathy) and geographic origin (cerebral toxoplasmosis).
b
Period of diagnosis.
Neurology 76
February 15, 2011
5
which CNS pharmacodynamic and pharmacokinetic
data were not available. However, given the values
close to 1.0 of the RRs when accounting for CD4 cell
count and plasma HIV-RNA, it is unlikely that including more cases would lead to a significant association of CPE score with survival after HIV-related
encephalopathy or cerebral toxoplasmosis; for cryptococcal meningitis and PML, we could not exclude
that including additional cases could allow us to detect a small association of survival with CPE score.
The 4 neurologic pathologies were all associated
with very high mortality rates before cART. While
HIV-related encephalopathy is directly linked to
HIV infection by itself, the others are opportunistic
complications of immunosuppression. Overall, survival after each of the 4 neurologic AIDS-defining
events improved between the pre-cART era and the
cART era, as previously reported.6,8,19 In addition,
survival continued to improve gradually over time
after the advent of cART, with the exception of postPML survival. PML was one of the AIDS-defining
events with the poorest vital prognosis in the precART era, and showed the smallest improvement in
the cART era,8 underlying the complexity of this severe complication.20 The higher incidence of PML in
HIV infection than in other immunodeficiencies
suggests an interaction between HIV and JC virus
(JCV). HIV could facilitate brain entry of JCVinfected B lymphocytes by altering the blood– brain
barrier, and HIV Tat protein could promote JCV
replication in glial cells, either directly or indirectly
by cytokine/chemokine induction by HIV infection.21 The improved prognosis of PML after cARTinduced restoration of immune responses to JCV22,23
led to clinical trials of intensified cART intended to
hasten anti-JCV immune recovery.23
In the early cART era, patients treated by cART
with high CPE score after a diagnosis of HIV-related
encephalopathy or PML have better survival compared to patients treated by cART with low CPE
score. After 1999, the relationship between survival
and CPE score was no longer evidenced, probably
because this late cART period corresponded to the
arrival of more potent regimen associated with a better control of plasma viral load. The second analysis,
adjusting on HIV RNA, confirmed the major effect
of the control of viral replication independently of
the CPE score for survival after these 2 neurologic
events more directly linked to HIV infection. While
cerebral toxoplasmosis and cryptococcal meningitis
represent neurologic manifestations of immunodepression and benefit from specific therapies, it is interesting to note that the decline of mortality
associated with high CPE score regimen compared to
6
Neurology 76
February 15, 2011
low CPE regimen was no more evidenced after adjustment on HIV RNA.
ACKNOWLEDGMENT
The authors thank all the participants and research assistants of the
French Hospital Database on HIV. The French Hospital Database on
HIV is supported by Agence Nationale de Recherches sur le SIDA et les
Hépatites (ANRS), INSERM, and the French Ministry of Health.
DISCLOSURE
Dr. Lanoy, Dr. Guiguet, Dr. Bentata, Dr. Rouveix, Dr. Dhiver, and Dr.
Poizot-Martin report no disclosures. Dr. Costagliola has served on scientific advisory boards for Tibotec Therapeutics/Janssen, GlaxoSmithKline,
and ViiV Healthcare; has received funding for travel or speaker honoraria
from Gilead Sciences, Inc., Merck Serono, GlaxoSmithKline, and Boehringer Ingelheim; and receives research support from GlaxoSmithKline,
Bristol-Myers Squibb, Tibotec Therapeutics/Janssen, Roche, ANRS,
INSERM, Université Pierre et Marie Curie, and Sidaction. Dr. Gasnault
has served on a scientific advisory board for GlaxoSmithKline and has
received funding for travel and speaker honoraria from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Inc., GlaxoSmith
Kline, Tibotec Therapeutics/Janssen, and ViiV Healthcare.
APPENDIX
The FHDH-ANRS CO4: S. Abgrall (U943 INSERM and UPMC, Statistical Analysis Center, member of Scientific Committee); F. Barin (Corevih Centre, member of Scientific Committee); M. Bentata (Corevih Ile
de France Est, member of Scientific Committee); E. Billaud (Corevih
Pays de la Loire, Site Investigator, member of Scientific Committee); F.
Boué (Corevih Ile de France Sud, Site Investigator, member of Scientific
Committee); C. Burty (Corevih Lorraine, member of Scientific Committee); A. Cabié (Corevih de Martinique, Site Investigator, member of Scientific Committee); D. Costagliola (U943 INSERM and UPMC,
Director of Statistical Analysis Center, member of Scientific Committee);
L. Cotte (Corevih de la Vallée du Rhône, Site Investigator, member of
Scientific Committee); P. de Truchis (Corevih Ile de France Ouest, Site
Investigator, member of Scientific Committee); X. Duval (Corevih Ile de
France Nord, member of Scientific Committee); C. Duvivier (Corevih Ile
de France Sud, member of Scientific Committee); P. Enel (Corevih
PACA Ouest, member of Scientific Committee); J. Gasnault (Corevih Ile
de France Sud, member of Scientific Committee); C. Gaud (Corevih de
La Réunion, Site Investigator, member of Scientific Committee); J.
Gilquin (Corevih Ile de France Sud, Site Investigator, member of Scientific Committee); S. Grabar (U943 INSERM and UPMC, Statistical
Analysis Center, member of Scientific Committee); C. Katlama (Corevih
Ile de France Centre, Site Investigator, member of Scientific Committee);
M.A. Khuong (Corevih Ile de France Est, member of Scientific Committee); J.M. Lang (Corevih Alsace, Site Investigator, member of Scientific
Committee); A.S. Lascaux (Corevih Ile de France Sud, member of Scientific Committee); O. Launay (Corevih Ile de France Sud, member of
Scientific Committee); A. Mahamat (Corevih Guyane, member of Scientific Committee); M. Mary-Krause (U943 INSERM and UPMC, Statistical Analysis Center, member of Scientific Committee); S. Matheron
(Corevih Ile de France Nord, Site Investigator, member of Scientific
Committee); J.L. Meynard (Corevih Ile de France Centre, Site Investigator, member of Scientific Committee); J. Pavie (Corevih Ile de France Est,
member of Scientific Committee); G. Pialoux (Corevih Ile de France
Centre, Site Investigator, member of Scientific Committee); F. Pilorgé
(AIDES, member of Scientific Committee); I. Poizot-Martin (Corevih
PACA Ouest, Site Investigator, member of Scientific Committee); C.
Pradier (Corevih PACA Est, Site Investigator, member of Scientific Committee); J. Reynes (Corevih Languedoc-Roussillon, Site Investigator,
member of Scientific Committee); E. Rouveix (Corevih Ile de France
Ouest, member of Scientific Committee); A. Simon (Corevih Ile de
France Centre, Site Investigator, member of Scientific Committee); P.
Tattevin (Corevih Bretagne, member of Scientific Committee); H. TissotDupont (Corevih PACA Ouest, Site Investigator, member of Scientific
Committee); J.P. Viard (Corevih Ile de France Sud, Site Investigator,
member of Scientific Committee); N. Viget (Corevih Nord-Pas de Calais,
Site Investigator, member of Scientific Committee); M. Brosseau (French
Ministry of Health, DMI2 coordinating center); V. Salomon (French
Ministry of Health, DMI2 coordinating center); N. Jacquemet (DMI2
coordinating center, Technical Hospitalization Information Agency,
DMI2 coordinating center); M. Guiguet (U943 INSERM and UPMC,
Statistical Analysis Center); E. Lanoy (U943 INSERM and UPMC, Statistical Analysis Center); L. Lièvre (U943 INSERM and UPMC, Statistical Analysis Center); H. Selinger-Leneman (U943 INSERM and UPMC,
Statistical Analysis Center); J.M. Lacombe (INSERM Transfert, Statistical Analysis Center); V. Potard (INSERM Transfert, Statistical Analysis
Center); F. Bricaire (Corevih Ile de France Centre, Site Investigator); S.
Herson (Corevih Ile de France Centre, Site Investigator); N. Desplanque
(Corevih Ile de France Centre, Site Investigator); P.M. Girard (Corevih
Ile de France Centre, Site Investigator); M.C. Meyohas (Corevih Ile de
France Centre, Site Investigator); O. Picard (Corevih Ile de France Centre, Site Investigator); J. Cadranel (Corevih Ile de France Centre, Site
Investigator); C. Mayaud (Corevih Ile de France Centre, Site Investigator); J.P. Clauvel (Corevih Ile de France Est, Site Investigator); J.M. Decazes (Corevih Ile de France Est, Site Investigator); L. Gerard (Corevih Ile
de France Est, Site Investigator); J.M. Molina (Corevih Ile de France Est,
Site Investigator); M. Diemer (Corevih Ile de France Est, Site Investigator); P. Sellier (Corevih Ile de France Est, Site Investigator); P. Honoré
(Corevih Ile de France Est, Site Investigator); V. Jeantils (Corevih Ile de
France Est, Site Investigator); S. Tassi (Corevih Ile de France Est, Site
Investigator); D. Mechali (Corevih Ile de France Est, Site Investigator); B.
Taverne (Corevih Ile de France Est, Site Investigator); E. Bouvet (Corevih
Ile de France Nord, Site Investigator); B. Crickx (Corevih Ile de France
Nord, Site Investigator); J.L. Ecobichon (Corevih Ile de France Nord, Site
Investigator); C. Picard-Dahan (Corevih Ile de France Nord, Site Investigator); P. Yeni (Corevih Ile de France Nord, Site Investigator); H. Berthé
(Corevih Ile de France Ouest, Site Investigator); C. Dupont (Corevih Ile
de France Ouest, Site Investigator); C. Chandemerle (Corevih Ile de
France Ouest, Site Investigator); E. Mortier (Corevih Ile de France Ouest,
Site Investigator); D. Tisne-Dessus (Corevih Ile de France Sud, Site Investigator); L. Weiss (Corevih Ile de France Sud, Site Investigator); D.
Salmon (Corevih Ile de France Sud, Site Investigator); I. Auperin (Corevih Ile de France Sud, Site Investigator); L. Roudière (Corevih Ile de
France Sud, Site Investigator); R. Fior (Corevih Ile de France Sud, Site
Investigator); J.F. Delfraissy (Corevih Ile de France Sud, Site Investigator); C. Goujard (Corevih Ile de France Sud, Site Investigator); C. Jung
(Corevih Ile de France Sud, Site Investigator); P. Lesprit (Corevih Ile de
France Sud, Site Investigator); D. Vittecoq (Corevih Ile de France Sud,
Site Investigator); P. Fraisse (Corevih Alsace, Site Investigator); D. Rey
(Corevih Alsace, Site Investigator); G. Beck-Wirth (Corevih Alsace, Site
Investigator); J.P. Stahl (Corevih de l’Arc Alpin, Site Investigator); P.
Lecercq (Corevih de l’Arc Alpin, Site Investigator); F. Gourdon (Corevih
Auvergne-Loire, Site Investigator); H. Laurichesse (Corevih AuvergneLoire, Site Investigator); A. Fresard (Corevih Auvergne-Loire, Site Investigator); F. Lucht (Corevih Auvergne-Loire, Site Investigator); C. Bazin
(Corevih Basse-Normandie, Site Investigator); R. Verdon (Corevih BasseNormandie, Site Investigator); P. Chavanet (Corevih Bourgogne, Site Investigator); C. Arvieux (Corevih Bretagne, Site Investigator); C. Michelet
(Corevih Bretagne, Site Investigator); P. Choutet (Corevih Centre, Site
Investigator); A. Goudeau (Corevih Centre, Site Investigator); M.F.
Maître (Corevih Centre, Site Investigator); B. Hoen (Corevih FrancheComté, Site Investigator); P. Elinger (Corevih Franche-Comté, Site Investigator); J.P. Faller (Corevih Franche-Comté, Site Investigator); F. Borsa-Lebas
(Corevih Haute-Normandie, Site Investigator); F. Caron (Corevih
Haute-Normandie, Site Investigator); J.P. Daurès (Corevih LanguedocRoussillon, Site Investigator); T. May (Corevih Lorraine, Site Investigator); C. Rabaud (Corevih Lorraine, Site Investigator); J.L. Berger
(Corevih Lorraine, Site Investigator); G. Rémy (Corevih Lorraine, Site
Investigator); E. Arlet-Suau (Corevih de Midi-Pyrénées, Site Investigator); L. Cuzin (Corevih de Midi-Pyrénées, Site Investigator); P. Massip
(Corevih de Midi-Pyrénées, Site Investigator); M.F. Thiercelin Legrand
(Corevih de Midi-Pyrénées, Site Investigator); G. Pontonnier (Corevih de
Midi-Pyrénées, Site Investigator); Y. Yasdanpanah (Corevih Nord-Pas de
Calais, Site Investigator); P. Dellamonica (Corevih PACA Est, Site Investigator); P. Pugliese (Corevih PACA Est, Site Investigator); K. Aleksandrowicz (Corevih PACA Est, Site Investigator); D. Quinsat (Corevih
PACA Est, Site Investigator); I. Ravaux (Corevih PACA Ouest, Site Investigator); J.P. Delmont (Corevih PACA Ouest, Site Investigator); J. Moreau (Corevih PACA Ouest, Site Investigator); J.A. Gastaut (Corevih
PACA Ouest, Site Investigator); F. Retornaz (Corevih PACA Ouest, Site
Investigator); J. Soubeyrand (Corevih PACA Ouest, Site Investigator); A.
Galinier (Corevih PACA Ouest, Site Investigator); J.M. Ruiz (Corevih
PACA Ouest, Site Investigator); T. Allegre (Corevih PACA Ouest, Site
Investigator); P.A. Blanc (Corevih PACA Ouest, Site Investigator); D.
Bonnet-Montchardon (Corevih PACA Ouest, Site Investigator); G.
Lepeu (Corevih PACA Ouest, Site Investigator); P. Granet-Brunello
(Corevih PACA Ouest, Site Investigator); J.P. Esterni (Corevih PACA
Ouest, Site Investigator); L. Pelissier (Corevih PACA Ouest, Site Investigator); R. Cohen-Valensi (Corevih PACA Ouest, Site Investigator); M.
Nezri (Corevih PACA Ouest, Site Investigator); S. Chapadaud (Corevih
PACA Ouest, Site Investigator); A. Laffeuillade (Corevih PACA Ouest,
Site Investigator); F. Raffi (Corevih Pays de la Loire, Site Investigator); A.
Boibieux (Corevih de la Vallée du Rhône, Site Investigator); D. Peyramond (Corevih de la Vallée du Rhône, Site Investigator); J.M. Livrozet
(Corevih de la Vallée du Rhône, Site Investigator); J.L. Touraine (Corevih
de la Vallée du Rhône, Site Investigator); C. Trepo (Corevih de la Vallée
du Rhône, Site Investigator); M. Strobel (Corevih de Guadeloupe, Site
Investigator); F. Bissuel (Corevih de Guadeloupe, Site Investigator); R.
Pradinaud (Corevih de Guyane, Site Investigator); M. Sobesky (Corevih
de Guyane, Site Investigator); and M. Contant (Corevih de La Réunion,
Site Investigator).
Received May 25, 2010. Accepted in final form October 21, 2010.
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Survival after neuroAIDS - CHU de Clermont

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