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Changing incidence of central nervous system diseases in the EuroSIDA cohort.

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Changing Incidence of Central Nervous
System Diseases in the EuroSIDA Cohort
Antonella d’Arminio Monforte, MD,1 Paola Cinque, MD,2 Amanda Mocroft, PhD,3
Frank-Detlev Goebel, MD,4 Francisco Antunes, MD,5 Christine Katlama, MD,6 Ulrik Stenz Justesen, MD,7
Stefano Vella, MD,8 Ole Kirk, MD,9 and Jens Lundgren, MD,9 for the EuroSIDA Study Group
A drastic decrease in incidence has been observed for most human immunodeficiency virus (HIV)–related opportunistic
manifestations after use of highly active antiretroviral therapy (HAART). We assessed the trend of incidence of central
nervous system (CNS) diseases in a prospective multicenter observational study involving 9,803 patients across Europe in
the period 1994 to 2002 and analyzed patient and treatment variables associated with these conditions. Overall, 568
patients (5.8%) received a diagnosis of a new CNS disease. Incidence decreased significantly from 5.9 per 100 personyear in 1994 to 0.5 in 2002. Overall, the decrease was 40% per calendar year, and it was similar to that of non-CNS
diseases and less evident after year 1998. In multivariable models, low CD4 cell count and high plasma viral load, but
not HAART or calendar year, were significantly associated with risk to develop CNS disease, indicating that the effect of
HAART was likely mediated by both improved immunological conditions and inhibition of viral replication. In contrast,
use of nucleoside reverse transcriptase inhibitors, irrespective of use of protease inhibitors or non-nucleoside reverse
transcriptase inhibitors, appeared to protect specifically against acquired immunodeficiency disease syndrome dementia
complex, suggesting that, in this condition, therapy might have a direct, additive effect in the CNS.
Ann Neurol 2004;55:320 –328
Acquired immunodeficiency disease syndrome (AIDS)–
related diseases of the central nervous system (CNS)
occur in late stages of human immunodeficiency virus
(HIV) infection and are associated with poor prognosis. These include opportunistic infections and tumors
and a spectrum of neurological disorders associated
with CNS infection by HIV itself, generally referred to
as AIDS dementia complex (ADC). Similar to what
has been observed for extracerebral complications of
HIV infection, a drastic decline of incidence and prevalence has been documented for both opportunistic
CNS diseases and ADC by several retrospective or cohort studies after the introduction of highly active antiretroviral therapy (HAART).1–7
Theoretically, the effect of HAART on CNS diseases
might differ from that on extracerebral complications
because of the anatomical and functional properties of
the CNS itself. The presence of the brain barriers
might limit anti-HIV drug penetration into this com-
partment and subsequent suppression of viral replication. Furthermore, unlike systemic infection, the principal CNS cells harboring HIV are macrophages and
microglial cells, in which dynamics of viral replication
and response to antiretroviral drugs may be different
compared with peripheral lymphocytes.8 –10 These features, along with an increased patient survival induced
by HAART, might expose patients to a risk of developing HIV-related complications in the CNS, especially ADC. Actually, an increased prevalence of HIV
encephalopathy recently has been reported in postmortem cases associated with the use of HAART,11,12 but
this finding is controversial.13
With this study, we assessed the trend of incidence
of CNS diseases in Europe, including both CNS opportunistic diseases and ADC, during the period 1994
to 2002. In particular, we evaluated whether the overall
trend paralleled that observed for non-CNS opportunistic diseases and whether this differed between ADC
From the 1Institute of Infectious and Tropical Diseases, University
of Milan; 2Clinic of Infectious Diseases, San Raffaele Hospital, Milan, Italy; 3Royal Free and University College Medical School, Department of Primary Care and Population Sciences, London, United
Kingdom; 4Klinikum Innerstadt Medizinische Poliklinik Infektionsambulanz and Tagesklinik, Munich, Germany; 5Department of Infectious Diseases, Hospital Santa Maria, Lisbon, Portugal; 6Department de Medicine Tropicale, Hospital de la Pitié-Salpêtriére, Paris,
France; 7Department of Infectious Diseases, Odense University
Hospital, Odense, Denmark; 8Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy; and 9EuroSIDA Coordinating Centre, Copenhagen HIV Programme, Department 044, Hvidovre University Hospital, Hvidovre, Denmark.
Received Jun 30, 2003, and in revised form Sep 17. Accepted for
publication Sep 17, 2003.
320
Members of the multicenter study group on EuroSIDA are listed in
the Appendix on pages 326 –327.
Address correspondence to Dr d’Arminio Monforte, Institute of Infectious and Tropical Diseases, University of Milan, L Sacco Hospital, Via GB Grassi, 74, 20157 Milan, Italy.
E-mail: antonella.darminio@unimi.it
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
and CNS opportunistic diseases and among the individual CNS opportunistic diseases. Finally, we investigated the possible influence of various factors on development of CNS diseases.
Patients and Methods
The EuroSIDA Study Cohort
The EuroSIDA study is a prospective, European study of patients with HIV-1 infection in 70 centers across Europe also
including Israel and Argentina (see appendix). Details of the
study have been published.14 In brief, five cohorts of patients
have been recruited. Eligible patients were older than 16
years at the time of enrolment and had a CD4 lymphocyte
count of below 500/mm3 in the previous 4 months for Cohort I to III but no CD4 count restriction for Cohorts IV
and V. Clinical and laboratory information was provided on
a standardized data collection form at baseline and every 6
months thereafter. Dates of diagnosis of all AIDS defining
illnesses were recorded using the 1993 AIDS definition from
the Centers for Disease Control.15 Presumptive diagnoses of
primary CNS lymphoma, progressive multifocal leukoencephalopathy (PML), or ADC were accepted; for full details
on data collection and diagnostic criteria refer to http://www.
cphiv.dk.
Statistical Methods
All patients with at least one follow-up visit after recruitment
to EuroSIDA were included in this study and follow-up is to
autumn 2002. The following CNS diseases have been included: toxoplasmosis, cryptococcosis, PML, primary brain
lymphoma (PBL), ADC, and focal brain lesions (FBLs) without an causative diagnosis.
The incidence of CNS diagnoses overall and individually
was calculated using a person-years analysis. Person-years of
follow-up were calculated from date of recruitment to the
EuroSIDA study and ended at last clinical follow-up, date of
death, or development of CNS disease (CNS-D), whichever
occurred first. The follow-up was further stratified according
to calendar period.
Tests for changes in the incidence of CNS-D over time
were performed using Poisson regression. Patients with a
CNS-D at recruitment were included and were followed up
until the diagnosis of their next, distinct CNS-D. Only the
first event of a given disease was included.
Standard Cox proportional hazards models were used to
investigate progression to CNS-D and individually for ADC
or all other CNS-D combined. Demographic factors, such as
sex, age, and exposure category were included in models to
determine their relationship with progression to CNS-D. All
Cox models were stratified by center and factors which were
significant in univariable analyses with p value less than 0.1
then were included in multivariable models. Because models
were stratified by center, it was not possible to investigate
differences between regions of Europe. Factors known to be
related to progression of HIV disease (the development of
AIDS and CD4 lymphocyte count) were included in Cox
models as time dependent. To investigate whether the risk of
CNS-D had changed over time, we modeled calendar period
as a time-dependent covariate using 1998 as the reference
period. Antiretroviral treatment regimen also was included as
time-dependent covariates, as starting any nucleoside reverse
transcriptase inhibitor (NRTI)–containing therapy, either in
combination or not with antiretroviral drugs of other classes,
starting a protease inhibitor (PI)–based HAART regimen, or
starting a non-NRTI (NNRTI)–based HAART regimen,
HAART being defined as at least triple therapy including a
PI or a NNRTI. Treatment was included as an intent-totreat variable.
A further Cox model was constructed to determine the
effects of drugs thought to cross the blood–brain barrier (all
nucleosides, NNRTIs and indinavir); this model was adjusted for the same factors as previously described, and antiretroviral treatment was included as two variables which
counted the number of drugs in the regimen which do or do
not cross the blood–brain barrier.
Results
A total of 9,803 patients of the EuroSIDA cohort were
enrolled; 9,348 were free from CNS diseases at enrollment and 455 had already suffered at least from one
CNS-D for a total of 479 diagnoses. Characteristics of
the patients are summarized in Table 1.
Median follow-up after recruitment was significantly
higher in patients free from CNS diseases (42.0
months IQR 13– 65 vs 17 months IQR 6 –54; p ⬍
0.0001).
In a median follow-up of 40.9 months (IQR, 12.0 –
65.0), 568 patients (5.8%) received a diagnosis of a
first new CNS-D. This was the first AIDS-defining illness in 174 patients (30.6%). ADC was the most frequent disease after recruitment, diagnosed in 190 patients (33.5%), followed by toxoplasmosis in 152
(26.8%), PML in 83 (14.6%), cryptococcosis in 64
(11.3%), PBL in 52 (9.2%), and FBL in 27 (4.8%).
Figure 1 illustrates the incidence of CNS diseases
considered as a whole according to calendar period.
The rate of decline in CNS-D was 40% per calendar
year (95% confidence interval [CI], 37– 42%) and was
very similar to that of non-CNS diseases (40%; 95%
CI, 30 – 41%). Starting from 1998, there was no evidence of any further decline in CNS-D (9% per year,
95% CI: 8% increase to 23% decrease; p ⫽ 0.29). The
455 patients already suffering from CNS diseases at recruitment showed a higher incidence of new diagnoses
of CNS-D as compared with the whole population,
but a similar decline over time (estimated 32% per
year, 95% CI: 31– 41%, p ⬍ 0.0001; data not shown).
Considering the incidence of individual CNS diseases
(Fig 2), the rate of annual decrease for ADC (45%,
95% CI, 40 – 49%) was statistically higher than that of
opportunistic CNS diseases as a whole (37%, 95% CI,
34 – 41%; p ⬍ 0.01). Differences were observed between individual CNS diseases, with the lowest annual
decrease of incidence observed for PML (31%, 95%
CI, 24 –38%) and the highest for PBL (48%, 95% CI,
39 –59%).
Table 2 gives an overview of the CNS diagnoses in
d’Arminio Monforte et al: CNS Diseases
321
Table 1. Characteristics of the Study Population at Recruitment to EuroSIDA
Without Previous CNS
Disease
All
Characteristic
All
Sex
Men
Women
Risk
Homosexual
IDU
Heterosexual
Other
Race
White
Other
Region
South
Central
North
East
Argentina
Treatment ever taken before/at
None
HAART
PI
NNRTI
Nucsa
All three classes
Other AIDS at recruitment
No
Yes
Other values median (IQR)
Age
CD4 at recruitment
VL at recruitment
N
%
N
%
9,803
100
9,348
95.4
With Previous CNS
Disease
N
%
p
455
4.6
—
7,678
2,125
78.3
21.7
7,298
2,050
78.1
21.9
380
75
83.5
16.5
0.0059
4,403
2,405
2,319
676
44.9
24.5
23.7
6.9
4,185
2,294
2,222
647
49.8
24.5
23.8
6.9
218
111
97
29
47.9
24.4
21.3
6.4
0.52
4,403
5,400
44.9
55.1
4,185
5,163
44.8
55.2
218
237
47.9
52.1
0.19
29.5
26.6
32.5
10.3
1.0
2,773
2,470
3,043
971
91
29.7
26.4
32.6
10.4
1.0
118
139
148
41
9
25.9
30.5
32.5
9.0
2.0
0.042
21.8
30.0
30.8
9.7
77.3
5.4
2,097
2,772
2,820
910
7,169
494
22.4
29.7
30.2
9.7
76.7
5.3
39
171
199
43
414
32
8.6
37.6
43.7
9.4
91.0
7.0
⬍0.0001
0.0003
⬍0.0001
0.84
⬍0.0001
0.11
71.6
28.4
6,826
2,522
73.0
27.0
188
267
41.3
58.7
⬍0.0001
32.6–43.9
16–184
2.39–4.42
0.0012
⬍0.0001
0.30
2,891
2,609
3,191
1,012
100
recruitment
2,136
2,943
3,019
953
7,583
526
7,014
2,789
36.2
238
3.11
31.3–43.2
108–380
2.30–4.38
36.1
245
3.11
31.3–43.2
115–384
2.30–4.38
37.6
78
3.02
A total of 467 diagnoses of CNS-D were made in these 455 patients a median of 12 mo before recruitment to EuroSIDA (IQR: 6 –25 mo).
These included toxoplasmosis in 217 patients (48%), ADC in 120 (26%), cryptococcosis in 88 (19%), PML in 40 (9%), FBL in 8 (2%), and
PBL in 6 (1%).
VL was available at recruitment to EuroSIDA for 5,169 patients (52.7%); 4,934 (52.8%) without, and 235 (51.7%) with previous CNS at
recruitment ( p ⫽ 0.64, ␹2 test).
a
Any regimen containing NRTIs.
CNS ⫽ central nervous system; IDU ⫽ intravenous drug user; IQR ⫽ interquartile range; VL ⫽ viral load; HAART ⫽ highly active
antiretroviral therapy; PI ⫽ protease inhibitor; NNRTI ⫽ nonnucleoside reverse transcriptase inhibitor; IDU ⫽ intervenous drug user.
consecutive calendar years. CD4 cell counts at the diagnosis of CNS-D were higher in later as compared
with earlier years ( p ⬍ 0.0001, Wilcoxon test), although the increase was mainly among diagnoses made
in 2001 or later. There was no significant change over
time in the relative proportion of cases with ADC or
opportunistic CNS infections ( p ⫽ 0.095, ␹ test), in
the HIV-RNA copy levels at diagnosis ( p ⫽ 0.11, Wilcoxon test) or in the proportion of CNS diseases as
index diseases ( p ⫽ 0.57, ␹ test, see Table 2).
Possible factors predicting progression to any
CNS-D were evaluated by univariable and multivariable analyses, either excluding or including viral load
(Table 3). Although a very strong effect of anti-HIV
322
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March 2004
therapy on the risk of CNS diseases was shown in the
univariable analysis, this effect disappeared after adjusting for calendar year and latest CD4 count. In the first
multivariable model, in which viral load was not analyzed, the latest CD4 counts were the most significant
independent variable associated with CNS-D, whereas
calendar year after 1998 and antiretroviral regimens
were not significant risk predictors. By considering
only patients with available viral load, we found that
both latest CD4 count and HIV-RNA copy levels were
strong predictors of CNS-D, but, again, neither therapy regimen nor calendar year after 1998 were predictive.
By using the same model, we also evaluated the risk
Fig 1. Incidence of central nervous system (CNS) (circles) and
non-CNS (diamonds) AIDS-defining diseases in the EuroSIDA cohort, years 1994 to 2002. PYFU ⫽ person-year
follow-up.
of developing ADC or CNS opportunistic infections
separately (Table 4). The risk of both conditions was
significantly reduced in patients with higher CD4
counts; moreover, higher risk of ADC was significantly
associated with age and intravenous drug usage. In addition, starting any NRTI-containing regimen was independently associated with a reduced risk of developing ADC hazard ratio (HR, 0.59; 95% CI, 0.39 – 0.90;
p ⫽ 0.013), irrespective of the presence of PI or NNRTIs in a given regimen. In subset analyses, a higher
latest viral load was not associated with an increased
risk of ADC (HR, 1.20; 95% CI, 0.92–1.56, p ⫽
0.17), but with an increased risk of other CNS diseases
(HR 1.61 per 1 log higher 95% CI 1.37–1.89, p ⬍
0.0001) (data not shown).
In the univariable analysis, there was a 39% reduced
risk of CNS-D (HR, 0.61; 95% CI, 0.45– 0.84; p ⫽
0.0021) for each extra drug though to cross the blood–
brain barrier, that is, all NRTIs, all NNRTIs, and indinavir.10,16,17 However, a nonsignificant reduced risk of
CNS-D for each extra drug thought to cross the
blood–brain barrier was observed after adjusting for exposure group, year of follow-up, age, diagnosis of a
new AIDS defining illness, and CD4 both at recruitment or at last examination (HR, 0.77; 95% CI, 0.56 –
1.05; p ⫽ 0.093 and HR 0.81, 95% CI, 0.59 –1.11;
p ⫽ 0.19).
Discussion
In this study, we observed a significant decrease of the
incidence of AIDS-defining CNS diseases through Europe, after the extensive usage of HAART. This decrease was generalized to all individual CNS diseases
and similar to that observed in non-CNS, HIV-related
opportunistic diseases. To our knowledge, this is the
largest study addressing this topic, with nearly 10,000
patients included.
HAART was introduced in Europe starting from
1995 to 1996, with regional differences.16 This analysis
shows that the incidence decline of CNS diseases was
evident since 1996, that is, a few months after HAART
introduction, similarly to what observed in other studies.2–7 Because only a small proportion of patients in
the cohort had access to HAART in that year, it is
possible that double combination therapy, widely used
since 1995, might have been in part responsible of the
initial decline. On the other hand, a slower decline in
incidence was observed after 1998, with overall incidence leveling at between 0.3 and 0.5 per 100 persons
per year of follow-up. A similar, slowing rate of decline
recently has been reported for both global AIDSrelated events and deaths during the same period.17,18
It will be essential to observe whether incidence figures
increase in the coming years, as a result of the increasing number of treatment failures.19
As already observed for all AIDS-defining events,
CD4 counts at the diagnosis of CNS-D increased over
time.2,14,20,21 It is possible that the initially HAARTinduced increase in circulating CD4 cells was not protective against infections in the first months of therapy.22 Alternatively, this finding might reflect the
proportion of events occurring in patients with relatively high CD4 counts, due to a cohort effect.14 Nevertheless, by multivariable analysis, CD4 counts, together with viral load, but not treatment regimen, were
predictors of risk to develop CNS-D.
This observation can be explained by the effect of
antiretroviral therapy on viral replication, resulting in
restoration of the immune system and prevention of
AIDS events. In fact, excluding latest CD4 counts
from the multivariable model, the protective effect of
HAART is maintained (data not shown).
Fig 2. Incidence of individual central nervous system (CNS)
diseases in the EuroSIDA cohort, years 1994 to 2002.
ADC ⫽ AIDS-dementia complex; TOX ⫽ brian toxoplasmosis; CCOC ⫽ cryptococcosis; PML ⫽ progressive multifocal
encephalopathy; PBL ⫽ primary brain lymphoma; FBL ⫽
focal brain lesions; CI ⫽ confidence interval. PYFU ⫽
person-year follow-up.
d’Arminio Monforte et al: CNS Diseases
323
Table 2. Number of CNS Diagnoses, CD4 Cell Counts, and HIV-RNA Copy Levels at the Time of Diagnosis and Rate of CNS
Disease as AIDS Index Disease over Calendar Time
CNS diagnoses, N
(%)
CNS-OI
ADC
CNS disease as
ID
CD4 at diagnosis,
median (IQR)
VL at diagnosis
(range),
median (IQR)
Patients with VL
data, N (%)
1994
1995
1996
1997
1998
1999
2000
2001 and after
103
164
141
54
28
32
22
24
101 (61.6)
63 (38.4)
48 (29.3)
89 (63.1)
52 (36.9)
46 (32.6)
42 (77.8)
12 (22.2)
19 (35.2)
20 (71.4)
8 (28.6)
10 (35.7)
27 (84.4)
5 (15.9)
11 (34.4)
16 (72.7)
6 (27.3)
9 (40.9)
27 (10–69)
20 (7–70)
21 (8–71)
46 (8–101)
30 (10–77)
64 (21–185)
30 (9–68)
109 (20–156)
3.08 (—)
4.80
(4.67–5.00)
5.29
(4.66–5.64)
4.92
(3.60–5.60)
4.70
(3.92–5.30)
4.62
(2.60–5.32)
4.46
(2.60–5.13)
4.87
(2.48–5.60)
3 (1.8)
30 (21.3)
36 (66.7)
27 (96.4)
31 (96.9)
65 (63.1)
38 (36.9)
27 (26.2)
1 (1.0)
18 (75.0)
6 (25.0)
4 (16.7)
21 (95.5)
24 (100)
CNS ⫽ central nervous system; HIV ⫽ human immunodeficiency virus; AIDS ⫽ acquired immunodeficiency syndrome; OI ⫽ opportunistic
diseases; ADC ⫽ AIDS dementia complex; ID ⫽ index disease; IQR ⫽ interquartile range; VL ⫽ viral load.
It has been hypothesized that, because of poor penetration of some drugs into the CNS, HAART could
be less efficient in preventing CNS than non-CNS diseases. This was particularly a concern for ADC, in
which failing to achieve therapeutical antiretroviral
drug levels in the brain might theoretically prevent efficient viral suppression locally.10 Furthermore, HIV
has been shown in vitro to transactivate several opportunistic agents, including JC virus, Mycobacterium tu-
berculosis, or Cryptococcus neoformans,23–25 and therefore lack of HIV inhibition in the CNS might
theoretically favor the local development of opportunistic manifestations. However, the observation of a similar
incidence trend observed in CNS and non-CNS diseases
argues against a lower neuroprotective effect of HAART.
Furthermore, we found no significant association between the number of drugs thought to cross the blood–
brain barrier and the development of CNS-D.
Table 3. Relative Risk of Any CNS Disease after Recruitment to the EuroSIDA Study
Multivariablea
Univariable
Risk
Homosexual
IDU
Heterosexual
Other
Yearc
1994
1995
1996
1997
1998
1999
2000
2001 or later
Age (per 10 yr older)
AIDSc (Tdc)
Latest CD4c (50% higher)
Started nucsd (Tdc)
Started PI-HAARTc (Tdc)
Started NNRTI-HAARTc
(Tdc)
VLc (log higher)
Multivariableb
RH
95% CI
p
RH
95% CI
p
RH
95% CI
p
1.00
1.06
0.85
0.60
—
0.85–1.39
0.68–1.08
0.38–0.93
—
0.59
0.18
0.024
1.00
1.12
0.99
0.56
—
0.88–1.42
0.78–1.26
0.35–0.88
—
0.35
0.93
0.011
1.00
1.41
1.18
0.49
—
0.88–2.25
0.77–1.80
0.21–1.12
17.17
14.27
9.12
2.02
1.00
0.94
0.50
0.55
1.04
1.84
0.60
1.08
0.36
9.21–32.02
8.43–24.16
5.43–15.30
1.19–3.45
—
0.49–1.79
0.24–1.05
0.25–1.20
0.94–1.14
1.16–2.93
0.58–0.62
0.86–1.35
0.29–0.45
⬍0.0001
⬍0.0001
⬍0.0001
0.0096
—
0.84
0.065
0.13
0.47
0.0098
⬍0.0001
0.51
⬍0.0001
7.11
4.23
4.23
1.66
1.00
1.13
0.68
0.82
1.10
0.93
0.63
0.95
0.81
3.45–14.65
2.34–7.64
2.38–7.55
0.96–2.89
—
0.58–2.19
0.32–1.45
0.36–1.84
1.00–1.22
0.58–1.50
0.61–0.65
0.75–1.20
0.61–1.09
⬍0.0001
⬍0.0001
⬍0.0001
0.070
—
0.72
0.32
0.63
0.055
0.76
⬍0.0001
0.65
0.86
5.66
5.68
2.65
1.13
1.00
1.21
0.86
1.08
1.15
1.12
0.57
0.94
0.93
0.30–105.44
0.75–42.85
1.12–6.29
0.58–2.19
—
0.58–2.53
0.38–1.96
0.45–2.61
0.96–1.37
0.50–2.51
0.53–0.62
0.62–1.43
0.65–1.35
0.25
0.092
0.027
0.72
—
0.62
0.72
0.87
0.13
0.78
⬍0.0001
0.76
0.71
0.59
2.29
0.42–0.82
2.02–2.60
0.0016 1.04
⬍0.0001 —
0.69–1.57
—
0.86
—
0.77
1.43
0.48–1.22
1.24–1.65
0.26
⬍0.0001
—
0.15
0.45
0.090
CNS ⫽ central nervous system; CI ⫽ confidence interval; IDU ⫽ intravenous drug user; PI ⫽ protease inhibitor; HAART ⫽ highly active
antiretroviral therapy; NNRTI ⫽ nonnucleoside reverse transcriptase inhibitor; VL ⫽ viral load; RH ⫽ relative hazard.
a
Multivariable model excluding viral load.
Multivariable model including viral load.
Fitted as time-dependent covariate (tdc).
d
Nucs is any regimen containing NRTIs.
b
c
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March 2004
Table 4. Multivariable Relative Risk of Any AIDS Dementia or Other CNS Disease after Recruitment to the EuroSIDA Study
AIDS Dementia Complex
Risk
Homosexual
IDU
Heterosexual
Other
Yeara
1994
1995
1996
1997
1998
1999
2000
2001 and after
Age (per 10 yr older)
AIDSa (Tdc)
Latest CD4a (50%
higher)
Started Nucsa (Tdc)
Started PI-HAARTa
(Tdc)
Started NNRTIHAARTa (Tdc)
RH
95% CI
1.00
1.84
1.18
0.71
—
1.23–2.77
0.78–1.77
0.34–1.46
8.48
7.63
3.89
1.10
1.00
0.54
0.63
0.36
1.38
0.72
Other CNS Disease
p
RH
95% CI
p
—
0.0032
0.43
0.35
1.00
0.87
1.06
0.48
—
0.65–1.16
0.81–1.39
0.28–0.84
—
0.87
0.67
0.011
2.23–32.33
2.62–22.28
1.35–11.24
0.38–3.15
—
0.13–2.17
0.17–2.31
0.07–1.82
1.17–1.63
0.31–1.68
0.0017
0.0002
0.012
0.87
—
0.39
0.48
0.22
⬍0.0001
0.44
6.03
3.04
4.01
1.85
1.00
1.30
0.61
0.85
1.06
1.18
2.61–13.94
1.55–5.96
2.08–7.72
0.99–3.45
—
0.62–2.72
0.25–1.48
0.34–2.13
0.94–1.19
0.71–1.97
⬍0.0001
0.0012
⬍0.0001
0.053
—
0.48
0.27
0.73
0.36
0.52
0.64
0.59
0.61–0.68
0.39–0.90
⬍0.0001
0.013
0.62
1.06
0.60–0.65
0.80–1.40
⬍0.0001
0.69
0.83
0.48–1.41
0.48
0.81
0.59–1.12
0.20
0.96
0.43–2.15
0.91
1.01
0.64–1.59
0.98
AIDS ⫽ acquired immunodeficiency syndrome; CNS ⫽ central nervous system; CI ⫽ confidence interval; IDU ⫽ intravenous drug user; PI ⫽
protease inhibitor; HAART ⫽ highly active antiretroviral therapy; NNRTI ⫽ nonnucleoside reverse transcriptase inhibitor; RH ⫽ relative
hazard.
a
Fitted as time-dependent covariate (tdc).
Any regimen containing NRTIs.
b
However, considering the individual CNS diseases,
we observed variation in the incidence decline, with
decrease rates higher for ADC and PBL and slower for
PML. The relatively slow incidence decline of PML is
consistent with recent prevalence data, showing a relatively high frequency of PML cases in the HAART era,
second only to toxoplasmosis as more frequent opportunistic CNS-D.26 This observation might partly be
explained by considering the proportion of PML cases
that become manifest in the context of HAARTinduced immune reconstitution.27,28 With regard to
ADC, literature data on the effect of HAART on this
disease are contrasting. Whereas some authors showed
a positive correlation between HAART usage and reduction of ADC or HIV-related lesions,3,6,13 others reported the persistence of a relevant number of HIVinduced CNS disease cases despite HAART.2,11,12,29 In
this regard, our findings show that the effect of
HAART on ADC incidence was at least as important,
if not superior to that on other CNS diseases.
The multivariable model showed that having started
NRTIs in any regimen was associated with a 41% reduction of the risk of ADC, over and above the protective effect of starting any HAART regimen. Because
higher CD4 counts were significantly associated with a
reduced risk of both ADC and opportunistic CNS diseases, the protective effect of NRTIs in ADC appears
to lay beyond that exerted through the CD4 cells increase.
It is known that even zidovudine alone is effective in
both prevention and treatment of HIV-related encephalopathy.30,31 A decline of ADC incidence and of prevalence of HIV-related brain lesions was indeed observed in the years after the introduction of this drug
in clinical practice.30,32 Furthermore, more recent data
indicate that dual NRTI combinations preserve or improve neurological performance.33 Whereas the benefit
of single or dual NRTIs regimens on systemic immunological and virological markers is usually mild and
transitory,16 these same regimens might be effective in
the CNS because of the peculiarity of the brain compartment for HIV replication, and their use have contributed substantially to the marked decline of ADC
incidence.
Our study has some limitations. First, the actual
number of events probably was underdiagnosed, because we did not consider the diagnosis of some CNS
diseases, such as cytomegalovirus (CMV) encephalitis
or mycobacteriosis. Although mycobacteriosis is uncommon in the CNS, CMV encephalitis used to be
d’Arminio Monforte et al: CNS Diseases
325
very frequent in the years immediately preceding the
introduction of HAART, being reported in approximately 20% of postmortem AIDS cases.11 In addition,
we examined only the incidence of the first diagnoses
of CNS diseases after recruitment, thus excluding both
recurrences of the same CNS event and new events in
the same patient. Second, plasma viral load was not
available from most of the patients during the first
years of EuroSIDA, thus reducing the possibility of examining this marker as risk predictor. Finally, data on
primary prophylaxis for opportunistic CNS diseases,
namely, toxoplasmosis and cryptococcosis, were not
collected in detail and therefore not included in this
analysis. Nonetheless, we briefly examined the use of
primary prophylaxis for toxoplasmosis and verified that
it remained fairly stable over calendar time approximately 70 to 80% among patients with severe immune
deficiency, that is, with CD4 counts less than 100/␮l
(data not shown). Thus, changes in use of prophylaxis
did not explain the decreasing incidence of toxoplasmosis. On the other hand, an increasing proportion of
patients stopped specific prophylaxis after HAARTinduced increase of CD4 cell counts,34 and thus
changes in use of prophylaxis was unlikely to explain
the decreasing incidence of toxoplasmosis.
In conclusion, this study showed a reduction of incidence of CNS diseases across Europe after the introduction of HAART. High CD4 counts and low
plasma viral load were strongly associated with a lower
risk of CNS-D, indicating that the immune reconstitution is the main factor responsible for this incidence
decline. However, an additive, direct effect of antiretroviral therapy on virus replication in CNS might have
accounted for the marked incidence decline observed
in ADC. This study also showed a stabilization of CNS
disease incidence after 1998. This finding, together
with the consideration that an increasing proportion of
HIV-infected patients undergo multiple treatment failure, underscores the importance of continuing surveillance for CNS disease manifestations.
Appendix
The EuroSIDA Study Group
The multicenter study group on EuroSIDA (national
coordinators in parentheses) included the following:
Argentina: (M. Losso), A. Duran, Hospital J. M.
Ramos Mejia, Buenos Aires; Austria: (N. Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna; Belgium: (N. Clumeck) P. Hermans, B. Sommereijns,
Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; Czech Republic:
(L. Machala) H. Rozsypal, Faculty Hospital Bulovka,
Prague; Denmark: (J. Nielsen) J. Lundgren, T. Benfield, O. Kirk, Hvidovre Hospital, Copenhagen; J.
Gerstoft, T. Katzenstein, A.-B. E. Hansen, P. Skinhøj,
326
Annals of Neurology
Vol 55
No 3
March 2004
Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense; Estonia: (K. Zilmer) Tallinn
Merimetsa Hospital, Tallinn; France: (C. Katlama) M.
De Sa, Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard,
Hôpital Necker-Enfants Malades, Paris; T. Saint-Marc,
Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de
l’Archet, Nice; Germany: (M. Dietrich) C. Manegold,
Bernhard-Nocht-Institut for Tropical Medicine, Hamburg; J. van Lunzen, H.-J. Stellbrink, Eppendorf
Medizinische Kernklinik, Hamburg; V. Miller, S.
Staszewski, J. W. Goethe University Hospital, Frankfurt; F.-D. Goebel, Medizinische Poliklinik, Munich;
Bernd Salzberger, Universität Köln, Cologne; J. Rockstroh, Universitäts Klinik, Bonn; Greece: (J. Kosmidis)
P. Gargalianos, H. Sambatakou, J. Perdios, Athens
General Hospital, Athens; G. Panos, I. Karydis, A.
Filandras, 1st IKA Hospital, Athens; Hungary: (D
Banhegyi) Szent Lásló Hospital, Budapest; Ireland: (F.
Mulcahy) St. James’s Hospital, Dublin; Israel: (I. Yust)
M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, Z.
Ben-Ishai, Rambam Medical Center, Haifa: Z.
Sthoeger, Kaplan Hospital, Rehovot; S. Maayan, Hadassah University Hospital, Jerusalem; Italy: (S. Vella,
A. Chiesi) Istituto Superiore di Sanita, Rome; C. Arici,
Ospedale Riuniti, Bergamo; R. Pristerá, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti,
Ospedale S. Maria Annunziata, Florence; R. Esposito,
A. Bedini, Università di Modena, Modena; A. Chirianni, E. Montesarchio, Presidio Ospedaliero A.D.
Cotugno, Naples; V. Vullo, P. Santopadre, Università
di Roma La Sapienza, Rome; P. Narciso, A. Antinori,
P. Franci, M. Zaccarelli, Ospedale Spallanzani, Rome;
A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan;
A. D’Arminio Monforte, Osp. L. Sacco, Milan; Latvia:
(L. Viksna) Infectology Centre of Latvia, Riga; Lithuania: (S. Chaplinskas) Lithuanian AIDS Centre, Vilnius;
Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg; Netherlands: (P. Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam; Norway: (J. Bruun) A. Maeland,
V. Ormaasen, Ullevål Hospital, Oslo; Poland: (B.
Knysz) J. Gasiorowski, Medical University, Wroclaw;
A. Horban, Centrum Diagnostyki i Terapii AIDS,
Warsaw; D. Prokopowicz, A. Wiercinska-Drapalo,
Medical University, Bialystok; A. Boron-Kaczmarska,
M. Pynka, Medical Univesity, Szczecin; M. Beniowski,
Osrodek Diagnostyki i Terapii AIDS, Chorzow; H.
Trocha, Medical University, Gdansk; Portugal: (F. Antunes) Hospital Santa Maria, Lisbon; K. Mansinho,
Hospital de Egas Moniz, Lisbon; R. Proenca, Hospital
Curry Cabral, Lisbon; Romania: D. Duiculescu, Spitalul de Boli Infectioase si Tropicale Dr Victor Babes,
Bucarest; A. Streinu-Cercel, Institute of Infectious Diseases, Bucarest; Slovakia: (M. Mokrá) D. Staneková,
M. Hábeková, V. Mayer, Dérer Hospital, Bratislava;
Spain: (J. González-Lahoz) B. Diaz, T. Garcı́a-Benayas,
L. Martin-Carbonero, V. Soriano, Hospital Carlos III,
Madrid; B. Clotet, A. Jou, J. Conejero, C. Tural, Hospital Germans Trias i Pujol, Badalona; J. M. Gatell, J.
M. Miró, Hospital Clinic i Provincial, Barcelona; Sweden: (A. Blaxhult) Karolinska Hospital, Stockholm; A.
Karlsson, Södersjukhuset, Stockholm; P. Pehrson,
Huddinge Sjukhus, Stockholm; Switzerland: (B. Ledergerber) R. Weber, University Hospital, Zürich; P.
Francioli, A. Telenti, Centre Hospitalier Universitaire
Vaudois, Lausanne; B. Hirschel, V. Soravia-Dunand,
Hospital Cantonal Universitaire de Geneve, Geneve;
H. Furrer, Inselspital Bern, Bern; Ukraine: (N.
Chentsova) Kyiv Centre for AIDS, Kyiv; United Kingdom: (S. Barton) St. Stephen’s Clinic, Chelsea and
Westminster Hospital, London; A. M. Johnson, D.
Mercey, Royal Free and University College London
Medical School, London (University College Campus);
A. Phillips, M. A. Johnson, A. Mocroft, Royal Free
and University College Medical School, London (Royal
Free Campus); A. Pinching, J. Parkin, Medical College
of Saint Bartholomew’s Hospital, London; J. Weber,
G. Scullard, Imperial College School of Medicine at St.
Mary’s, London; M. Fisher, Royal Sussex County Hospital, Brighton; R. Brettle, Western General Hospital,
Edinburgh.
Virology Group
C. Loveday, B. Clotet (Central Coordinators) plus ad
hoc virologists from participating sites in the EuroSIDA Study.
Steering Committee
Francisco Antunes, Anders Blaxhult, Nathan Clumeck,
Jose Gatell, Andrzej Horban, Anne Johnson, Christine
Katlama, Bruno Ledergerber (chair), Clive Loveday,
Andrew Phillips, Peter Reiss, Stefano Vella.
Coordinating Center Staff
J. Lundgren (project leader), I. Gjørup, O. Kirk, N.
Friis-Moeller, A. Mocroft, A. Cozzi-Lepri, L. Paddam,
D. Mollerup, M. Nielsen, A. Hansen, D. Kristensen,
L. Kolte, L. Hansen, J. Kjær.
This study was sponsored by the European Commission BIOMED
1 (CT94-1637), BIOMED 2 (CT97-2713), and the 5th framework
(QLK2-2000-00773) programs and grants from Bristol-Myers
Squibb, GlaxoSmithKline, Roche, and Boehringer-Ingelheim. The
participation of centers from Switzerland was supported by a grant
from the Swiss Federal Office for Education and Science.
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