Transcript Document

High prevalence and particular aspects of
HIV-related neurological complications in
a Romanian cohort of HIV-1 infected
children and young adults
Duiculescu D¹, Ene L¹, Radoi R¹, Ruta S², Achim CL³
¹ “Dr. Victor Babes” Hospital for Infectious and Tropical Diseases, Bucharest, Romania
² “Stefan S. Nicolau” Institute of Virology and „Carol Davila” University of Medicine, Bucharest,
Romania
³University of California at San Diego Department of Psychiatry and Pathology, La Jolla,
California, USA
Romanian cohort: homogenous & unique

Infected with HIV-1 in the first years of life 1987-1990,
with subtype F
Parenteral route of HIV transmission
 Currently aged 20-22 years
 Sex ratio male/female=54/46
 Common genetic background
 HAART starting 1998
 HBV co-infection (69% HBc Ab +, 44% HBs Ag +)
 TB co-infection (~1/3 of patients)


1660 children (~1/4 of pediatric HIV population from
Romania) followed in “Dr. Victor Babes” Hospital (VBH)
from Bucharest
*Ruta et al. MedGenMed. 2005 Mar 28;7(1):68.
Prevalence of AIDS defining diseases in VBH
Total
%
HIV encephalopathy
119
21.29
TB diseminated/extrapulmonary
78
13,95
Recurrent bacterial pneumonia
75
13,42
Oesophagial candidiasis
52
9,30
PCP
45
8.05
Subacute myoclonic measles encephalitis*
34
6,08
Cryptococosis
34
6.08
PML
27
4,83
Cerebral Toxoplasmosis
24
4,29
CMV diseases
15
2,68
Cryptosporidiasis + Isosporidiasis
14
2,50
Lymphoma (CDC)
12
2,15
Kaposi sarcoma
9
1,61
Other AIDS diseases (<1% each)
21
3.76
Total AIDS defining diseases
559
* Sugested to be clasified as AIDS defining disases Duiculescu et.al. WEPDB 03 - IAS Sydney 2007
Distribution by year of HIV-related neurological complications vs
non-neuro AIDS defining diseases
40
35
HIVE
Neuro AIDS OI
Non-neuro AIDS OI
30
25
20
15
10
5
0
Prevalence of neuroAIDS OI
Prevalence of HIVE
•preHAART: 24,13% of AIDS defining diseases (77/319) •preHAART: 21,94% of AIDS defining diseases (70/319)
•postHAART: 34.16% of AIDS defining diseases (82/240) •postHAART: 20.41% of AIDS defining diseases (49/240)
•P=0.01
General characteristics of patients with HIVassociated neurological complications
HIV-E
TBM
CNM
Cerebral
toxo
PML
SMME
Total
119
35
34
24
27
34
273
Age in years
(mean +/-SD, range)
11.8±4.86
(0.9-22)
10.0±4.1
(0.3-19)
12.6±5.8
(7.6-21)
13,1±3,3
(8.2-15.6)
13.5±4.4
(8.3-23)
11.7±4.1
(9.6-20)
12.1±4.8
(0.3-23)
HIV infection route parenteral
100
32
32
23
27
32
246
Median CD4 count,
range
64
(0-800)
45.5
(3-1030)
50
(3-187)
45
(0-375)
22
(0-131)
112
(1-294)
70
(0-1030)
HIV diagnosed at time
of CNS –OI
26
9
3
5
11
2
46
HAART at the moment
of CNS-OI
47
10
5
5
9
16
92
No of death related to
CNS-OI
13
30
20
8
15
34
120
Definitive diagnosis
119
22
28
2
2
9
182
-
13
4 smear
2 C.N. Ag.
22
20 PCR
5 pres
25
No of patients
Presumptive
diagnosis
HIV-E – encephalopathy; TBM – TB meningitis; CNM – cryptococcal meningitis; Toxo – Toxoplasmosis; PML – progressive multifocal
leucoencephalopathy ; SMME – subacute myoclonic measles encephalitis
Survival probability in patients with HIV-related neurological disorders
100
90
80
HIVE
70
Tx
disea
60
50
PML
CNM
40
30
20
TBM
10
0
50
100
150
Time (months)
200
250
HIVE
 Similar prevalence pre- post HAART period
Clinical diagnosis criteria
Hyperreflexia
45.5%
Pyramidal syndrome
39.1%
Cerebellar syndrome
37.3%
Behavioral disorders
24.5 %
Cognitive deficit
memory
reduced performances
68.1%
20%
41.8%
 CSF study:
 Positive correlation between pleocytosis and CSF albumin levels
(rho=0.29, p=0.02)
 Higher CSF HIV RNA compared to plasma
Paired plasma-CSF HIV RNA values in a
subgroup of 29 adolescents with HIVE
7
log10 HIV RNA (copies/ml)
6
5
4
3
2
1
0
log 10 HIV RNA plasma
log10 HIV RNA CSF
HIV RNA plasma
HIV RNA CSF
Mean =4.57 ±1.26 log10 c/ml
Mean=4.60 ±.51 log10 c/ml
14 of 29 patients with HIVE and paired plasma-CSF samples had higher CSF HIV RNA
levels compared to plasma (5.381.09 log10 c/ml vs. 4.561.17 log10c/ml, p<0.05)
Diagnosis of neurocognitive deficit according to HAND
criteria in a subgroup of adolescents and young adults
evaluated with HNRC test battery*
no
Age mean  SD (years)
M/F
Education
Impairment rate
HIV +
HIV -
49
20
18.40.7
18.81.0
23/26
12/8
10.11.5
11.02.2
47%
15%
Among the HIV + group

71.4% had a low nadir CD4

At the moment of neurocognitive evaluation all patients were on stable
HAART


87.7% with good immunological status
81.6% with undetectable HIV RNA
*supported by R21 MH0077487-01 and intramural funding from the HNRC International Core at UCSD
Domain specific impairment rates in
Romanian HIV+ young adults
PML
No of patients
27
Age in years
(mean +/-SD, range)
13.51+/-4.47
(8,3-23)
HIV infection route parenteral
27
Median CD4 count, range
22
(0-131)
HIV diagnosed
concomitant CNS –OI
11
HAART at the moment of
CNS complication
9
No of death related to
CNS-OI
In house PCR for Polyomavirus (2000- 2005)
15
Confirmed cases
2 histo
Molecular diagnosis
20 PCR
5 pres
RT PCR for JCV (2009- 2010)
Particular features: cerebellar and brainstem lesions
Survival probability according to cART duration
100
80
60
40
without cART
with cART < 6 months
with cART > 6 months
20
0
0
10
20
30
40
50
60
Time (months)
11 patients with survival >6 months (40.74%)
•
Factors associated with survival in the group with ART
• older age
• HAART regimen with better CSF penetration score
•
Atypical MRI findings (cavitation, enhancement)
70
80
90
100
Subacute measles encephalitis (SME):



SME = a rare and severe measles complication in
immune suppressed patients
SME occurs 2-12 months after exposure to measles
(usually overlooked)
34 patients diagnosed with SME




SME was observed as a cluster during 2 consecutive measles
epidemics (1996-1998 and 2006-2008)
All had severe immune supression (median CD4=112/mmc
(range 1-294)
Continuous myoclonus was the characteristic symptom
(epilepsia partialis continua)
Poor outcome
Neuroimaging
MRI –T1
MRI –T2
17 y.o patient diagnosed with SMME during
Measles epidemic 2006 (FLAIR)
9 y.o. child with epilepsia partialis continua (EPC)
diagnosed with SMME during measles
epidemics 1997-1998

Diagnosis confirmation


PCR (evaluation)
Immunocytochemistry
Treatment
High
mortality
Practical issues:



low protection against
measles
need for prophylaxis
emerging diseases in poor
resources settings
Subacute myoclonic measles encephalitis
26 pts with +ve plasma HBs Ag
18 pts with + ve HBV DNA in plasma
Median CD4 = 92 lf/mmc (1-490)
HBV DNA = 6.01±2.09 log₁₀IU/ml
HIV RNA plasma* = 4.38 ± 1.22 log₁₀ c/ml
HIV RNA CSF = 3.27 ± 1.25 log₁₀ c/ml
11 pts with +ve HBV DNA in CSF
Median CD4= 59 lf/mmc (1-490)
HBV DNA plasma** = 7.25 ± 1.52 log₁₀IU/ml
HBV DNA CSF = 4.06 ± 1.06 log₁₀ IU/ml
HIV RNA plasma = 4.80 ± 0.99 log₁₀ c/m
HIV RNA CSF =3.60 ± 1.28 log₁₀ c/ml
*p<0.05
**p<0.001
8 pts – ve HBV DNA - in plasma
Median CD4 = 237 lf/mmc (1-738)
HBV DNA = ND
HIV RNA plasma* = 2.7 ± 1.12 log₁₀ c/ml
HIV RNA CSF = 2.61 ± 1.28 log₁₀ c/ml
7 pts with – ve HBV DNA in CSF
Median CD4 = 306 lf/mmc (7-380)
HBV DNA plasma** = 4.06 ± 1.11 log₁₀ IU/ml
HBV DNA CSF = ND
HIV RNA plasma = 3.71 ± 1.31 log₁₀ c/ml
HIV RNA CSF = 2.75 ± 0.54 log₁₀ c/ml
Investigation of HBV antiviral-resistant variants in the CSF-plasma
using the reverse hybridization line probe assay (INNO LiPA HBV DR
v.2, Innogenetics) with distinct genetic profile suggest
compartmentalization of HBV in CSF of HBV co-infected patients
Pt.
DI
TV
L80
Plasma
wt
CSF
wt
Plasma
CSF
V173
L173*
L180/A181
L181/T181*
M180/A181**
M204-WT
V204**
N236
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
Distinct genetic profile
IF
DR
SI
Plasma
wt
wt
CSF
wt
Plasma
L173
wt
wt
wt
V204
wt
wt
wt
wt
wt
V204
wt
wt
wt
wt
wt
wt
V204
wt
CSF
wt
wt
wt
wt
wt
V204
wt
Plasma
wt
wt
wt
wt
wt
CSF
wt
wt
wt
L181/T181
L181/T181
wt
*possibly relevant for lamivudine compensatory mutation
** relevant for lamivudine resistance mutations
wt
V204
wt
Summary

Unique cohort of children surviving over 20 years
with chronic HIV-1 infection - evolution pattern
similar to adults
High rate of PML, Cerebral toxo and Criptococcal
meningitis
 Neurocognitive impairment will be one of the main
challenges for the future – need for adequate evaluation
 What will be the impact of aging in this cohort compared
with adult HIV+ population

Summary
As measles is still an emerging disease (pediatric HIV
population has low protection antibodies) -SMME is
a severe complication that has to be considered
 HBV in CSF




Is there a neurotropism of HBV?
Does HIV play a role in HBV penetration into CSF in
chronic HIV/HBV coinfected patients?
What is the clinical signifficance of HBV in the brain?
Acknowledgements

VBH team:








Ruxandra Burlacu
Andreea Blaglosov
Petronela Ionescu
Anca Luca
Maria Nica
Cristiana Oprea
Gratiela Tardei
Eugenia Ungureanu

HNRC team





Thomas Marcotte
Ronald Ellis
Terry Alexander and
Donald Franklin
Sarah Archibald, Christine
Fennema and Terry
Jernigan for the
neuroimaging analyses
Igor Grant
Part of this work was supported by R21 MH0077487-01 and
intramural funding from the HNRC International Core at UCSD