Duiculescu D¹, Ene L¹, Radoi R¹, Ruta S², Achim CL³ and HNRC ¹ Dr. Victor Babes Hospital for InfecFous and Tropical Diseases, Bucharest, Romania ²

Transcription

1 Duiculescu D¹, Ene L¹, Radoi R¹, Ruta S², Achim CL³ and HNRC ¹ Dr. Victor Babes Hospital for InfecFous and Tropical Diseases, Bucharest, Romania ² Stefan S. Nicolau InsFtute 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

2 Romanian cohort: homogenous & unique Infected with HIV- 1 in the first years of life , with subtype F Parenteral route of HIV transmission Currently aged years Sex rafo male/female=54/46 Common genefc background HAART starfng 1998 HBV co- infecfon (69% HBc Ab +, 44% HBs Ag +) TB co- infecfon (~1/3 of pafents) Since the start of the HIV epidemic, 1660 (approx ¼ of the Romanian pediatric HIV populafon) have been followed at Dr. Victor Babes Hospital in Bucharest *Ruta et al. MedGenMed Mar 28;7(1):68.

3 Similar prevalence pre- post HAART era 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 studies: Positive correlation between pleocytosis and CSF albumin levels (rho=0.29, p=0.02; 95%) Higher CSF HIV RNA compared to plasma

4 Diagnosis of neurocogni.ve deficit according to HAND criteria in a subgroup of adolescents and young adults evaluated with the HNRC test ba>ery* HIV + HIV - no Age mean ± SD (years) 18.4± ±1.0 M/F 23/26 12/8 EducaFon 10.1± ±2.2 Impairment rate 47% 15% Among the HIV + group 71.4% (35/49) had a low nadir CD4 At the moment of neurocognifve evaluafon all pafents were on stable HAART 87.7% with good immunological status 81.6% with undetectable HIV RNA *supported by R21 MH and intramural funding from the HNRC International Core at UCSD

5 Domain specific impairment rates in Romanian HIV+ young adults

6 Number of patients 35 Age in years (mean +/-SD, range) HIV infection route - parenteral Median CD4 count, range HIV diagnosed concomitant CNS OI HAART at the moment of CNS involvement Number of deaths related to TBM Confirmed cases 10.0+/-4.1 (0.3-19) (3-1030) culture High incidence of TB in Romania (non- HIV populafon): 134 in 10 6 adults 46 in 10 6 children In VBH 539 pafents with HIV- 1/TB co- infecfon TBM (6.5% of total TB cases) TBM features in the VBH cohort: 17 pafents with history of pulmonary TB 26 pts with diseminated TB 13 pts with drug resistance Presumptive diagnosis 13 smear

7 No of patients 27 Age in years (mean +/-SD, range) HIV infection route - parenteral Median CD4 count, range HIV diagnosed concomitant CNS OI HAART at the moment of CNS complication No of death related to CNS-OI Confirmed cases Molecular diagnosis /-4.47 (8,3-23) (0-131) histo 20 PCR 5 pres In house PCR for Polyomavirus ( ) RT PCR for JCV ( )

8 Particular features: cerebellar and brainstem lesions

9 SME = a rare and severe measles complicafon in immune suppressed pafents SME occurs 2-12 months amer exposure to measles (usually overlooked) At VBH 34 pafents diagnosed with SME SME was observed as a cluster during 2 consecufve measles epidemics ( and ) All 34 pafents had severe immune supression (median CD4=112 (range 1-294) ConFnuous myoclonus was the characterisfc symptom (epilepsia parfalis confnua) Poor outcome

10 Neuroimaging MRI T1 MRI T2 MRI pac MS (FLAIR) Child with epilepsia partialis continua (EPC) Diagnosed with measles subacute encephalitis

11 HBV: 26 pa.ents with +HBs Ag in plasma 18 pts with posi.ve HBV DNA in plasma 8 pts nega.ve HBV DNA in plasma Median CD4 = 92 (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 Median CD4 = 237 (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 11 pts with posi.ve HBV DNA in the 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 7 pts with nega.ve HBV DNA in CSF Median CD4 = (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 *p<0.05 **p<0.001

12 Inves.ga.on of HBV an.viral- resistant variants in the CSF- plasma using the reverse hybridiza.on line probe assay (INNO LiPA HBV DR v. 2, Innogene.cs) with dis.nct gene.c profile suggest compartmentaliza.on of HBV in CSF of co- infected pa.ents Pt. L80 V173 L173* L180/A181 L181/T181* M180/A181** M204-WT V204** N236 DI TV Plasma CSF Plasma CSF wt wt 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 L173 wt wt wt V204 wt CSF wt wt wt wt wt V204 wt Plasma wt wt wt wt wt V204 wt CSF wt wt wt L181/T181 wt wt V204 wt Plasma wt wt wt wt wt wt CSF wt wt wt L181/T181 wt V204 wt *possibly relevant for lamivudine compensatory mutation ** relevant for lamivudine resistance mutations

13 Conclusions We found a high prevalence of neurocognifve impairment and of AIDS- defining opportunisfc diseases suggesfng neurotropism of clade F High prevalence of PML and cerebral toxo are indicafng a patern of reacfvafon of latent infecfons similar to the adult populafon New challenges for future studies in this cohort: subacute myoclonic measles encephalifs could become a new AIDS defining disease the clinical significance of HBV presence and compartmentalisafon in the CSF

14 Acknowledgements VBH team: Ruxandra Burlacu Andreea Blaglosov Petronela Ionescu Anca Luca Maria Nica CrisFana Oprea GraFela Tardei Eugenia Ungureanu HNRC team Thomas Marcote Ronald Ellis Terry Alexander and Donald Franklin Sarah Archibald, ChrisFne Fennema and Terry Jernigan for the neuroimaging analyses Igor Grant Part of this work was supported by R21 MH and intramural funding from the HNRC International Core at UCSD