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Duiculescu D¹, Ene L¹, Radoi R¹, Ruta S², Achim CL³

High prevalence and particular aspects of HIV-related neurological complications in a Romanian cohort of HIV- 1 infected children and young adult s. Duiculescu D¹, Ene L¹, Radoi R¹, Ruta S², Achim CL³ ¹ “Dr. Victor Babes” Hospital for Infectious and Tropical Diseases , Bucharest, Romania

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Duiculescu D¹, Ene L¹, Radoi R¹, Ruta S², Achim CL³

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  1. 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

  2. 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% HBcAb +, 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.

  3. Prevalence of AIDS defining diseases in VBH * Sugested to be clasified as AIDS defining disases Duiculescu et.al. WEPDB 03 - IAS Sydney 2007

  4. Distribution by year of HIV-related neurological complications vs non-neuro AIDS defining diseases • Prevalence of neuroAIDS OI • preHAART: 24,13% of AIDS defining diseases (77/319) • postHAART: 34.16% of AIDS defining diseases (82/240) • P=0.01 • Prevalence of HIVE • preHAART: 21,94% of AIDS defining diseases (70/319) • postHAART: 20.41% of AIDS defining diseases (49/240)

  5. General characteristics of patients with HIV-associated neurological complications HIV-E – encephalopathy; TBM – TB meningitis; CNM – cryptococcal meningitis; Toxo – Toxoplasmosis; PML – progressive multifocal leucoencephalopathy ; SMME – subacute myoclonic measles encephalitis

  6. HIVE Tx PML CNM TBM

  7. HIVE • Similar prevalence pre- post HAART period • CSF study: • Positive correlation between pleocytosis and CSF albumin levels (rho=0.29, p=0.02) • Higher CSF HIV RNA compared to plasma

  8. Paired plasma-CSF HIV RNA values in a subgroup of 29 adolescents with HIVE • 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)

  9. Diagnosis of neurocognitive deficit according to HAND criteria in a subgroup of adolescents and young adults evaluated with HNRC test battery* 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

  10. Domain specific impairment rates in Romanian HIV+ young adults

  11. PML In house PCR for Polyomavirus (2000- 2005) RT PCR for JCV (2009- 2010)

  12. Particular features: cerebellar and brainstem lesions

  13. 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)

  14. 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

  15. Neuroimaging MRI –T1 MRI –T2 9 y.o. child with epilepsia partialis continua (EPC) diagnosed with SMME during measles epidemics 1997-1998 17 y.o patient diagnosed with SMME during Measles epidemic 2006 (FLAIR)

  16. Diagnosis confirmation PCR (evaluation) Immunocytochemistry Treatment High mortality Practical issues: low protection against measles need for prophylaxis emerging diseases in poor resources settings Subacutemyoclonicmeasles encephalitis

  17. 26 pts with +ve plasma HBs Ag 18 pts with + ve HBV DNA in plasma 8 pts – 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 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 11 pts with +ve HBV DNA in CSF 7 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 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 *p<0.05 **p<0.001

  18. 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 Distinct genetic profile *possibly relevant for lamivudine compensatory mutation ** relevant for lamivudine resistance mutations

  19. Summary • Unique cohort of childrensurviving over 20 years with chronic HIV-1 infection - evolutionpattern 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

  20. 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?

  21. 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

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