DR AMEET DRAVID *,DR MILIND KULKARNI ** *RUBY HALL CLINIC, PUNE,INDIA ** NATIONAL AIDS RESEARCH INSTITUTE, PUNE,INDIA

Transcription

1 HIV encephalopathy developing in patients on long term suppressive antiretroviral therapy (ART) due to discordance in plasma and cerebrospinal fluid HIV replication: a single centre case series from Western India DR AMEET DRAVID *,DR MILIND KULKARNI ** *RUBY HALL CLINIC, PUNE,INDIA ** NATIONAL AIDS RESEARCH INSTITUTE, PUNE,INDIA

2 Index case (Patient history) 32 yr old female, was diagnosed HIV-1 positive in 2005 with baseline CD4 count of 123 cells/mm 3 Patient was started on Zidovudine/Lamivudine/Nevirapine which she took for 4 years with adherence rate of around 75 %. She was diagnosed to have 1 st line antiretroviral therapy(art) failure in May 2009 and was shifted to 2 nd line ART (Zidovudine/ Lamivudine/ Tenofovir/Lopinavir/ritonavir ) in May After 6 months on 2 nd line ART, CD4 count was 311 cells/mm 3 and Plasma HIV-1 viral load < 400 copies/ml. She requested simplification of ART regimen and hence was shifted to Tenofovir/ Emtricitabine/ Lopinavir/ ritonavir in December 2009 ART was continued regularly for 1 year after which it was simplified further to Tenofovir /Emtricitabine / Atazanavir/ ritonavir due to cost constraints and for reduction in pill burden Patient started receiving 2 nd line ART (Tenofovir/ Lamivudine/ Atazanavir/ritonavir) from Government of India Free ART program since March 2011.

3 Antiretroviral drug history REGIMEN DURATION CD4 COUNT AT REGIMEN SWITCH PLASMA VIRAL LOAD AT REGIMEN SWITCH AZT/3TC/NVP July May cells/mm copies/ml AZT/3TC/TDF/LPV/r May 2009 December 2009 TDF/FTC/LPV/r December 2009 December 2010 TDF/FTC/ATV/r December 2010 March cells/mm 3 < 400 copies/ml 359 cells/mm 3 < 400 copies/ml 610 cells/mm 3 < 400 copies/ml TDF/3TC/ATV/r March 2011-July cells/mm 3 < 400 copies/ml

4 Clinical history In July 2011, pt presented with h/o Imbalance during walking, slurred speech and irrelevant talk since 15 days Urinary incontinence since 10 days 2 episodes of generalized tonic clonic convulsions followed by stupor since 7 days Patient was completely bedridden when she was brought to Pune On examination, she was drowsy with eye opening only to deep pain stimuli Glasgow coma scale : E2,M4,V1 No neck rigidity, no apparent cranial nerve abnormality Dolls eye movement was present, pupils were bilaterally equal reacting to light She was moving all 4 limbs on deep pain stimulus (withdrawal reflex) with bilateral extensor plantar reflex

5 Investigations INVESTIGATIONS RESULT INVESTIGATIONS RESULT Hb 9.5 Creatinine 0.9 WBC 8800 CD4 count 585 Platelet count CD8 count 1210 Total bilirubin 1.1 Plasma HIV-1 viral load <400 copies/ml Direct bilirubin 0.4 HBsAg/Hep C negative Indirect bilirubin 0.7 VDRL negative SGPT/SGOT 34/35 Xray chest P/A wnl Serum sodium 135 USG Abdomen wnl Potassium 4.4

6 MRI Brain (full study)

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11 Investigations MRI Brain (P+C) : cerebral atrophy, periventricular hyperintensities s/o severe HIV encephalopathy CSF report : CSF protein 88 mg/dl, CSF glucose 60 mg/dl, Cells 2 all lymphocytes. CSF TB PCR negative CSF cryptococcal antigen - negative CSF HSV,VZV,CMV PCR negative Plasma HIV viral load < 50 copies/ml CSF HIV viral load : 4800 copies/ml (re-confirmed)

12 Final Diagnosis HIV ASSOCIATED NEUROCOGNITIVE DISEASE (SEVERE HIV ENCEPHALOPATHY) IN A PATIENT WITH PLASMA HIV VIRAL LOAD SUPPRESSION BUT CSF VIRAL LOAD REBOUND (COMPARTMENTAL DISCORDANCE) Most probable causes : Poor penetration of antiretroviral drugs in CNS Drug resistant virus in CNS

13 HIV associated neurocognitive disease (HAND) Includes 3 conditions with increasing severity : HIV associated asymptomatic neurocognitive impairment (ANI) HIV-associated mild neurocognitive disorders (MND) HIV-associated dementia (HIV-D) and HIV encephalopathy( HIV E)

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15 CPE score of prior ART regimens REGIMEN CPE SCORE Zidovudine/Lamivudine/ Tenofovir/Lopinavir/ ritonavir Tenofovir/Emtricitabine/ Lopinavir/ritonavir Tenofovir/Emtricitabine/ Atazanavir/ritonavir Tenofovir/Lamivudine/ Atazanavir/ritonavir

16 Higher CPE score = better cognition She was started on Zidovudine/Lamivudine/Tenofovir/Lopinavir/ ritonavir (CPE score -10) Patient showed dramatic improvement in sensorium and was taken off ventilator on Day 8 of ICU stay Became ambulatory and regained bowel and bladder control by Day 15 of hospital stay Could remember names of all her relatives and could answer all questions related to her past. Was discharged on Day 21 and continued to improve neurologically over next 2 months MRI Brain done showed improvement in HIV encephalopathy.

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20 Objective and design We report data of 5 patients on long term stable antiretroviral therapy presenting with symptoms of neurocognitive impairment. On investigating further, uncontrolled human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia despite suppressed plasma HIV RNA leading to HIV encephalopathy was found to be the only cause of neurologic deterioration. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >400 copies/ml while plasma levels were < 50 copies/ml or by a CSF HIV RNA level that was 1 log greater than the plasma HIV RNA level.

21 Results 5 patients had experienced acute or subacute neurological symptoms Median age 45 years Male: female - 4:1 Patients had been receiving combination antiretroviral therapy for a median of 72 months (range, months). None of the patient was on Thymidine analog (Zidovudine/Stavudine) based treatment at the time of neurocognitive impairment. Median duration of Thymidine analog free ARV regimen prior to neurocognitive impairment was 22 months. 4/5 patients were on Atazanavir/ritonavir (boosted protease inhibitor) based regimen and 1 patient was on Non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen. Tenofovir was the NRTI backbone in all patients. Mean CD4 count at the time of neurologic deterioration was 334 cells/mm 3 (range cells/mm 3, Median -367). 3 out of 5 patients had a plasma HIV RNA level < 400 copies/ml (Roche Cobas Taqman version 1.5) and 2 had low level plasma HIV RNA with their CSF HIV RNA level >1 log higher than their plasma HIV RNA level. Median CSF HIV RNA level was copies/ml (range, copies/ml).

22 Results Signs and Symptoms Frequency Imbalance during walking (gait ataxia) 5/5 Tremulousness 3/5 Headache 2/5 Generalised tonic clonic seizures 3/5 Slurred speech 2/5 Increased somnolence progressing to stupor 3/5 Urinary/Faecal incontinence 2/5

23 Plasma viral load suppression, CSF viral rebound Patient number ART Regimen at the time of neurocognitive impairment (NCI) CD4 count at the time of neurocognitive impairment(nci) Plasma viral load at the time of NCI 1 TDF/3TC/ATV/r 585 cells/mm 3 <400 copies/ml 2 TDF/FTC/NVP 108 cells/mm 3 < 400 copies/ml 3 TDF/FTC/ATV/r 200 cells/mm copies/ml 4 TDF/FTC/ATV/r 409 cells/mm 3 < 400 copies/ml 5 TDF/ABC/3TC/ATV/r 367 cells/mm copies/ml CSF HIV viral load at the time of NCI 4800 copies/ml 10,000 copies/ml 439,400 copies/ml 54,000 copies/ml 19,000 copies/ml

24 Results 2 patients had past history of CNS opportunistic infection or insult (cryptococcal meningitis 1, subdural hematoma 1 and tubercular meningitis 1). Magnetic resonance imaging (MRI) of Brain showed severe cortical atrophy and periventricular white matter hyper intensities in all the patients. CSF pleocytosis was seen in 2 patients. The median central nervous system penetration-effectiveness (CPE) score of ART regimens at the time of admission was 6 (range 5 8, Letendre et al 2010) 3 patients had a baseline CPE < 7. After antiretroviral therapy optimization based on CPE, all patients clinically improved. CPE score after therapy optimization was 10 (range 7-13). CSF genotypic resistance testing was not performed in our patients. Follow up CSF viral load was available for only 2/5 patients (mean 365 copies/ml)

25 Improvement in CPE score leads to neurocognitive improvement and CSF viral load suppression Patient number ART Regimen at the time of neurocognitive impairment (NCI) CPE score New antiretroviral regimen CPE score 1 TDF/3TC/ATV/r 5 AZT/3TC/TDF/LPV/r 10 CSF viral load after regimen change 2 TDF/FTC/NVP 8 AZT/3TC/ABC/NVP 13 3 TDF/FTC/ATV/r 6 d4t/tdf/ftc/atv/r 8 4 TDF/FTC/ATV/r 6 ABC/3TC/LPV/r copies/ml 5 TDF/ABC/3TC/ATV/r 8 AZT/3TC/TDF/LPV/r copies/ml

26 Final Comments Tenofovir based antiretroviral regimens are increasingly used for treatment naive and treatment experienced patients in India. Tenofovir and Atazanavir-ritonavir have poor CNS penetration which leads to lower CSF HIV viral load suppression. Data regarding improving neuro-cognition by including drugs with higher CPE scores in ART regimens is controversial but our cases tend to point towards significant benefit. CSF HIV drug resistance testing should be encouraged to construct a regimen for optimal CSF viral load suppression. HAND should be kept as a differential diagnosis in patients presenting with neurologic deterioration on stable virologically suppressive ART Totally banishing older drugs like Zidovudine and Lopinavir-ritonavir might not be possible due to obvious benefits

27 THANK YOU