Post on 28-Jun-2019
transcript
Management of CNS Complicationsin HIV: a case-based discussion
Andrea Calcagno
Scott Letendre
• 2,952 CSF-Plasma pairs
• 1,446 Adults
• No ART by Self-Report
• CSF ≤ 50: 16.1%
• CSF-Plasma Difference
• Median -1.35
• Range (-4.84)-(+2.11)
• Difference ≥ 0: 5.6%• Difference ≥ -0.5: 18.7%
• CSF ≥ 10% Plasma: 35.9%
Ferrara et al, Manuscript in Development
Ma, Letendre et al, CROI 2018, Accepted
Elvitegravir & Tenofovir
Concentrations in CSF and BloodTDF TAF
Darunavir/cobicistat
Bartels H, et al. J Antimicrob Chemother 2017
Animal Models Support Higher ART
Concentrations in Brain Tissue
Curley et al, AAC
2017, 61(1): e01841-16
Srinivas et al, IAS 2017,
Abstract WEAB0105
Fabbiani et al, Antiviral Ther
2015, 20: 441-7
Mukerji, et al. J Infect Dis 2018, Submitted
Duration of HIV Infection
Drug Resistance May
Alter Relationships
with Outcomes
Different Forms of CSF Viral Escape
0
50
100
150
200
VIS 1 VIS 2 VIS 3 VIS 4 VIS 5 VIS 6
0
50
100
150
200
VIS 1 VIS 2 VIS 3 VIS 4 VIS 5 VIS 6
0
50
100
150
200
VIS 1 VIS 2 VIS 3 VIS 4 VIS 5 VIS 6
CSF Blip
Single occurrence of CVE
while suppressed in
plasma
Persistent CSF VE
≥ 2 consecutive CVE while
suppressed in plasma
CSF Slow Suppression (SS)
CVE with preceding lack of
suppression in plasma
Perez-Valero et al, J Intl AIDS Soc 2012,
15(Suppl 4):18189
Partial Differential Diagnosis of Acute CNS Syndromes in PLWH
• Viral
– Enteroviruses
– JCV Encephalitis
– Herpesviruses
• CMV, VZV, HSV
– Primary CNS Lymphoma (EBV)
• Fungal
– Cryptococcus
• Bacterial
– Tuberculosis
– Typical bacteria
• Related to HIV or the Immune Response
– HIV Meningoencephalitis
– Acute retroviral syndrome• Acute HIV infection (Initial)
• ART failure (Relapse)
– Immune Recovery Syndrome
– CSF viral escape
– Rebound encephalitis
– CD8+ T-cell encephalitis
Questions that should be asked…
1. When should I perform lumbar puncture?
2. When should I change therapy?
3. When does PK matter?
4. What biomarkers should I measure?
Patient #1
Age 71 Gender M
HIV since 1994 Nadir CD4 215
Current VL TND Current CD4 693 (19%)
Undet VL for 12 years
HAART ABC/3TC + ATV/r (300/100) (CPE=7)
ComorbiditiesDyslipidemia & overweight (BMI 27)
(rosuvastatine 5 mg)
HAART use
AZT + 3TC Virological Failure
d4T + ABV + NVP Virological Failure
ddI + ABV + LPV/rSince 2001: good adherence
(apart from a 3-month interruption in 2004)
TDF + ABV + ATV/r Since 2005
Since 2008 ABV + 3TC + ATV/r
RAMs Subt Ind Trop ?
NRTI67N, 70R,
M184V, 219QPI 0
NN 103 N INT ne
Screening and diagnosis
Brain MRI
Diffuse cerebral atrophy, no WM abnormalities
NC Tests
MMSE 29/30IHDS 10/12
IADL 5/5Full NC evaluation: Attention and short-term memory below the average (<1
SD) with normal IADL: ANI
Self-reporting no symptoms, negative 3 questions, lives alone
Brain MRI
Diffuse cerebral atrophy, no WM abnormalities
1. Age-associated NCI?
2. Vascular dementia?
3. Alzheimer’s dementia?
4. Neurotoxicity?
❖ LP? Lumbar punctures in patients with ANI?
LAB Testsplasma
HIV RNATND
CSF HIV RNA
60
plasmaRAMs
67N, 70R, M184V, 219Q
CSF RAMs not amplified
JCV neg EBV neg
CMV neg CSFProt 41 Gluc 59No cells
BBBnormal, CSAR =
4.9AD markers
normal tau and p-tau, low
amyloid β1-42
CSF PKATV 31.4 ng/mL, ABV 39 ng/mL,
3TC 204 ng/mL
1. Functional ATV/r monotherapy
2. Low level CSF HIV RNA
• clinical relevance?
• management??
3. How to follow up?
Asymptomatic CSF escape?
RAL + ATV/r
(DTG + ATV/r)
4 year follow up
• Remains asymptomatic
• Stable NC tests
• Stable MRI (@ 1 year)
• Refuses to repeat LP
Patient #2• 52 yy, Male• HIV+ since 1993 (ex IDU)• HCV+ since 1993, chronic hepatitis, F2• Gastroesophageal reflux disease• Oxygen-dependent COPD
– Several hospital admission for exacerbations of COPD and pneumonia (2-3/year since 1996!!)
– Colonized by Pseudomonas aeruginosa
• Osteoporosis– Multiple vertebral fractures (L2, L3, L4)
• Sinus bradycardia and long QT syndrome• 2009 seizures (abnormal EEG, normal MRI)• Depression
HIV history
• Nadir CD4 48 cell/uL
• AIDS– Recurrent pneumonia
– Intestinal Cryptosporidiosis
• Several HAART regimens– Intolerance and inconsistent adherence
– Virological failure to 2 NRTIs + NVP (no RAMs detected)
– Always on LPV/r or ATV/r, then ATV
– Since 2012 ATV (200 mg twice-daily) + RAL (400 mg twice-daily)
Clinical Presentation
• 1 week history of fever and dyspnea
• ER:
– Tachypneic (40/min)
– Drowsy
– Type 2 respiratory insufficiency(pO2 55 mmHg, pCO2 45 mmHG)
– Multiple bronchiectasis, diffuse emphysema, several consolidations with tree-in-bud opacities
– Elevated CRP and WBC
Follow up
• CD4 650/uL (22%, 0.8 ratio)
• HIV RNA: TND (<20 copies/ml since 2013)
• HIV DNA: 91 copies/106 PBMCs
• Treated with:
– Oxygen
– Bronchodilators
– Methylprednisolone (20 mg x 2)
– Ceftazidime + amikacin(Pseudomonas aeruginosa R to fluoroquinolones)
• Beclomethasone/formeterol 2 puff x 2
• Tiotropium (bromide) 2 puff
• Pregabalin 150 mg x 2
• Oxcarbamazepine 300 mg x 2
• Pantoprazole 20 mg
• Delorazepam 0.5 mg x 2
• Flumazepam 15 mg
• Methadone 125 mg (!)
• Calcium/colecalciferol 1g/d – XXVIII/w
And…
o Atazanavir 200 mg x 2
o Raltegravir 400 mg x 2
o Ceftazidime 1g x3
o Amikacin 600 mg
o methylprednisolone 20 mgx2
Clinical Presentation (2)
• Good clinical evolution but episodes of drowsiness – no indication to non-invasive ventilation
• ANI (memory and visuospatial)
• Two days of:
–Mild headache
–Dizziness
–Dysesthesia left arm and leg
???
1. High CO2?2. Drug-drug interaction?
(Corticosteroids? tiotropium?)3. Drug abuse?4. Depression?5. Stroke?
Multiple focal areas of signal abnormality subcortical white matter (corticomedullary junction of frontal parietal lobes and left cerebellar
peduncle)Irregular contrast enhancement
Mild oedema, no associated mass effect.
CSF
• Clear, colourless
• No cell, normal glucose, protein 50 mg/dL (rv <45)
• HIV RNA 579 copies/mL
– No RAMs to PIs, N155H and Q95K to INT
– R5
• CMV, EBV, JCV neg
• Neopterin 2.54 ng/mL (ref ranges <1.5)
• Normal BBB permeability, IgG synthesis (18% of IgG from CSF)
Symptomatic CSF escape
• PK?
plasma PKng/mL
CSF PKng/mL
CSF/Plasma
ATV 54 0.9 1.7%
RAL 296 19 6.4%
RAL functional monotherapy in the
CSF/CNS
Pantoprazole lowers ATV
(70-90%)
• 3 DRUGS
– 2 NRTIs + PI/r
• TDF-FTC or ABC-3TC?
• ATV/r or DRV/r or LPV/r?
– 2 NRTIs + INSTI
• DTG 50 x 2
• 4 DRUGS
– 2 NRTIs + PI/r + MVC
– 2 NRTIs + PI + ETV
Which HAART?
Starts
ABC-3TC + DRV/r + MVC
Follow up
• Improved neurological symptoms upondischarge
• LP/MRI control?
– Repeat planned @3 months
• Car accident, passed away 3 months afterdischarge
Patient #3
• 47 yy woman of European ancestry
• HIV+ since 1999
– On HAART 1999-2004 then self-interrupted
– 2012 admitted for PJ pneumonia and wastingsyndrome
– HIV RNA 557351 copies/mL
– NRTIs RAMs K70R, M184V
– R5
– TDF + DRV/r (800/100) + MVC (300)
Neurological follow up
• Normal brain MRI
• Normal NP tests at baseline
• Mild depressive symptoms
0
2
4
6
8
BL M6 M12
pVL CSFVL
0
0,5
1
1,5
2
0
100
200
300
400
BL M6 M12
S100beta Neopterin
???
• Limited cellular activity(MΦ and Astrocytes) – switch to?
• Persistent low level replication -intensification?
• Neurotoxicity – switch to?
Follow up
• Discharged in good health
• Reported optimal adherence in the first 12 months– pVL slowly undetactable (26-<20-30 copies/mL)
• Uncertain adherence afterwards– Low level viremia/blips
– <20 – 56 – 84 - <20 - <20 – 105 – 62
• Unwilling to change treatment
Clinical Presentation - @3.5 years
• Complains of forgetfulness and troublesin concentrating lasting ~4 months– NP testing: moderate abnormalities in attention
and short-term memory(Rey’s Figure, Corsi test, etc.)
• CD4 714/uL (32%, ratio 0.9)
• 3 months later: Slow onset of dizziness, gaitabnormalities and unintentional tremors
Faint hyper-intensity on long TR: periventricular WM (left>right), temporal, cerebellum, brainstem
CSF
• Clear, colourless
• 44 cells (atypical T lymph)
• Protein 99 mg/dL (norm <45)
• HIV RNA 7566 copies/mL
– no RAMs and R5
• CMV & JCV neg, EBV DNA 82 copies/mL
• Minimal BBB impairment: CSAR 7.6 (n <6.5)
• High IgG production (70% of IgG from CSF)
Symptomatic CSF escape wo RAMs
• PK?
plasma PKng/mL
CSF PKng/mL
CSF/Plasma
DRV 1999 14.6 0.7%
TFV 51 60 120% (?)
MVC 118 4.6 3.9%
Partial env deep sequencing
Trunfio M, et al. JNV 2017
• 3 DRUGS
– PI/r + ETV + RAL/DTG
– PI/r + MVC + RAL/DTG
• 4 DRUGS
– Above plus AZT or ABV or TDF
Which HAART?
Starts
DTG (50 qd) + DRV/r (600/100 bid) + ETV (200 bid)
Follow up
???• Limited cellular activity?
• Incomplete penetration?
• Persistent low level replication?
• EBV??
• Incomplete adherence?
• Untreated depression?
Late Diagnosis?
Patient #4
• 55 yy woman of North African ancestry
• Obesity (BMI 32 kg/m2)
• Hypertension (on ACE-inhibitor)
• Type 2 DM (on diet)
• HIV+ since 2002
– CMV disease wo retinitis, nadir CD4 46/uL
– on HAART (2 NRTIs + LPV/r --> DRV/r)
– HIV RNA <50 copies/mL since 2008
Clinical Presentation
• Reports forgetfulness and difficulty in concentration
– Incomplete knowledge of the Italian language ---partial NC testing
– IHDS 9/12
– Clock drawing test 2/6
– Altered short-term memory
Lab tests
• HIV RNA: TND
• CD4 512/uL (24%, ratio 0.6)
• Tot Chol 212 mg/dL, HDL Chol 58 mg/dL, LDL Chol 132 mg/dL
• Blood Pressure 155/85
• Glycosylated hemoglobin 7.5% (target<6.5)
10y ASCVD 21.2%
Multiple long TR hyper-intensities, no alteration in diffusivity, non-contrast enhancement
LP?
CSF
• Clear, colourless
• No cells, normal glucose
• Protein 43 mg/dL (rv <45)
• HIV RNA Not-detected
• CMV, EBV, JCV neg
• Neopterin 1.2 ng/mL (rv <1.5)
• Normal BBB permeability, no IgG synthesis
Management?
Follow up
• Enrolled in an exercise program
• Improved control of CV risk factors:
– Amlodipine 5 mg
– Rosuvastatin 5 mg
– ASA 100 mg
• Switched @ 6mm to TDF/FTC/RPV (for patient’s request and LDL management) -atorvastatin 40 mg
Follow up @ 1 year
• HIV RNA: TND
• CD4 543/uL (21%, ratio 0.6)
• Tot Chol 195 mg/dL, HDL Chol 60 mg/dL, LDL Chol 88 mg/dL
• SBP 135/75
• Glycosylated hemoglobin 6.5% (rv<6.5)
10y ASCVD 13.1%
Follow up @ 1 year (2)
• No self-reported changes
Minimal improvement in short-termmemory…
Patient #5
• Male, 46 yy
• HIV+ since 1999, nadir 328/uL, no OIs
• NP intolerance to EFV
• HIV RNA not detected, CD4 332/uL (39%, CD4/CD8 ratio 1) on ABC/3TC + NVP
• Mild depression (on valproic acid)
• NASH
• normal brain MRI
• Short term memory impairment
• CSF
– No cells, proteins 84 mg/dL
– HIV RNA 77 copies/mL
– Not amplified, R5
– Normal neopterin (1.25 ng/mL), high S100β (414.9 ng/mL)
– High BBB permeability (CSAR 15.5)
C15 Plasma CSF CSF/Plasma
Lamivudine 280 176 62.8%
Abacavir 113 102 90.2%
Nevirapine 3643 527 14.4%
CSF?
Management ?
Switched to ABC/3TC/DTG
8 months later…
• Slight worsening in NP tests (ANI)• Antidepressants changed to vortioxetine and low dose
quetiapine; slight improvement in mood• CD4 595 (35%, ratio 0.8), HIV RNA not detected• CSF
– No cells, protein 90 mg/dL– HIV RNA 157 copies/mL, not amplified– Normal neopterin (1.07 ng/mL), normal S100β (202 ng/mL)– High BBB permeability (CSAR 14.2)
C4 Plasma CSF ratio
Lamivudine 2960 69 2.3%
Abacavir 2666 724 27.1%
Dolutegravir 848 11 1.3%
Persistent low level CSF escape: Management ?
Switched to DRV/c +3TC + DTG
Further 8 months later…
• Slight improvement in NP tests
• CD4 707 (34%, ratio 0.8), HIV RNA TND, R5-tropic, HIV DNA 70 copies*106 PBMCs
• CSF
– No cells, protein 91 mg/dL
– HIV RNA not detected
– Normal S100β (308 ng/mL)
– CSAR and other markers not yet available
Summary
DescriptionIndication for
LP?Treatment
optimization?PK role?
1Elderly, ANI with low level escape
?? ??
2Symptomatic CSF escape with DDI
3Symptomatic CSF escape with LLV
??
4 Vascular involvement
5 Persistent CSF escape ?? ??
Guidelines: Indications for LP
Brain MRI and LP suggested in patients with symptomatic HAND (MND/HAD) - AII
Suggested in case of risk factors for viral escape:
• nadir CD4 <200/uL
• previous HAD diagnosis
• RAMs
• Poor adherence
Guidelines: Treatment modification
HAND
NaiveTreated with CSF
escape
Start HAART (following
general guidelines) + including as
many “neuroeffective” drugs as possible
Modify HAART according to Resistance testing (allagenotypes,
plasma and CSF)and using
“neuroeffective” drugs
Conclusions
• Spectrum of CNS disease continues to evolve
with the evolution of ART and the aging of patients
– Polypharmacy and drug-drug interactions
– High index of suspicion is recommended
• Functional monotherapy appears to occur in the
CNS of some patients and may be responsible for
at least some cases of CSF viral escape
• ART change – or “optimization” – may benefit
some CNS diseases but standardized
recommendations remain challenging