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