Clinical Resolution and CSF Viral Suppression Following Switching to a Genotype-guided South African Antiretroviral Third Line Regimen with Good CSF Penetration

Cerebrospinal Fluid HIV Viral EscapeKabengele Kayembe D.; Nxele N.P.; Famoroti T.; Gordon M.

# livesmatter

Brain

Individual and programmatic impact and management implications

Clinical and virologic

ObjectiveEscapeCerebrospinal fluidNeuro-symptomatic

outcomes

Figure 1. Geographic distribution of cohorts presented at the Global HIV-1 CSF Escape Meeting 2016

HIV infected ART experiencedSouth Africa1in 5

UNAIDS Data 2017 | Journal of Virus Eradication 2016; 2: 243–250 | J Acquir Immune Defic Syndr 2017;75:246–255

Uncommon or unrecognized or under reported

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The prevalence of CSF viral escape estimated at 4%‒20%among ART-experienced HIV+ adults

Deep rural Zulu Kingdom | KwaZulu-Natal province | South Africa

The setting

EshoweDistrict hospital

ClinicalSuspicion“With a high suspicion, every effort to obtain these assessments should be made

since they are essentialfor diagnosis and rational management.”

at the onset of new or progress of CNS symptoms

Clin Infect Dis. 2010; 50:773–8 | AIDS. 2012 September 10; 26(14) | J Neurovirol . 2013 August ; 19(4): 402–405 | AIDS. 2016;30(7):1143–1144 | Curr HIV/AIDS Rep (2015) 12:280–288 | Clin Infect Dis 2017;64(8):1059–65 | J Acquir Immune Defic Syndr 2017;75:246–255) | AIDS 2016, Vol 30 No 7:1143-1144 | AIDS. 2012 September 10; 26(14)

EscapeCerebrospinal fluidNeuro-symptomatic

EscapeCerebrospinal fluidNeuro-symptomatic

Plasma/CSF viral loads Genotyping

Magnetic resonance imaging

September 2016 October 2016*December 2016

January 2017

*October 2016 plasma genotyping not reported (viral load 386 copies/mL)

HIV infection diagnosis in February 2010 Baseline CD4 cell count (%) of 264 cells/µL (6%) and viremia of 156,162 copies/mL (cpm) (5.20 Log)

Shift worker process control officer at a pulp and containerboard mill since 1987Married (spouse optimally suppressed on NNRTI based ART) and father to six children

The patient55-year-old male

0.01.02.03.04.05.06.0

01.534.567.59

10.51213.515

Feb-10Jun-10

Dec-10Jan-11Jun-11

Dec-11Jun-12

Aug-12

Nov-12Apr-13Oct-13Apr-14Sep-14Jul-15Oct-15Jun-16Jul-16

Sep-16

Dec-16Jan-17Apr-17

Viral load Log

CD4 percentage

% CD4 p-Log VL

Suboptimal and labile

Mar-2010* Jul-2015** Oct-2015⋊ Apr-2016∅ Jun-2016⋕

D4T, 3TC, NVP

TDF, FTC, ATV/r

TDF, FTC, LPV/r

TDF, FTC, ATV/r

TDF, FTC, LPV/r

Initiation SwitchART

regimenexposure

Intermittent

Severe

adherence

immune suppression

viral suppression

History of HIV care

Figure 2. Viremia & immune suppression levels

Figure 3. Antiretroviral therapy regimens

History of HIV care

Ritonavir boosted protease Inhibitorbased antiretroviraltherapymonths14

“Established” neurologic impairment

despite

improvementviremia control

Worsening

unremarkable brain computed tomography

Spectrum & severity fluctuated with viremia

Tremors & UnsteadinessProgressive

Insidious onset

“Established” neurologic impairmentCulminated with status epilepticus

Incapacitation

Semi-consciousness

Total dependenceNeurogenic dysphagia

WorseningTremors & Unsteadiness

ProgressiveInsidious onset

4.0

4.4

2.3

3.4

1.7

1

-1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Sep-16

Dec-16

Discordance Plasma CSF

EscapeCerebrospinal fluidDefinition criteria

*AIDS. 2012 September 10; 26(14) | *Clin Infect Dis. 2010; 50:773–8 | **Curr HIV/AIDS Rep (2015) 12:280–288 | ***J Acquir Immune Defic Syndr 2017;75:246–255) | ***J Infect 2012;65(3):239–245 | ***J. Neurovirol. (2016) 22:852–860

Cerebrospinal fluid HIV-1 RNA higher than paired plasma levels

>0.5 Log*** >2 times**≥1 Log*

Figure 5. CSF/Plasma dissociationFigure 4. CSF escape criteria

EscapeCerebrospinal fluidConfirmation

J Acquir Immune Defic Syndr 2017;75:246–255) | Curr HIV/AIDS Rep (2015) 12:280–288 | AIDS. 2012 September 10; 26(14) | Clin Infect Dis. 2010; 50:773–8 | J Infect Dis. 2010; 202:1819–25 | J Virus Erad. 2016 Oct; 2(4): 242 | Clin Infect Dis. 2017;64(8):1059–65 | J. Neurovirol. (2016) 22:852–860 | AIDS. 2016;30(7):1143–1144

Meningeal inflammation Neuro-Imaging HIV encephalitis Absence of alternative neuro-pathology diagnosis

4.0

4.4

2.3

3.4

1.7

1

-1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Sep-16

Dec-16

Discordance Plasma CSF

Figure 5. CSF/Plasma dissociation

Cerebrospinal fluid

EscapeCerebrospinal fluidCNS drug resistance

**J Acquir Immune Defic Syndr 2017;75:246–255) | Curr HIV/AIDS Rep (2015) 12:280–288 | *AIDS. 2012 September 10; 26(14) | ***Clin Infect Dis. 2010; 50:773–8 | J Infect Dis. 2010; 202:1819–25 | J Virus Erad. 2016 Oct; 2(4): 242 | Clin Infect Dis. 2017;64(8):1059–65 | #J. Neurovirol. (2016) 22:852–860 | AIDS. 2016;30(7):1143–1144

Cerebrospinal fluid

some*, many**, majority***, all# cases had developed unique and significant resistance mutations in the CSF

Suggesting failure of the current treatment regimen in the central nervous system

EscapeCompartmentalized, asynchronous, “discordant”?

Reverse transcriptase (RT) gene

D67N K70R T215F M184V K103N K238T

Protease(PR) gene M46I L10F

Cerebrospinal fluid

October 2016: Failure of boosted PIsbased second-line ART regimen in the CSF

CNS drug resistance

EscapeCerebrospinal fluid

Reverse transcriptase (RT) gene

D67N K70R T215F M184V K103N K238T

Protease(PR) gene M46I L10F V82A/V

December 2016: Failure of boosted PIsbased second-line ART regimen in the plasma

Plasma drug resistance

EscapeCerebrospinal fluid

Compartmentalized, Asynchronous, discordance drug resistance?

Table 1. Reverse transcriptase (RT) gene drug resistance mutations & levelsMutations Drugs Mutation Scoring Resistance Levels***

CSF* Plasma** CSF Plasma CSF Plasma

D67N, K70R, M184V,T215F

D67N, K70R, M184V,T215F

ABC 40 40 Intermediate IntermediateAZT 80 80 High HighD4T 65 65 High HighFTC 60 60 High High3TC 60 60 High HighTDF 15 15 Low Low

K103N, K238T

K103N, K238T

EFV 90 90 High HighETR 0 0 Susceptible SusceptibleNVP 90 90 High HighRPV 0 0 Susceptible Susceptible

EscapeCerebrospinal fluid

Compartmentalized, Asynchronous, discordance drug resistance?

Table 2. Protease (PR) gene drug resistance mutations & levelsMutations Drugs Mutation Scoring Resistance Levels***

CSF* Plasma** CSF Plasma CSF Plasma

M46I, L10FM46I,

V82A/VL10F

ATV/r 10 35 Potential Low IntermediateDRV/r 5 5 Susceptible SusceptibleFPV/r 25 50 Low IntermediateIDV/r 20 60 Low HighLPV/r 15 55 Low IntermediateNFV 45 85 Intermediate HighSQV/r 10 35 Potential Low IntermediateTPV/r 5 5 Susceptible Susceptible

Plasma PIs resistance one or two levels relatively higher

Our Father

A CABBAGE !!!!!!!!

EscapeCerebrospinal fluidRational management

EscapeCerebrospinal fluidRational management

Antiretroviral therapy alteration

*J. Neurovirol. (2016) 22:852–860 | *Curr HIV/AIDS Rep (2015) 12:280–288** | *AIDS. 2012 September 10; 26(14)** | *Clin Infect Dis. 2010; 50(5):773–8**| J Virus Erad. 2016 Oct; 2(4): 242 | AIDS. 2016;30(7):1143–1144** | J Acquir Immune Defic Syndr 2017;75:246–255) | *J Neurol (2017) 264:1715–1727 **

Drugresistance*& previous exposureCentral nervous system drug penetration**

Patient’s adherencemotivation, support & sustainmentRegimen switch and/or intensification

EscapeCerebrospinal fluidSouth African third line antiretroviral therapy

≥15two months earlier

Protease inhibitor resistance mutations scoring

than in the plasmain the central nervous system

Eligibility “criteria”

S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776

on the Stanford University HIV Drug resistance Database

EscapeCerebrospinal fluidSouth African third line antiretroviral therapy

Building the regimen according to the algorithmDrug CSF

scorePlasma score

ATV 10 35

LPV 15 55

TDF 15 15

AZT 80 80

Additional InSTIand/or ETV not required with respectively TDF and DRV mutations scoring less than 29 and 15

Third line optionCSF plasma

DRV

DRV

TDF

TDF

S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776

EscapeCerebrospinal fluidSouth African third line antiretroviral therapy

Building the regimen according to the algorithmDrug CSF

scorePlasma score

From the committee

ATV 10 35

LPV 15 55

TDF 15 15

AZT 80 80

DRVTDFFTC

Application submitted09/02/2017

Authorization granted09/05/2017

Treatment started09/04/2017

S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776

EscapeCerebrospinal fluidBettering the regimen penetration effectiveness

“CPE score > … 7”Controversies about improved neurocognitive scores or lower CSF HIV-1 RNA with higher CPE values“Adjusted” CPE value thought to be a more accurate reflection of ART penetration in CSF escapeClin Infect Dis 2018;XX(00):1–9 | Arch Neurol. 2008;65(1):65-70 | Top Antivir Med. 2011 November ; 19(4): 137–142 | J Neurol (2017) 264:1715–1727 | AIDS. 2012 September 10; 26(14)

Central nervous system penetration effectiveness (CPE)

Neuro-symptomatic

EscapeBettering the regimen penetration effectivenessCerebrospinal fluid

Central nervous system penetration effectiveness (CPE)

Neuro-symptomatic

Table 3. CNS penetration effectiveness score (CPE), updated according to Letendre 2014

J Neurol (2017) 264:1715–1727 | Top Antivir Med (2011) 19:137–142

4 3 2 1NRTI’s Zidovudine Abacavir

EmtricitabineDidanosineLamivudineStavudine

Tenofovir

NNRTI’s Nevirapine EfavirenzEtravirine

Rilpivirine

PI’s Indinavir/r Darunavir/rFosamprenavir/rIndinavirLopinavir/r

AtazanavirAtazanavir/rFosamprenavir

NelfinavirRitonavirSaquinavirSaquinavir/rTipranavir

Entry/fusion inhibitors Maraviroc EnfuvirtideIntegrase inhibitors Dolutegravir Raltegravir Elvitegravir

The higher the score, the better the penetration into the CNS

Regimen CPE score

EscapeBettering the regimen penetration effectiveness

Drug CSF score

Plasma score

From the committee

ATV 10 35

LPV 15 55

TDF 15 15

AZT 80 80

TDFFTC

CPE “raw” CPE

“adjusted”

3 31 03 07 3

DRV

Cerebrospinal fluid

Central nervous system penetration effectiveness (CPE)

Neuro-symptomatic

J Neurol (2017) 264:1715–1727 | Top Antivir Med (2011) 19:137–142

Intensified Regimen CPE score

EscapeBettering the regimen penetration effectiveness

Drug CSF score

Plasma score

Pending approval

ATV 10 35

LPV 15 55

TDF 15 15

AZT 80 80

TDFFTC

CPE “raw” CPE

“adjusted”

9 91 03 013 9

RAL ETVDRV

Cerebrospinal fluid

Central nervous system penetration effectiveness (CPE)

Neuro-symptomatic

J Neurol (2017) 264:1715–1727 | Top Antivir Med (2011) 19:137–142

EscapeCerebrospinal fluidClinical outcomes

Neuro-symptomatic

Arrestof neurological deficitsreversal

in the majority of reported cases *J. Neurovirol. (2016) 22:852–860 | *Curr HIV/AIDS Rep (2015) 12:280–288** | *AIDS. 2012 September 10; 26(14)** | *Clin Infect Dis. 2010; 50(5):773–8**| | J Virus Erad. 2016 Oct; 2(4): 242 | AIDS. 2016;30(7):1143–1144** | J Acquir Immune Defic Syndr 2017;75:246–255) | *J Neurol (2017) 264:1715–1727 **

and

EscapeReversalClinical outcomes

Neurological deficits

Day-7

Day8

Day0

Day14

ambulation

Unsteady

Gradual independency

of daily livingactivities

gait

wheelchair

Alert

Discharged

SeatedTalking

in a

Indwelling feeding

Crushedtreatment

gastric tube obtundation aphasia

Status epilepticus

Admission

neurogenic dysphagia

Escape8 days plasma HIV RNA

2 Log drop

4 months CSF HIV RNA Complete suppression

From 162,000 cpm (5.2 Log) to 1550 cpm (3.2 Log)

Viral suppression

Cerebrospinal fluidVirologic outcomes

Neuro-symptomatic

Figure 5. CSF/Plasma viral suppression (Log HIV RNA)

4.0

4.4

1.3

2.3

3.4

5.2

3.2

2.1

1.7

1

-0.8

-1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5

Sep-16

Dec-16

Apr-17*

Apr-17**

Aug-17Discordance Plasma CSF

EscapeCerebrospinal fluidConclusion

Neuro-symptomatic

“Real and emerging” clinical phenomenon

Significant impact and management implications

Asynchronous and discordant emergence of resistance

Context-specific management clinical guidance

Bi-compartmental suppression and neurological improvement

Acknowledgments

The patient & his familyEshowe District Hospital managementExperts (local and international)Ndlela LC & Mzilakazi S (students UKZN)

Nxele Nombuso Precious Famoroti TemitayoGordon MichelleMathilda Classen