Clinical Resolution and CSF Viral Suppression Following Switching - - PowerPoint PPT Presentation

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Clinical Resolution and CSF Viral Suppression Following Switching - - PowerPoint PPT Presentation

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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 Escape Kabengele Kayembe D. ; Nxele N.P.; Famoroti

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SLIDE 1

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 Escape

Kabengele Kayembe D.; Nxele N.P.; Famoroti T.; Gordon M.

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SLIDE 2

#

lives matter

Brain

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SLIDE 3

Individual and programmatic impact and management implications

Clinical and virologic

ObjectiveEscape

Cerebrospinal fluid

Neuro-symptomatic

  • utcomes
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SLIDE 4 Figure 1. Geographic distribution of cohorts presented at the Global HIV-1 CSF Escape Meeting 2016

HIV infected ART experienced

South Africa

1in 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

€ € €€ €

The prevalence

  • f CSF viral escape

estimated at 4%‒20% among ART-experienced HIV+ adults

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SLIDE 5

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

The setting Eshowe

District hospital

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SLIDE 6

ClinicalSuspicion

“With a high suspicion, every effort to obtain

these assessments should be made

since they are essential

for 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)

Escape

Cerebrospinal fluid

Neuro-symptomatic

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SLIDE 7

Escape

Cerebrospinal fluid

Neuro-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)

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SLIDE 8

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 1987

Married (spouse optimally suppressed on

NNRTI based ART) and father to six children

The patient

55-year-old male

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SLIDE 9 0.0 1.0 2.0 3.0 4.0 5.0 6.0 1.5 3 4.5 6 7.5 9 10.5 12 13.5 15 F e b
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1 D e c
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1 J u n
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2 A u g
  • 1
2 N
  • v
  • 1
2 A p r
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3 O c t
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7 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 Switch ART

regimen

exposure Intermittent Severe

adherence immune suppression viral suppression

History of HIV care

Figure 2. Viremia & immune suppression levels Figure 3. Antiretroviral therapy regimens
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SLIDE 10

History of HIV care

Ritonavir boosted

protease Inhibitor

based antiretroviral therapy

months

14

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SLIDE 11

“Established” neurologic impairment

despite

improvement

viremia control

Worsening

unremarkable

brain computed tomography

Spectrum & severity fluctuated with viremia

Tremors & Unsteadiness

Progressive

Insidious onset

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SLIDE 12

“Established” neurologic impairment

Culminated with status epilepticus

Incapacitation Semi-consciousness

Total dependence Neurogenic dysphagia

Worsening

Tremors & Unsteadiness

Progressive

Insidious onset

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SLIDE 13

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

Escape

Cerebrospinal fluid Definition 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 dissociation Figure 4. CSF escape criteria
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SLIDE 14

Escape

Cerebrospinal fluid Confirmation

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

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SLIDE 15

Escape

Cerebrospinal fluid CNS 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

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SLIDE 16

Escape

Compartmentalized, asynchronous, “discordant”?

Reverse transcriptase (RT) gene

D67N K70R T215F M184V K103N K238T

Protease

(PR) gene

M46I L10F

Cerebrospinal fluid

October 2016: Failure of boosted PIs

based second-line ART regimen in the CSF

CNS drug resistance

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SLIDE 17

Escape

Cerebrospinal fluid

Reverse transcriptase (RT) gene

D67N K70R T215F M184V K103N K238T

Protease

(PR) gene

M46I L10F

V82A/V

December 2016: Failure of boosted PIs

based second-line ART regimen in the plasma

Plasma drug resistance

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SLIDE 18

Escape

Cerebrospinal fluid

Compartmentalized, Asynchronous, discordance

drug resistance?

Table 1. Reverse transcriptase (RT) gene drug resistance mutations & levels Mutations Drugs Mutation Scoring Resistance Levels*** CSF* Plasma** CSF Plasma CSF Plasma D67N, K70R, M184V, T215F D67N, K70R, M184V, T215F ABC 40 40 Intermediate Intermediate AZT 80 80 High High D4T 65 65 High High FTC 60 60 High High 3TC 60 60 High High TDF 15 15 Low Low K103N, K238T K103N, K238T EFV 90 90 High High ETR Susceptible Susceptible NVP 90 90 High High RPV Susceptible Susceptible
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SLIDE 19

Escape

Cerebrospinal fluid

Compartmentalized, Asynchronous, discordance

drug resistance?

Table 2. Protease (PR) gene drug resistance mutations & levels Mutations Drugs Mutation Scoring Resistance Levels*** CSF* Plasma** CSF Plasma CSF Plasma M46I, L10F M46I,

V82A/V

L10F ATV/r 10 35 Potential Low Intermediate DRV/r 5 5 Susceptible Susceptible FPV/r 25 50 Low Intermediate IDV/r 20 60 Low High LPV/r 15 55 Low Intermediate NFV 45 85 Intermediate High SQV/r 10 35 Potential Low Intermediate TPV/r 5 5 Susceptible Susceptible

Plasma PIs resistance one or two levels relatively higher

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SLIDE 20

Our Father

A CABBAGE !!!!!!!!

Escape

Cerebrospinal fluid

Rational management

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SLIDE 21

Escape

Cerebrospinal fluid

Rational 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 exposure Central nervous system drug penetration** Patient’s adherence motivation, support & sustainment

Regimen switch and/or intensification

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SLIDE 22

Escape

Cerebrospinal fluid

South African

third line antiretroviral therapy

≥15

two months earlier

Protease inhibitor resistance mutations scoring

than in the plasma

in the central nervous system

Eligibility “criteria”

S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776
  • n the Stanford University HIV Drug resistance Database
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SLIDE 23

Escape

Cerebrospinal fluid

South African

third line antiretroviral therapy

Building the regimen according to the algorithm

Drug CSF score

Plasma score

ATV 10 35 LPV 15 55 TDF 15 15 AZT 80 80

Additional InSTI and/or ETV not required with

respectively TDF and DRV mutations scoring less than 29 and 15

Third line option

CSF plasma

DRV DRV

TDF TDF

S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776
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SLIDE 24

Escape

Cerebrospinal fluid

South African

third line antiretroviral therapy

Building the regimen according to the algorithm

Drug CSF score

Plasma score

From the committee

ATV 10 35 LPV 15 55 TDF 15 15 AZT 80 80

DRV TDF FTC Application submitted 09/02/2017

Authorization granted

09/05/2017

Treatment started

09/04/2017

S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776
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SLIDE 25

Escape

Cerebrospinal fluid

Bettering the regimen penetration effectiveness

“CPE score > … 7”

Controversies about improved neurocognitive scores

  • r lower CSF HIV-1 RNA with higher CPE values

“Adjusted” CPE value thought to be a more

accurate reflection of ART penetration in CSF

escape

Clin 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

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SLIDE 26

Escape

Bettering the regimen penetration effectiveness

Cerebrospinal 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 1 NRTI’s Zidovudine Abacavir Emtricitabine Didanosine Lamivudine Stavudine Tenofovir NNRTI’s Nevirapine Efavirenz Etravirine Rilpivirine PI’s Indinavir/r Darunavir/r Fosamprenavir/r Indinavir Lopinavir/r Atazanavir Atazanavir/r Fosamprenavir Nelfinavir Ritonavir Saquinavir Saquinavir/r Tipranavir Entry/fusion inhibitors Maraviroc Enfuvirtide Integrase inhibitors Dolutegravir Raltegravir Elvitegravir

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

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SLIDE 27

Regimen CPE score

Escape

Bettering the regimen penetration effectiveness

Drug CSF score

Plasma score

From the committee

ATV 10 35 LPV 15 55 TDF 15 15 AZT 80 80

TDF FTC

CPE “raw” CPE “adjusted”

3 3 1 3 7 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
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SLIDE 28

Intensified Regimen

CPE score

Escape

Bettering the regimen penetration effectiveness

Drug CSF score

Plasma score

Pending approval

ATV 10 35 LPV 15 55 TDF 15 15 AZT 80 80

TDF FTC

CPE “raw” CPE “adjusted”

9 9 1 3 13 9 RAL ETV DRV

Cerebrospinal fluid

Central nervous system penetration effectiveness (CPE)

Neuro-symptomatic

J Neurol (2017) 264:1715–1727 | Top Antivir Med (2011) 19:137–142
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SLIDE 29

Escape

Cerebrospinal fluid Clinical outcomes

Neuro-symptomatic

Arrest

  • f neurological deficits

reversal

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

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SLIDE 30

Escape

Reversal Clinical outcomes

Neurological deficits

Day

  • 7

Day

8

Day Day

14

ambulation Unsteady Gradual independency

  • f daily living

activities gait

wheelchair

Alert

Discharged

Seated Talking

in a Indwelling feeding

Crushed

treatment gastric tube

  • btundation

aphasia Status epilepticus Admission

neurogenic dysphagia

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SLIDE 31

Escape

8 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 fluid Virologic 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-17 Discordance Plasma CSF
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SLIDE 32

Escape

Cerebrospinal fluid

Conclusion

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

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SLIDE 33

Acknowledgments

The patient & his family

Eshowe District Hospital management Experts (local and international) Ndlela LC & Mzilakazi S (students UKZN) Nxele Nombuso Precious Famoroti Temitayo Gordon Michelle Mathilda Classen