cns toxicity of integrase inhibitors ¿myth or...

Ignacio Pérez Valero

Unidad de VIH. Hospital U. La Paz

CNS Toxicity of Integrase Inhibitors

¿Myth or Reality?

Do you think that any integrase inhibitor

drug produce CNS adverse events?

Question for the audience

CNS neurotoxicity is common to all antiretroviral drugs

Neuronal integrityNeuronal damage

Produced by ATV

Neuronal damage

Produced by EFV

Liner et al. CROI 2010. Abst 435.

CNS toxicity impairs normal functioning of the brain

Robertson K et al. J Neurovirol 2012;18(5):388-99.

Some antiretrovirals achieved neurotoxic concentrations

in the CSF (MAP-2 toxicity)

-2

-1,5

-1

-0,5

0

0,5

1

1,5

2

ABC ddC DDI FTC TDF 3TC AZT EFV ETR NVP APV ATV DRV RTV MVC

More Toxic

Less Toxic

To

xic

ity I

nd

ex (

log

TC

50

/ p

lasm

a c

on

c)

Clinical Case Report (I)

• Mr. J is a well educated man of 61 years old

• He was diagnosed of HIV in 2009 (unknown origin) due to a

wasting syndrome, subacute diarrhea and an oral

candidiasis.

• At that time he has a CD4 nadir of 30 cells and started ART

with TDF/FTC + ATV + RIT and received empiric therapy

with metronidazole and ganciclovir (diarrhea)

• The patient did not refer ART-related tolerability issues.

Real Case from our Cohort

Clinical Case Report (II)

• He was doing well with prescribed medication, the diarrhea

was resolved and he started to win weigh.

• Despite clinical recovering, the patients persist with low level

viremia for several moths (without evidence of resistance

mutations) despite high adherence rates.

• For that reason we decided to switch ART to TDF/FTC/EFV in

March 2010.


Do you think TDF/FTC/EFV was a good

option from a CNS-safety perspective?


EFV, a drug with a narrow therapeutic window:

The paradigm of CNS neurotoxicity

Marzolini C et al. AIDS 2001;15:71-5

• 130 patients with HAART based on EFV during >3 months

• 226 samples obtained with a concentration range between (125-15230)

• Therapeutical EFV range between 1000-4000 ((4μg/L)

• CNS EFV-related toxicity :

0% 6%

22%

Long-term CNS effects of EFV use: ACTG 5097s

Neurocognitive Score EFV-related symptoms Score

• Progressive neurocognitive worsening at 168 weeks

• Early high and long-term mild increases in EFV-related

symptoms Score

Clifford DB et al. HIV Clin Trials 2009;10:343–55

Mollan KR et al. Ann Intern Med 2014;161:308–18

Aging increases EFV in CSF and therefore old patients

are more likely to have toxic EFV levels in CSF

Croteau D. et al. CROI 2012, abstract 592.

• 71 patients/samples on EFV and 98 on ATV-based ART

• Patients had similar characteristics and similar overall neurocognitive performance

Aging affects efavirenz concentrations but not protease inhibitor concentrations in CSF

Clinical Case Report (III)

• EFV tolerance was good except for mild sleep disturbances.

• Patient maintained occasional low-level viremia rebounds

despite ART switch.

• In Feb 2015, our pharmacy decided to split TDF/FTC/EFV

into TDF/FTC + generic EFV.

• After that switch the patient started with diarrhea and

moderate sleep disturbances.

• Then, we decided to switch to ABC/3TC/DTG trying improve

HIV control and ART-related tolerability.


Switch to DTG in patients experiencing

EFV-related CNS adverse events

Bracchi M et al. HIV Glasgow 2016. P209

0

2

4

6

8

10

12

14

16

18

20

Proportion of patients with grade 2-3 CNS AE

IS DS

33

10 10

4033

10

BL W4 12 W post-switch

IS DS

CNS TOXICITY

Clinical Case Report (IV)

• Two weeks after switching to ABC/3TC/DTG the patient

came to our clinic without an appointment. He was very

nervous and anxious. After starting the new ART he started

with recurrent nightmares. He was unable to recognize when

he was awake or sleep. He though we were trying to do

experiments with him.


Clinical Case Report (V)

• At the beginning we though that these symptoms could be

associated with ABC and therefore we switched ART to

TDF/FTC + DTG.


Schweinsburg BC et al. J Neurovirol 2005;11:356-64.

Neuronal toxicity has been associated with thymidine

NRTIs use, including abacavir

Objective: Measure NRTIs CNS mitochondrial toxicity using MRS (NAA)

Patients: 18 HIV+ using d4T+/-ddI

14 HIV+ using AZT+3TC

16 HIV+ without HAART

17 HIV - controls

* Abacavir was also independently associated with NAA reduction

*

Clinical Case Report (VI)

• The patient experience a mild improvement of symptoms after

the switch but he demand us to return to TDF/FTC/EFV.

• We switched ART back to TDF/FTC/EFV.

• One month after the switch the patient was again completely

recovery and asymptomatic.


Are you seeing similar or less intense cases

of CNS AE related with DTG use?


CNS adverse events in naïve HIV patients in Clinical Trials

Querencia R et al. HIV Glasgow 2016.

CNS adverse events change in patients on any conventional

ART who continued therapy or switched to ABC/3TC/DTG

Koteff J et al. EACS 2015

Reasons for discontinuation after switching to ABC/3TC/DTG

in the STRIVING Trial

Koteff J et al. EACS 2015

DTG adverse events in naïve and experienced HIV patients:

Liverpool Hospital Experience

Fernandez C et al. HIV Glasgow 2016. P212

All suffered severe side effects (anxiety, depression, paranoia and personality change)

but only one patient suffered severe CNS disturbance with new suicidal ideation and

self-harm.

DTG adverse events in clinical practice:

Ramon y Cajal Hospital Experience

Vivancos-Gallego MJ et al. HIV Glasgow 2016. P212

• 837 patients on DTG-based ART were analyzed

• 104 stopped DTG (12.4%). 36 due to toxicity (4.3%)

• 69.4% of all AE-related discontinuations were due to CNS AE

DTG CSF concentrations in the ING116070 Trial

Letendre et al. CID 10.1093/cid/ciu477

CSF DTG levels were 90-fold and 66-fold above the IC50 (0.2 ng/mL) at

weeks 2 and 16 respectively (RTG exceeded the IC50 by 4.5-fold)

Relation between DTG plasma-trough concentrations and

CNS side-effects in Japanese HIV patients

Yagura H et al. HIV Glasgow 2016. P312

101 Japanese HIV-infected patients taking DTG (2014-2016)

37%

21%

8% 6% 3%

Any AE CNS AE Headache Insomnia Irritability

% of Adverse events

* DTG concentrations in mcg/mL

1,34

1,06

CNS AE Non-CNS AE

P<0.05

Correlations between [DTG] and UGT1A1 Genetic polymorphisms were not observed

Levels of DTG seem to increase with aging

Calcagno A et al. HIV Glasgow 2016. P212

High Rates of CNS AE leading to DTG discontinuation in

Women and older patients

Sabrinski M et al. HIV Glasgow 2016

n = 985

Is CNS toxicity only associates with DTG

or there is a class-effect for all the

Integrase Inhibitors?


Comparison of changes in CNS AE in patients starting

integrase inhibitor (compared to an EFV-based ART)

Walmsley S, et al. JAIDS 2015;70:515-9

Rockstroh JK et al. JAIDS 2013;63:77.85

Zolopa A et al. JAIDS 2013;63:96-100

33%

16%

6%7% 7%10%

Dizziness Abnormal dreams Insomnia

TDF/FTC/EFV

ABC/3TC/DTG 26%28%

16%

7%

15%11%


TDF/FTC/EFV

TDF/FTC/ELV/COBI

35%

13%8%8% 7% 7%


TDF/FTC + EFV

TDF/FTC + RTG

Adverse Events in >10% Patients at Week 96

Adverse Events in >5% Patients at 5 Yrs.

Rates of AE in patients starting integrase inhibitors

in clinical practice

Pro

po

rtio

n o

f p

atie

nts

tr

eat

ed w

ith

INST

I (%

)

ADR symptom category

8.0

6.0

4.0

2.0

0Any ADR

Raltegravir (n=553)

Elvitegravir-cobi (n = 395)

Dolutegravir (n = 519)

7.0

5.0

3.0

1.0

CNR GI Liver Skin General Other

Lepik KJ et al. HIV Glasgow 2016. TUPEB256

Rates of AE (and CNS AE) leading to Integrase Inhibitor

discontinuation during the first 12 months of use

Sabrinski M et al. HIV Glasgow 2016

Thanks for your attention

cns toxicity of integrase inhibitors ¿myth or...

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