cns toxicity of integrase inhibitors ¿myth or...
TRANSCRIPT
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.
Real Case from our Cohort
Do you think TDF/FTC/EFV was a good
option from a CNS-safety perspective?
Question for the audience
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.
Real Case from our Cohort
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.
Real Case from our Cohort
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.
Real Case from our Cohort
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.
Real Case from our Cohort
Are you seeing similar or less intense cases
of CNS AE related with DTG use?
Question for the audience
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?
Question for the audience
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%
Dizziness Abnormal dreams Insomnia
TDF/FTC/EFV
TDF/FTC/ELV/COBI
35%
13%8%8% 7% 7%
Dizziness Abnormal dreams Insomnia
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