CNS Toxicity of Integrase Inhibitors Myth or Reality? Ignacio Pérez Valero Unidad de VIH. Hospital U. La Paz

CNS Toxicity of Integrase Inhibitors Myth or Reality? Ignacio Pérez Valero Unidad de VIH. Hospital U. La Paz

Question for the audience Do you think that any integrase inhibitor drug produce CNS adverse events?

CNS neurotoxicity is common to all antiretroviral drugs Neuronal integrity Neuronal damage Produced by ATV Neuronal damage Produced by EFV CNS toxicity impairs normal functioning of the brain Liner et al. CROI 2010. Abst 435.

Toxicity Index (log TC 50 / plasma conc) Some antiretrovirals achieved neurotoxic concentrations in the CSF (MAP-2 toxicity) 2 1,5 1 More Toxic Less Toxic 0,5 0-0,5 ABC ddc DDI FTC TDF 3TC AZT EFV ETR NVP APV ATV DRV RTV MVC -1-1,5-2 Robertson K et al. J Neurovirol 2012;18(5):388-99.

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

Question for the audience 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 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% Marzolini C et al. AIDS 2001;15:71-5

Long-term CNS effects of EFV use: ACTG 5097s Progressive neurocognitive worsening at 168 weeks Early high and long-term mild increases in EFV-related symptoms Score Neurocognitive Score 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 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 Croteau D. et al. CROI 2012, abstract 592.

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 33 40 CNS TOXICITY 33 10 10 10 20 18 16 14 12 10 8 6 4 2 0 BL W4 12 W post-switch IS DS Proportion of patients with grade 2-3 CNS AE IS DS Bracchi M et al. HIV Glasgow 2016. P209

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

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

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

Question for the audience 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 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. Fernandez C et al. HIV Glasgow 2016. P212

DTG adverse events in clinical practice: Ramon y Cajal Hospital Experience 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 Vivancos-Gallego MJ et al. HIV Glasgow 2016. P212

DTG CSF concentrations in the ING116070 Trial CSF DTG levels were 90-fold and 66-fold above the IC 50 (0.2 ng/ml) at weeks 2 and 16 respectively (RTG exceeded the IC50 by 4.5-fold) Letendre et al. CID 10.1093/cid/ciu477

Relation between DTG plasma-trough concentrations and CNS side-effects in Japanese HIV patients 101 Japanese HIV-infected patients taking DTG (2014-2016) % of Adverse events P<0.05 1,34 1,06 37% 21% 8% 6% 3% Any AE CNS AE Headache Insomnia Irritability CNS AE Non-CNS AE Correlations between [DTG] and UGT1A1 Genetic polymorphisms were not observed * DTG concentrations in mcg/ml Yagura H et al. HIV Glasgow 2016. P312

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 n = 985 Sabrinski M et al. HIV Glasgow 2016

Question for the audience 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) Adverse Events in >10% Patients at Week 96 33% TDF/FTC/EFV ABC/3TC/DTG 26% 28% TDF/FTC/EFV TDF/FTC/ELV/COBI 16% 7% 7% 6% 10% 7% 15% 16% 11% Dizziness Abnormal dreams Insomnia Dizziness Abnormal dreams Insomnia Adverse Events in >5% Patients at 5 Yrs. 35% TDF/FTC + EFV TDF/FTC + RTG 13% 8% 7% 8% 7% Dizziness Abnormal dreams Insomnia 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

Proportion of patients treated with INSTI (%) Rates of AE in patients starting integrase inhibitors in clinical practice 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 Raltegravir (n=553) Elvitegravir-cobi (n = 395) Dolutegravir (n = 519) 0 Any ADR CNR GI Liver Skin General Other ADR symptom category 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