Monitoring and Avoiding Integrase Inhibitor Toxicity

Dr. Gordon Arbess, MD, CCFP HIV Program Director St. Michael’s Hospital Family Health Team Dept. Family & Community Medicine University of Toronto Disclosures

▪ Grants: CIHR, OHTN, St. Michael’s Hospital Foundation, Gilead ▪ Advisory Boards: Gilead, Viiv, Merck ▪ Honoraria: Gilead, Merck Outline

▪ The Optimism of Integrase Inhibitors (game changer) ▪ Overall safety of Integrase Inhibitors ▪ CNS/Neurocognitive ▪ Weight Gain ▪ Pregnancy What makes the Ideal Antiretroviral?

▪ Efficacy/Potency ▪ Tolerability/Lack of Toxicity ▪ Convenience ▪ Resistance Profile ▪ Cost ▪ Use in Coinfection/comorbidities ▪ Pregnancy

The Long Road to Better Tolerated Regimens! • Avoidance of Thymidine analogues (AZT, ddI, d4T) • Switching away from use of PIs • Avoidance of Efavirenz • Move away from TDF to TAF • Widespread use of Integrase Inhibitors

Ms. RC

▪ 27 year old woman from Zimbabwe ▪ HIV + since 2015 ▪ Ready to start ARV ▪ She is HLA B5701 negative, no baseline resistance, no hx Hep B/C, no significant comorbidities, no medications ▪ She is on ODSP ▪ She is interested in the integrase inhibitor class but wants to know what side effects or safety/toxicity issues she should be concerned about?

2016 Guidelines

Safety & Tolerability Disadvantages of INSTIs

IAS-USA1 DHHS2 • Cobi inhibits active tubular secretion of Cr Elvitegravir • COBI raises SCr due to inhibition of resulting in increased SCr without (EVG) tubular secretion of creatinine affecting renal glomerular function • Nausea, diarrhea • Raises SCr due to inhibition of • Inhibits renal tubular secretion of Cr and tubular secretion of Cr Dolutegravir can increase serum Cr, without affecting • Higher rates of insomnia and glomerular function. (DTG) headache than comparators in • Insomnia, headache some studies3,4 • Increase in creatine kinase, myopathy, Raltegravir and rhabdomyolysis have been reported. - • Rare severe hypersensitivity reactions (RAL) (including SJS and TEN), nausea, diarrhea, pyrexia, insomnia, headache • INSTIs are associated with insomnia • Insomnia, depression and suicidality All INSTI infrequently reported, primarily in patients with preexisting psychiatric conditions

Cr: creatinine, SJS: Stevens-Johnson syndrome; and TEN: toxic epidermal necrosis 1. Gunthard H, et al. JAMA 2016;316(2):191-210. 2. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. July 14, 2016. Available at: http://www.aidsinfo.nih.gov/Guidelines 3. Walmsley SL, et al. SINGLE. NEJM 2013;369(19):1807-1818. 4. Clotet B, et al. FLAMINGO. Lancet 2014;383(9936):2222-2231.

Dolutegravir (DTG) CNS Toxicity Not Limited to Patients with Psychiatric Conditions Retrospective, single center, German database analysis of patients on DTG (N=861), including those with pre-existing depressive disorders (18%) or other neuropsychiatric diagnoses (6%), and reasons for discontinuation from 2014-2017 Discontinuation Due to NPAEs (Stratified by Sex, Pre-existing Psychiatric Disorders)

1 male (n=768) 1

0,9 0,9

Depressive disorders (red, n=155), other neuro- 0,8 female (n=93) 0,8 psychiatric ICDs (blue, n=55), no (black, n=651)

0,7 Gender 0,7 p = 0.0153 (logrank test) Psychiatric conditions p = 0.9957 0,6 0,6 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time Time • 6% of patients discontinued DTG due to neuropsychiatric adverse events (NPAEs) • DTG discontinuation was not associated with pre-existing psychiatric disorders, but with female sex and older age • No association between DTG plasma levels and risk of discontinuation due to NPAEs in this analysis DTG discontinuation rates were similar in patients with and without prior neuropsychiatric comorbidities NPAEs, neuropsychiatric adverse events Hoffman C, et al. CROI 2018. Boston, MA. Poster 424. Comparison of Adverse Events (AEs) Leading to INSTI Discontinuation (DC)1 Retrospective analysis of anonymized data for all HIV+ patients (1704 patients, 1950 INSTI therapies) under routine care in two large German HIV centres (Jan 2007 – April 2016) DTG EVG RAL % Discontinuation due to neuropsychiatric AEs n=985 n=287 n=678 AEs Leading to Discontinuation (>2% with any INSTI) 1.00 EVG (n=287) Renal 0.2 3.5 0 RAL (n=678) 0.95 Gastro-Intestinal 0.7 2.8 0.9 Neuropsychiatric 5.0 1.0 2.1 0.90 DTG (n=985) -sleep disturbance 3.7 0.7 0.6 -headache, dizziness, or 2.9 0.7 1.3 0.85 paresthesia -depression 0.7 0 0.1 0.80 Estimated AE Discontinuation Rates within 12 Months 0.75 Log rank test p<0.0001 Any AE 7.6 7.6 3.3 0 5 10 15 20 25 Neuropsychiatric AE 5.6 0.7 1.9 Months on INSTI ▪ Neuropsychiatric symptoms reproducible in 6 out of 6 cases with DTG re-exposure2 ▪ 86% of patients had no tolerability problems after DTG switched to another ART ▪ Likelihood of neuropsychiatric discontinuation more than doubled for DTG with ABC vs. without ABC Neuropsychiatric AEs were most common with DTG and resulted in greater discontinuations compared to EVG or RAL 1. Sabranski M et al.. HIV Drug Therapy 2016. #O214 2. Hoffman, C, et al. HIV Medicine 2016. Psychiatric Adverse Events across DTG Treatment-Naïve Phase III Clinical Trials

Analysis of psychiatric adverse events in four, Phase 3 DTG trials 1315 treatment-naïve patients with DTG, 1319 with EFV, DRV/r or RAL

25 Insomnia Anxiety Depression Suicidality Nightmares/Abnormal dreams 21 20 17 15 12 10 11 10 8 8 6 7 7 7 7 7 5 6 5 5 5 5 4 5 4 4 4 4 2 2 2 2 2 3 3 <1 1 <1 1 <1 1 1 2 <1

Subjects with psychiatric AEs, % AEs, with psychiatric Subjects 0 DTG RAL DTG DRV/r DTG EFV DTG ATV/r SPRING-2 FLAMINGO SINGLE ARIA 96 weeks, double blind 96 weeks, open label 144 weeks, double blind 48 weeks, open label ▪ In these trials, majority of DTG psychiatric AEs were grade 1/2, leading to few discontinuations ▪ Insomnia was the most frequent psychiatric AEs with 2 discontinuations. ▪ The rates of insomnia was similar across different trials (4%-8%), except SINGLE (17%). ▪ The rate of insomnia reported in the SINGLE study may be partially due to the study design bias related to the comparator arm in the context of a double blind study

AE: Adverse event Quercia R, et al. HIV Drug Therapy, Glasgow 2016, Oral Poster #P210 CROI 2016 / BHIVA 2016 / AFRAVIH 2016 / RICAI 2015/ Glasgow 2016

Experience with DTG in Clinical Practice

No. of d/c due to AEs Average Clinic Main reasons for d/c patients n (%) time to d/c

OLVG1 387 62 (16%) 78 d Sleeping, gastro-intestinal, neurological

Brighton2 128 16 (13%) 120 d Sleep

Foch3 105 11 (10.4%) 80 d Vertigo, headache, insomnia, malaise Cardiff4 63 6 (10%) 87 d Sleep Cochin5 279 26 (9.3%) n/a Arthralgia, myalgia, nausea, vomiting, vertigo, rash, digestive troubles Belfast6 68 6 (9%) n/a Anxiety, poor sleep, gastro-intestinal, low mood Manchester7 178 15 (8.4%) 91 d CNS, malaise and joint pain

Neuropsychiatric (5.0%), gastro-intestinal (0.7%), skin (0.3%), renal (0.2%), Cologne13 985 67 (6.8%) n/a hepatic (0.1%) St Thomas’8 181 9 (5%) n/a Insomnia, malaise/myalgia

DOL-ART12 411 18 (4,4%) n/a Depression (1.2%), GI symptoms (1%)

Ramòn Y Cajal11 827 36 (4,3%) n/a Headache, dyslipidemia, insomnia, dizziness, mood disorders

Cruser Kobler AIDS CNS (2), gastro-intestinal (1) 73 3 (4.1%) n/a Center10 19% patients had AEs, and 11% CNS AEs n/a, 33% have AEs of whom 20% CNS, 10% gastrointestinal, 7% Liverpool14 178 8 (4%) 2w to 5mo neurological, 3% musculoskeletal, 3% lethargy

Imperial9 138 3 (2%) n/a Sleep dizziness

Osaka15 101 n/a - 20.8% reported CNS AEs : headche (7.9%) insomnia (7.9%)

1. Brinkman K, et al. CROI 2016, Boston, MA. #948 9. Negedu, et al. BHIVA, Manchester UK. April 2016. p 28 d/c, discontinuation 2. Kirby, et al. BHIVA 2016, Manchester UK. P26 10. Tau L, et al. HIV Drug Therapy, Glasgow, UK. 2016. P108 AE, Adverse Events 3. Zucman D, et al. AFRAVIH 2016, Brussels, Belgium. Poster # 1405 11. Vivancos-Gallego M, et al. HIV Drug Therapy, Glasgow, UK, 2016. P116 CNS, Central Nervous system 4. Cunningham, et al, BHIVA 2016, Manchester, UK. P36 12. Postel N, et al. HIV Drug Therapy, Glasgow, UK, 2016. P133 n/a, not available 5. Le Baut V, et al. RICAI 2015, Paris. Poster # 475 13. Sabranski M, et al. HIV Drug Therapy, Glasgow, UK, 2016. O214 6. Todd, et al. BHIVA 2015. P8. 14. Fernandez C, et al. HIV Drug Therapy, Glasgow, UK, 2016. P212 7. Jewsbury S, et al. BHIVA, Manchester, UK. 2016. P20. 15. Yagura H, et al. HIV Drug Therapy, Glasgow, UK, 2016. P312 8. Simons R, et al. Guy’s and St Thomas’ NHS Foundation Trust, P9. What about weight gain?

What’s New? Bictegravir/FTC/TAF FDA Approved for Initial/Maintenance Therapy

▪ Once-daily single-tablet regimen with novel, unboosted INSTI Key US Label Information ▪ For treatment-naive pts Indications ▪ For pts with HIV-1 RNA < 50 copies/mL for ≥ 3 mos, no history of treatment failure, and no resistance to regimen components ▪ Contraindicated with rifampin, dofetilide ▪ May increase metformin concentrations Key DDIs ▪ Polyvalent cation–containing supplements/medications (including antacids) may decrease BIC concentration Special ▪ Not recommended for pts with estimated CrCl < 30 mL/min populations ▪ BIC only available in combination STR; not approved for use with other ARVs

BIC/FTC/TAF [package insert]. February 2018. Slide credit: clinicaloptions.com Bictegravir/FTC/TAF vs Dolutegravir-Containing Regimens for Treatment-Naive Pts ▪ GS-1489: randomized, double-blind, active-controlled phase III trial[1] Wk 48

Bictegravir/FTC/TAF* ART-naive, HLA-B*5701–negative (n = 314)

pts with eGFRCG ≥ 50 mL/min (N = 629) Dolutegravir/ABC/3TC† (n = 315)

▪ GS-1490: randomized, double-blind, active-controlled phase III trial[2] Wk 48

Bictegravir/FTC/TAF* ART-naive pts with (n = 320)

eGFRCG ≥ 30 mL/min (N = 645) Dolutegravir + FTC/TAF‡ (n = 325)

All pts also received placebo tablets for comparator regimen (eg, pts in GS-1489 who received BIC/FTC/TAF also received DTG/ABC/3TC placebo). *BIC/FTC/TAF 50/200/25 mg PO QD. †DTG/ABC/3TC 50/600/300 mg PO QD. ‡DTG + FTC/TAF 50 + 200/25 mg PO QD

1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082. Slide credit: clinicaloptions.com BIC/FTC/TAF vs DTG-Containing Regimens: Key Efficacy Findings

GS-1489: Wk 48 Virologic Efficacy[1] GS-1490: Wk 48 Virologic Efficacy[2] 99 > 99 100 92 93 100 93 BIC/FTC/TAF (n = 314) 89 1° PP DTG/ABC/3TC (n = 315) 80 80 BIC/FTC/TAF DTG + FTC/TAF Treatment difference: -0.6% 60 (95% CI: -4.8% to 3.6%) 60

Treatment difference (1o): -3.5% Pts (%) Pts 40 (%) Pts 40 (95% CI: -7.9% to 1.0%)

20 20 3 7 4 4 6 6 1 1 1 < 0 0 0 0 1 HIV-1 RNA HIV-1 RNA No Virologic HIV-1 RNA HIV-1 RNA No Virologic < 50 c/mL ≥ 50 c/mL Data < 50 c/mL ≥ 50 c/mL Data

▪ No resistance for any regimen ▪ No resistance for any regimen components detected for either components detected for either group group 1. Gallant J, et al. Lancet. 2017;390:2063-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082. Slide credit: clinicaloptions.com BIC/FTC/TAF vs DTG-Containing Regimens: Key Safety Findings

GS-1489[1] GS-1490[2] Outcome Through Wk 48 BIC/FTC/TAF DTG/ABC/3TC BIC/FTC/TAF DTG + FTC/TAF (n = 314) (n = 315) (n = 320) (n = 325) Diarrhea, % 13 13 12 12 Headache, % 11 14 13 12 Nausea, % 10 23* 8 9 Insomnia, % 4 6 5 4 Upper respiratory tract infection, % 6 11 5 7 † Median eGFRCG ∆ from BL, mL/min -10.5 -10.8 -7.3 -10.8 Mean BMD ∆ from BL, % spine/hip -0.83/-0.78 -0.60/-1.02 NR NR D/c for AE, n (%) 0 4 (1) 5 (2) 1 (< 1) *P < .0001; †P = .02 ▪ No d/c for renal AEs and no proximal tubulopathy

1. Gallant forJ, et al. anyLancet. 2017;390:2063 regimen-2072. 2. Sax PE, et al. Lancet. 2017;390:2073-2082. Slide credit: clinicaloptions.com Integrase Inhibitors in Pregnancy

Author’s Last Name, Conference Name, 32 Year, Presentation # Integrase Inhibitors are the safest class of ARVs to date

Low rates of Psychiatric/Other AEs have been demonstrated with all agents in clinical trials

Observational data are reporting unexpected high rates of discontinuation of Dolutegravir in Conclusions real life settings (methodologic issues/bias)

Need for good quality data in real life settings re: AEs in integrase inhibitors

Updated guidelines on use of Dolutegravir in Pregnancy (possibility of class effect?)