Mountain West AIDS Education and Training Center Dolutegravir: Pros and Cons (Are There Any Cons?) Brian R. Wood, MD Assistant Professor of Medicine, University of Washington Medical Director, MW AETC ECHO Last Updated: 10/20/16 This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient. Dolutegravir Pros and Cons • Pros: • Cons: - High resistance barrier - Headache and insomnia - Small, once-daily tab - Interactions with metformin, cations, and other ARV’s - Doesn’t require booster - Raises serum creatinine - Few drug interactions - No TDF or TAF coformulation - Overall well tolerated - Relatively lipid friendly Raltegravir Dolutegravir Dolutegravir Phase 3 Studies Study ARV History Comparison Results (HIV RNA <50) Dolutegravir QD vs. • Non-inferior 1 SPRING-2 ARV-Naïve Raltegravir (81% vs. 76%) Dolutegravir QD vs. • Dolutegravir superior 2 SINGLE ARV-Naïve Efavirenz (71% vs. 63%) Dolutegravir QD vs. • Dolutegravir superior 3 FLAMINGO ARV-Naïve Darunavir-RTV (80% vs. 68%) >2-class Dolutegravir QD vs. • Dolutegravir superior 4 SAILING ARV resistance Raltegravir (71% vs. 64%) Integrase Single-arm, • Virological suppression 5 VIKING-3 resistance Dolutegravir BID (69%) 1) Raffi F, et al. Lancet Infect Dis. 2013;13(11):927-35. 2) Walmsley S et al. J Acquir Immune Defic Syndr. 2015:70(5):515-9. 3) Molina JM, et al. Lancet HIV. 2015;2(4):e127-36. 4) Cahn P, et al. Lancet 2013;382:700–8. • . 5) Castanga A, et al. J Infect Dis. 2014;210(3):354-62. Review of Integrase and Dolutegravir Resistance Dolutegravir in Patients with Raltegravir Resistance VIKING III: Results 100 80 80 64 60 56 54 40 20 18 Patients with HIV RNA (%) copies/ml 50 < RNA HIV with Patients 0 All Patients N155H Y143C/H/R Q148H/R + Q148H/R + ≥ 2 without Q148 without Q148 G140A/S* INSTI mutations *without additional INSTI mutations Source: Dolutegravir Product Information. “Virological failure with resistance mutations in treatment-naïve patients treated with dolutegravir has not been reported.” Sources: Wainberg MA, et al. BMC Medicine. 2013;11:249. Wainberg MA, et al. Can J Microbiol. 2016;62(5):375-82. Dolutegravir Resistance • Resistance mutations not yet reported in treatment-naïve individuals (neither INSTI nor NRTI resistance) • Reports of R263K & other mutations in treatment- experienced patients and in vitro, yet dolutegravir generally retains activity Source: Wainberg MA, Han YS. Front Pharmacol. 2015;6:90. Why are Dolutegravir Resistance Mutations So Rare in Treatment-Naïve Persons? • Reduced viral fitness & integrase enzyme activity - No compensatory secondary mutations develop - Mutations also delay development of NRTI/NNRTI mutations - And common NRTI mutations prevent DTG mutations • Drug has strong affinity/binding to integrase enzyme • ?Resistance strains less likely to be archived Source: Wainberg MA, et al. BMC Medicine. 2013;11:249- Summary of Integrase Resistance Pathways Raltegravir Elvitegravir Dolutegravir Primary N155 N155 R263 Q148 Q148 G118 Y143 E92 H51 T66 E138 S153 N155 Secondary Common Common Rare *RAL and ELV primary mutations lead to resistance but also reduced viral fitness; secondary mutations increase resistance further and rescue viral fitness, but this doesn’t happen with DTG Source: Brenner BG, Wainberg MA. Virus Res. 2016. pii:S0168-1702(16)30283-0. Dolutegravir Tolerability, Side Effects, and Drug Interactions Dolutegravir Side Effects Intolerance of DTG-Containing Regimens in Clinical Practice • Two centers in the Netherlands • Review of all ART-naïve and exp. patients starting DTG • 556 patients included • 85 (15.3%) discontinued the drug • 75 (13.7%) discontinued due to intolerance • Most frequent reason: insomnia/sleep disturbance • Intolerance more frequent if combined with ABC (RR 1.92) Source: de Boer M et al. AIDS. 2016. DOI:10.1097/QAD.0000000000001279. STRIIVING Study Switch to ABC/3TC/DTG from Other Standard ART ABC/3TC/DTG Other ART (n=275) (n=276) Any adverse 180 (65%) 124 (45%) event (AE) Grade 3 or 4 AE 8 (3%) 5 (2%) Discontinuation 10 (4%) 0 (0%) due to AE *However, reported treatment satisfaction scores significantly higher in those who switched to ABC/3TC/DTG Source: Koteff J et al. EACS 2015, Barcelona, Spain. Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of Creatinine Bowman’s Capsule Proximal Tubule Distal Tubule Organic Cation Transporter 2 (OCT2) Dolutegravir Collecting Tubule Inhibits tubular secretion of creatinine via inhibition of OCT2 Loop of Henle Excretion Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6. Dolutegravir Drug Interactions and Dosing Recommended Dolutegravir Dosing Adult Population Recommended Dose Treatment-naïve or 50 mg once daily Treatment-experienced INSTI-naïve Coadministered with potent UGT1A/CYP3A inducer: Efavirenz Fosamprenavir/ritonavir 50 mg twice daily Tipranavir/ritonavir Rifampin INSTI-experienced with certain INSTI mutations* or 50 mg twice daily Clinically suspected INSTI resistance Poor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutations Source: Dolutegravir Prescribing Information Additional Dolutegravir Drug Interactions Medication Interaction Recommendation Etravirine Dolutegravir Avoid unless a boosted PI is also in the regimen Oxcarbazepine, phenytoin, Dolutegravir Avoid phenobarbital, carbamazepine, St. John’s Wort Cation-containing antacids or Dolutegravir Dolutegravir should be laxatives (sucralfate, oral Fe, oral administered 2 hours Ca) or buffered medications before or 6 hours after Metformin Metformin Close monitoring, consider metformin dose adjustment Dofelitide Dofelitide Avoid Source: Dolutegravir (Tivicay) Prescribing Information Summary • Dolutegravir is a revolutionary ARV and an excellent medication for many persons living with HIV, but not all • Failure of raltegravir or elvitegravir can cause significant dolutegravir resistance, but failure of dolutegravir generally does not lead to resistance mutations • 10-15% of individuals don’t tolerate dolutegravir due to insomnia, headache, or other side effects; intolerance may be more likely if combined with abacavir • Remember the benign effects on serum creatinine and a few key drug-drug interactions Question? • What would be better than dolutegravir? What will be the next revolutionary step? - Cabotegravir? - GS-9883 (Bictegravir)? - MK-8591 (EFdA)?.