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: - High resistance barrier - Small, once-daily tab - Doesn t require booster - Few drug interactions - Overall well tolerated Cons: - Headache and insomnia - Interactions with metformin, cations, and other ARV s - Raises serum creatinine - No TDF or TAF coformulation - Relatively lipid friendly Raltegravir Dolutegravir
Dolutegravir Phase 3 Studies Study ARV History Comparison Results (HIV RNA <50) 1 SPRING-2 ARV-Naïve 2 SINGLE ARV-Naïve 3 FLAMINGO ARV-Naïve Dolutegravir QD vs. Raltegravir Dolutegravir QD vs. Efavirenz Dolutegravir QD vs. Darunavir-RTV Non-inferior (81% vs. 76%) Dolutegravir superior (71% vs. 63%) Dolutegravir superior (80% vs. 68%) 4 SAILING >2-class ARV resistance Dolutegravir QD vs. Raltegravir Dolutegravir superior (71% vs. 64%) 5 VIKING-3 Integrase resistance Single-arm, Dolutegravir BID Virological suppression (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
Patients with HIV RNA < 50 copies/ml (%) 100 Dolutegravir in Patients with Raltegravir Resistance VIKING III: Results 80 80 64 60 56 54 40 20 18 0 All Patients N155H without Q148 Y143C/H/R without Q148 Q148H/R + G140A/S* Q148H/R + 2 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 treatmentexperienced 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 Primary Raltegravir Elvitegravir Dolutegravir N155 Q148 Y143 N155 Q148 E92 T66 R263 G118 H51 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 Any adverse event (AE) ABC/3TC/DTG (n=275) Other ART (n=276) 180 (65%) 124 (45%) Grade 3 or 4 AE 8 (3%) 5 (2%) Discontinuation due to AE 10 (4%) 0 (0%) *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 Inhibits tubular secretion of creatinine via inhibition of OCT2 Collecting Tubule 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 Treatment-naïve or Treatment-experienced INSTI-naïve Coadministered with potent UGT1A/CYP3A inducer: Efavirenz Fosamprenavir/ritonavir Tipranavir/ritonavir Rifampin INSTI-experienced with certain INSTI mutations* or Clinically suspected INSTI resistance Recommended Dose 50 mg once daily 50 mg twice daily 50 mg twice daily 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, phenobarbital, carbamazepine, St. John s Wort Cation-containing antacids or laxatives (sucralfate, oral Fe, oral Ca) or buffered medications Dolutegravir Dolutegravir Avoid Dolutegravir should be administered 2 hours 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)?