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A PROVEN HIGH BARRIER TO RESISTANCE 

WHY WE SHOULD REFER TO “BARRIER TO RESISTANCE”

“Barrier to Resistance” Is Well-defined by Virological, Pharmacological and Target-binding Properties, Ensuring[1-14]:

  • Long-term durability
  • Reduced risk of resistance
  • Preservation of future treatment options

WHAT ABOUT “FORGIVENESS”?

“Forgiveness” of a regimen implies that intermittent non-adherence can still maintain virological suppression with no resistance.[15]

Non-adherence Can Lead To[16]:

  • Virological failure
  • Development of resistance
  • Limited treatment options
  • Increased transmission risk

All oral therapies are required to be taken at least once daily.[17]

References:

  1. Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25(14):1737-1745. doi:10.1097/ QAD.0b013e32834a1dd9 
  2. Rousseau FS, Wakeford C, Mommeja-Marin H, et al; for the FTC-102 Clinical Trial Group. Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus-infected patients. J Infect Dis. 2003;188(11):1652-1658. doi:10.1086/379667 
  3. Cahn P, Sierra Madero J, Arribas JR, et al; for the GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naïve adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143-155. doi:10.1016/S0140-6736(18)32462-0
  4. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60(12):7086-7097. doi:10.1128/AAC.01474-16 
  5. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naïve adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111-118. doi:10.1016/S1473-3099(11)70290-0 
  6. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254-258. doi:10.1128/AAC.00842-09 
  7. Else LJ, Jackson A, Puls R, et al. Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study. Antimicrob Agents Chemother. 2012;56(3):1427-1433. doi:10.1128/AAC.05599-11 
  8. Moore KHP, Barrett JE, Shaw S, et al. The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. AIDS. 1999;13(16): 2239-2250. doi:10.1097/00002030-199911120-00006 
  9. Yuen GJ, Lou Y, Bumgarner NF, et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother. 2004;48(1):176-182. doi:10.1128/AAC.48.1.176-182.2004
  10. DeAnda F, Hightower KE, Nolte RT, et al. Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS One. 2013;8(10):e77448. doi:10.1371/journal.pone.0077448 
  11. Hightower KE, Wang R, DeAnda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother. 2011;55(10):4552-4559. doi:10.1128/AAC.00157-11
  12. DOVATO Summary of Product Characteristics. 
  13. Cahn P, Sierra Madero J, Arribas JR, et al. Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy-naïve adults with HIV-1 infection. AIDS. 2022;36(1):39-48. doi:10.1097/QAD.0000000000003070
  14. Osiyemi O, De Wit S, Ajana F, et al. Efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) versus continuing a tenofovir alafenamide-based 3- or 4-drug regimen for maintenance of virologic suppression in adults living with HIV-1: results through week 144 from the phase 3, non-inferiority TANGO randomized trial. Clin Infect Dis. 2022;ciac036 and suppl 1-18. doi:10.1093/cid/ciac036
  15. Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. J Antimicrob Chemother. 2008;61(4):769-773. doi:10.1093/jac/dkn020
  16. von Wyl V, Klimkait T, Yerly S, et al; for the Swiss HIV Cohort Study. Adherence as a predictor of the development of class-specific resistance mutations: the Swiss HIV cohort study. PLoS One. 2013;8(10):e77691. doi:10.1371/journal.pone.0077691
  17. National Institutes of Health. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Updated June 3, 2021. Accessed August 16, 2021. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new-guidelines

October 2022 PM-GB-DLL-WCNT-220005 

Prescribing Information

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