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Efficacy of DTG vs LPV/r in HIV-1 Participants with Baseline NRTI Resistance and Second-Line NRTI Use

This study compared the efficacy and safety of DTG plus 2 NRTIs versus LPV/r plus 2 NRTIs in HIV-1 infected patients failing first-line therapy. The analysis focused on the outcomes of different NRTI combinations in the presence of existing NRTI resistance.

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Efficacy of DTG vs LPV/r in HIV-1 Participants with Baseline NRTI Resistance and Second-Line NRTI Use

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  1. DTG vs LPV/r (DAWNING): Efficacy by Baseline NRTI Resistance and Second-Line NRTI Use Dannae Brown,1Ruolan Wang,2 Mark Underwood,2 Judy Hopking,3 Maria Claudia Nascimento,4Michael Aboud,4Jörg Sievers4 1Viiv Healthcare, Abbotsford, Australia; 2ViiV Healthcare, Research Triangle Park, NC; 3GlaxoSmithKline, Stockley Park, UK; 4ViiV Healthcare, Brentford, UK

  2. DAWNING: Introduction • The DAWNING study was conducted to evaluate the efficacy and safety of DTG + 2 NRTIs vs a current WHO-recommended regimen of LPV/r + 2 NRTIs in HIV-1-infected participants failing first-line therapy of an NNRTI + 2 NRTIs (ClinicalTrials.gov: NCT02227238) • DTG + 2 NRTIs was shown to be superior in the proportion of participants achieving viral suppression (plasma HIV-1 RNA <50 c/mL) at Week 48 compared with LPV/r + 2 NRTIs • NRTI resistance is common following virologic failure on historic first-line regimens in resource- limited settings (especially M184V/I and K65R) • Recycling of 3TC or FTC is recommended in NRTI sequencing algorithms • The current post hoc analysis examined efficacy outcomes for different NRTI combinations in the presence of existing NRTI resistance, including when 3TC or FTC was used in the presence of M184V/I WHO, World Health Organization. Aboud et al. Lancet Infect Dis. 2019 [Epub ahead of print]. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  3. Study Design Open-label, randomized noninferiority phase IIIb study Screening 1:1 randomized Stratification BL HIV ≤ or >100,000 c/mLFully active NRTIs (2 or <2) DTG + 2 NRTIs DTG + 2 NRTIs Continuation phase LPV/r + 2 NRTIs Randomization Week 52 Week 24interim analysis CountriesArgentina Kenya China Romania Brazil South Africa Thailand Russia Chile UkraineColombia Mexico Peru Inclusion criteria • On first-line 2 NRTIs + NNRTI regimen for ≥6 mo, failing virologically (HIV-1 RNA ≥400 c/mL on 2 occasions) • No primary viral resistance to PIs or INSTIs • Investigator-selected NRTIs had to include ≥1 fully active NRTI based on viral resistance testing at screening Primary endpoint at 48 wk: participants withVL <50 c/mL (ITT-E snapshot)a a−12% noninferiority margin. BL, baseline; ITT-E, intent-to-treat–exposed; VL, viral load. Aboud et al. Lancet Infect Dis. 2019 [Epub ahead of print]. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  4. Demographics and Baseline Characteristics CDC, Centers for Disease Control and Prevention. Aboud et al. Lancet Infect Dis. 2019 [Epub ahead of print]. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  5. Baseline Resistance Profile and NRTI Background Regimen After Randomization M184V/I present at baseline: DTG: 84% LPV/r: 81% XTC use with M184V/I: DTG: 220/312 (71%) LPV/r: 210/312 (67%) XTC use: DTG: 86% LPV/r:87% RAM, resistance associated mutation; TAM, thymidine analogue mutation; XTC, 3TC or FTC. Aboud et al. Lancet Infect Dis. 2019 [Epub ahead of print]. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  6. Response Rates by Presence of M184V/I at Baseline at Week 48: ITT-E Analysis • Response rates were consistently higher for the DTG arm regardless of the presence of M184V/I and use or not of 3TC or FTC Treatment differences (95% CI) Virologic outcomes LPV/r DTG 261/312 219/312 220/261 182/252 M184V/I presenta 41/51 37/60 187/220 M184V/I with and without XTCa 152/210 n/N 33/41 30/42 HIV-1 RNA <50 c/mL, % aM184V/I alone or plus additional NRTI mutations. ITT-E, intent-to-treat–exposed; XTC, 3TC or FTC. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  7. Snapshot Outcomes by Key Baseline Subgroups at Week 48: ITT-E by TDF Use With K65R and AZT Use With TAMs Treatment differences (95% CI) DTG LPV/r 261/312 219/312 80/95 68/92 6/7 7/8 62/71 61/81 30/35 n/N 40/51 HIV-1 RNA <50 c/mL ITT-E, intent-to-treat–exposed; TAM, thymidine analogue mutation. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  8. Response Rates by Presence of M184V/I at Baseline With or Without Additional NRTI Mutations at Week 48: ITT-E Analysis Virologic outcomes Treatment differences (95% CI) DTG LPV/r 261/312 219/312 With XTC use 187/220 a 152/210 47/57 44/65 140/163 108/145 54/60 46/64 23/27 15/22 HIV-1 RNA <50 c/mL, % aM184V/I alone or plus additional NRTI mutations. TAM, thymidine analogue mutation. XTC, 3TC or FTC. Brown et al. CROI 2019; Seattle, WA. Slides 144

  9. Snapshot Outcomes for Overall and M184V/I With XTC Population at Week 48: ITT-E Analysis Overall M184V/Iawith XTC use aM184V/I alone or plus additional NRTI mutations. ITT-E, intent to treat–exposed; XTC, 3TC or FTC use. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  10. Confirmed Virologic Withdrawals Through Week 48 • Among the 11 (4%) CVWs in the DTG group, 5/11 (45%) had M184V/I at baseline with use of XTC • Among the 30 (10%) CVWs in the LPV/r group, 15/30 (50%) had M184V/I at baseline with use of XTC FC, fold-change; GSS, genotypic susceptibility score; PSS, phenotypic susceptibility score; RAM, resistance-associated mutation; RC, replication capacity; XTC, 3TC or FTC. Aboud et al. Lancet Infect Dis. 2019 [Epub ahead of print]. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  11. Conclusions • Week 48 results demonstrated superior efficacy (adjusted treatment difference, 13.8%; 95% CI, 7.3-20.3; P<0.001) of DTG + 2 NRTIs vs LPV/r + 2 NRTIs • Response rates were high in participants receiving DTG + 2 NRTIs regardless of pre-existing resistance to one of the NRTIs in the background regimen, including when 3TC or FTC was used in the presence of M184V/I • Rates of virologic failure were lower in the DTG arm regardless of baseline NRTI resistance patterns and second-line background NRTI use • WHO interim guidelines with updated recommendations for first- and second-line ART now include DTG + 2 NRTIs as a recommended second-line treatment option for patients failing an NNRTI or PI first-line ARV regimen WHO, World Health Organization. World Health Organization. http://www.who.int/hiv/pub/guidelines/ARV2018update/en/. Accessed February 14, 2019. Brown et al. CROI 2019; Seattle, WA. Slides 144.

  12. Acknowledgments • We thank everyone who has contributed to the success of this study, including • All study participants and their families • IDMC • The clinical investigators and their staff: Argentina: P Cahn, I Cassetti, M Losso, N Luna, S Lupo, N Porteiro, C Zala; Brazil: C Brites, B Grinsztejn, T Newman, J Madruga; Chile: C Beltran, M Lasso, A Rojas, M Wolff; China: W Cai, H Lu, T Zhang, H Zhao; Colombia: C Alvarez, O Sussmann; Kenya: E Amukoye; Mexico: J Andrade-Villanueva, E Granados-Reyes, M Santoscoy-Gómez, J Sierra-Madero; Peru: L Hercilla, J Hidalgo, J Lama, E Montalban, C Seas; Romania: C Jianu, A Oprea, L Preotescu, S Rugina, E Zaharia Kezdi; Russian Federation: O Borodkina, O Chernova, V Kulagin, E Orlova-Morozova, F Nagimova, V Pokrovsky, T Shimonova, L Sultanov, O Tsybakova, S Volkova, N Zakharova; South Africa: R Kaplan, G Latiff, J Lombaard, L Mohapi, M Rassool; Thailand: P Chetchotisakd, S Kiertiburanakul, W Manosuthi, K Ruxrungtham, K Supparatpinyo; Ukraine: V Lukianenko, E Mamedova, L Moroz, S Servetskiy, S Yesypenko, D Zhivitsa • The GlaxoSmithKline and ViiV Healthcare study teams Brown et al. CROI 2019; Seattle, WA. Slides 144.

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