Title

Resistance through week 48 in the DAWNING study comparing dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/r) plus 2 NRTIs in second-line treatment

Presenter

Mark Underwood

Authors

R. Wang¹, J. Horton², J. Hopking², K. King³, K. Smith¹, M. Aboud⁴, B. Wynne⁵, J. Sievers⁴, M. Underwood¹

Institutions

¹ViiV Healthcare, Research Triangle Park, United States, ²GlaxoSmithKline, Stockley Park, United Kingdom, ³PAREXEL, Glendale, United States, ⁴ViiV Healthcare, Brentford, United Kingdom, ⁵ViiV Healthcare, Upper Merion, United States

Background: DAWNING is a Phase 3b non-inferiority study comparing DTG plus 2 NRTIs with a WHO-recommended regimen of LPV/r + 2 NRTIs in HIV-1 infected adults failing first-line therapy (HIV-1 RNA ≥400 copies [c]/mL) of a non-nucleoside reverse transcriptase inhibitor (NNRTI) + 2 NRTIs (ClinicalTrials.gov: NCT02227238). This analysis explores 48-week resistance outcomes.
Methods: DAWNING is a Phase 3b non-inferiority study comparing DTG plus 2 NRTIs with a WHO-recommended regimen of LPV/r + 2 NRTIs in HIV-1 infected adults failing first-line therapy (HIV-1 RNA ≥400 copies [c]/mL) of a non-nucleoside reverse transcriptase inhibitor (NNRTI) + 2 NRTIs (ClinicalTrials.gov: NCT02227238). This analysis explores 48-week resistance outcomes.
Results: Eleven DTG subjects and 30 LPV/r subjects met CVW criteria through Week 48. Baseline NRTI mutation M184I/V alone, and pathways K65R or M184I/V +≥ one other major NRTI mutation were common (Table). One subject receiving DTG+3TC+AZT with HIV-1 subtype C had NRTI mutations K70E+M184V at Baseline; NRTI mutation M184V and INSTI mutation mixture H51H/Y+G118R+E138E/K+R263R/K were observed at Week 48 CVW with DTG fold-change in IC50 vs wildtype (FC) = 15. At Baseline and Week 48, INSTI replication capacity (RC) was 236 and 36, and RT/PR RC was 41 and 41, respectively. A second subject receiving DTG+FTC+TDF, with HIV-1 subtype B, had NRTI mutations M184V+K219K/E at Baseline; NRTI mutations D67N+M184V and INSTI mutation G118R were observed with DTG FC= 30 at Week 36 CVW. At Baseline and Week 36 INSTI RC was 103 and 5.6 and RT/PR RC was 83 and 97, respectively. 3 LPV/r subjects had emergent NRTI but no PI mutations.
Conclusions: In DAWNING most subjects in each arm had Baseline M184I/V alone or with additional major RT mutations (82% across study). Despite this, three times fewer DTG subjects met CVW criteria than LPV/r subjects, and treatment emergent INSTI resistance was rare. The two patients with treatment emergent INSTI resistance substitutions showed increases in FC to DTG and substantial decreases in INSTI replication capacity.

Table 1
[Table 1]

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