6th IAS Conference On HIV Pathogenesis, Treatment and Prevention

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Minority species resistance present at screening does not affect outcomes at week 48 in lersivirine (UK-453,061) phase IIb study A5271015 in treatment-naive patients

C. Craig1, C. Wang2, N. Cusack2, J. Mori1, B. Taillon3, M. Westby1, M. Tawadrous2

1Pfizer Global Research and Development, Sandwich, Kent, United Kingdom, 2Pfizer, Inc., New London, United States, 3454 Life Sciences, A Roche Company, Branford, United States

Background: Lersivirine (LRV, UK-453,061) is an NNRTI with a unique resistance profile. Study A5271015 is a 96-week, international, double-blind, randomised, Phase IIb study in HIV-1 infected, treatment-naïve patients, to assess the antiviral activity and safety of LRV (500/750mg once daily [QD]) or efavirenz (EFV, 600mg QD), each combined with tenofovir DF/emtricitabine (300mg/200mg QD). Minority species NNRTI resistance is a clinically significant problem in treatment-naïve HIV-1 infected persons. The objective of this analysis was to assess the impact of minority species resistance-associated mutations (RAMs) on response through Week 48.
Methods: Ultra-deep sequencing was performed successfully on 179/193 Screening samples across all treatment groups. Association between IAS USA or LRV minority RAMs (i.e. present in >1% to < 20% of sequences) and virologic outcome at Week 48 was examined. Mutations observed using population genotyping were excluded.
Results:


 LRV (500mg QD)LRV (750mg QD)EFV (600mg QD)
Patients with ≥1 minority NNRTI or LRV RAM at Screening, n/N (%)12/61 (20%)12/58 (21%)12/60 (20%)
Listing of patients with minority NNRTI and LRV RAMs at ScreeningE138K/G190E; L100I; Y188H; V90I; K103N; V90I; V106I/V108I; V106A; V90I?; V179D; F227L; V106IG190E; V90I/E138A; K103N; E138K; K103N/F227L; K101E/F227L ?; E138K; V108I; L100I; V106I; V106I; V179DL100I/K101E; F227L; Y188C; F227C; F227L; F227L; V108I ?; V106I/V108I/G190E; E138K/G190E; V108I; G190E; Y188H
?Week 48 TLOVR50 virologic failure (LRV RAMs underlined).
[Table 1]


Among the LRV treated patients, ≥1 minority LRV RAM was detected in virus from nine patients (8%) (three received LRV 500mg and six received LRV 750mg); eight of the nine responded to therapy through Week 48. In the remaining patient (K101E/F227L), the viral load response over time was consistent with poor adherence. Patients in the EFV-treated group with minority LRV RAMs at Screening (N=10) were not associated with virologic failure. The EFV RAM, K103N, was observed in three subjects at Screening; all were treated with LRV and responded to therapy.
Conclusion: The prevalence of LRV minority species RAMs was low and not associated with failure. Week 48 response was observed with LRV in patients with minority species K103N.

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