xcluding at Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravir FC is seen as the number of secondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). In contrast, starting passage with mutants with mutation Q148H (FC 1), a variety of raltegravir associated secondary mutations accumulated with a consequent increase of FC to values >10.
A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.
Rilpivirine-resistant strains were selected in cell culture starting from wild type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I. Resistance to rilpivirine was considered present when FC in EC50 value was above the biological cut-off (BCO) of the assay.
Resistance in vivo
Two subjects across the pooled SWORD-1 (201636) and SWORD-2 (201637) studies from each treatment arm experienced confirmed virologic failure leading to withdrawal at any time through Week 48. NNRTI resistance associated substitution K101K/E mixture with no decreased susceptibility to rilpivirine (FC=1.2) was observed in one subject with identified adherence issues that received dolutegravir plus rilpivirine. No integrase resistance was observed. This patient's viral load was 1,059,771 copies/mL at the suspected virologic withdrawal visit and was <50 copies/mL at the withdrawal visit. No treatment emergent resistance-associated substitutions were observed for the other three subjects who experienced confirmed virologic failure.
In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48-96 weeks).
In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase inhibitor experienced or infected with integrase inhibitor resistant virus by transmission. The R263K mutation was also selected in vitro (see above).
From rilpivirine Phase III trials, in the week 48 pooled resistance analysis conducted with previously untreated patients, 62 (of a total of 72) virologic failures in the rilpivirine arm had resistance data at baseline and time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. In the trials, the presence of the muta |
