Activity Despite K103N
K103N—the most prevalent NNRTI mutation at baseline—did not affect virologic response to INTELENCE® (etravirine)1
Impact of baseline NNRTI mutations on INTELENCE® virologic response
Virologic response decreased as the number of baseline IAS-USA NNRTI mutations increased
- IAS-USA NNRTI mutations list (2008): V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L
- The presence at baseline of the substitutions L100I, E138A, I167V, V179D/F, Y181I/V, or G190S was associated with a decreased virologic response to INTELENCE®
- Additional substitutions associated with a decreased virologic response to INTELENCE® when in the presence of ≥3 additional NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C
In vitro findings (NNRTI-resistant site-directed mutants)
- The single amino acid substitutions associated with an INTELENCE® reduction in susceptibility >3-fold were K101A/P/Q, E138G/Q, Y181C/I/T/V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC50) and Y181V (17-fold change in EC50)
Development of mutations upon virologic failure
- For patients in the DUET-1 and DUET-2 studies experiencing virologic failure at Week 48 on an INTELENCE®-containing regimen, the substitutions that developed most commonly were V179F/I and Y181C, which usually emerged in a background of multiple other NNRTI resistance-associated substitutions
- In all the studies conducted with INTELENCE® in HIV-1-infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F/I, Y181C, and H221Y. Other NNRTI resistance-associated substitutions which emerged on INTELENCE® treatment in <10% of the virologic failure isolates included K101E/H/P, K103N/R, V106I/M, V108I, Y181I, Y188L, V189I, G190C/S, N348I, and R356K
Cross-resistance
- Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an INTELENCE®-containing regimen
- In the DUET-1 and DUET-2 studies, 34% of the baseline isolates had decreased susceptibility to INTELENCE® (fold-change >3) and 60%, 69%, and 78% of all baseline isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively
Treatment Consideration
- In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only N[t]RTIs (please click here for more details)
Please see additional Important Safety Information.
Please see full description of study design and baseline characteristics.
*Treatment-experienced adult patients who had viral load (HIV-1 RNA) >5000 copies/mL, ≥1 NNRTI RAM (A98G, L100I, K101E/P/Q, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179I/F/G, Y181C/I/V, Y188C/H/L, G190A/E/S, P225H, F227C, M230I/L, P236L, K238N/T, Y318F) at screening or from prior genotypic analysis, ≥3 primary PI mutations (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M) at screening, and were on a stable ARV regimen for ≥8 weeks.2
†Based on intent-to-treat (ITT) analysis missing equals failure (M=F).
‡In the INTELENCE® arm (n=599), 25.5% of patients used ENF de novo and 20.0% reused ENF. In the placebo arm (n=604), 26.5% of patients used ENF de novo and 20.4% reused ENF.