Intelence (Page 6 of 9)

12.4 Microbiology

Mechanism of Action

Etravirine is an NNRTI of HIV-1. Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme’s catalytic site. Etravirine does not inhibit the human DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture

Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC50 values ranging from 0.29 to 1.65 nM and EC50 values ranging from 11.5 to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs—the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; the gp41 fusion inhibitor ENF; the integrase strand transfer inhibitor raltegravir and the CCR5 co-receptor antagonist maraviroc.


In Cell Culture

Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.

In Treatment-Experienced Subjects

In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the INTELENCE-containing regimen were V179F, V179I, and Y181C which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance-associated substitutions which emerged on etravirine treatment in less than 10% of the virologic failure isolates included K101E/H/P, K103N/R, V106I/M, V108I, Y181I, Y188L, V189I, G190S/C, N348I and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.


Cross-resistance among NNRTIs has been observed. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen. Virologic failure on a rilpivirine-containing regimen with development of rilpivirine resistance is likely to result in cross-resistance to etravirine (see Treatment-Naïve HIV-1-Infected Subjects in the Phase 3 Trials for EDURANT (rilpivirine) below). Cross-resistance to etravirine has been observed after virologic failure on a doravirine-containing regimen with development of doravirine resistance. Some NNRTI-resistant viruses are susceptible to etravirine, but genotypic and phenotypic testing should guide the use of etravirine (see Baseline Genotype/Phenotype and Virologic Outcome Analyses below).

Site-Directed NNRTI Mutant Virus

Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility greater than 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC50 value) and Y181V (17-fold change in EC50 value). Mutant strains containing a single NNRTI resistance-associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change greater than 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).

Clinical Isolates

Etravirine retained a fold-change less than or equal to 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125-C206 and TMC125-C216, 34% of the baseline isolates had decreased susceptibility to etravirine (fold-change greater than 3) and 60%, 69%, and 78% of all baseline isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Of subjects who received etravirine and were virologic failures in TMC125-C206 and TMC125-C216, 90%, 84%, and 96% of viral isolates obtained at the time of treatment failure were resistant to delavirdine, efavirenz, and nevirapine, respectively.

Treatment-Naïve HIV-1-Infected Subjects in the Phase 3 Trials for EDURANT (Rilpivirine)

There are currently no clinical data available on the use of etravirine in subjects who experienced virologic failure on a rilpivirine-containing regimen. However, in the rilpivirine adult clinical development program, there was evidence of phenotypic cross-resistance between rilpivirine and etravirine. In the pooled analyses of the Phase 3 clinical trials for rilpivirine, 38 rilpivirine virologic failure subjects had evidence of HIV-1 strains with genotypic and phenotypic resistance to rilpivirine. Of these subjects, 89% (34 subjects) of virologic failure isolates were cross-resistant to etravirine based on phenotype data. Consequently, it can be inferred that cross-resistance to etravirine is likely after virologic failure and development of rilpivirine resistance. Refer to the prescribing information for EDURANT (rilpivirine) for further information.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with a decreased virologic response to etravirine. Additional substitutions associated with a decreased virologic response to etravirine when in the presence of 3 or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load less than 50 plasma HIV RNA copies/mL at Week 48) (Table 10).

Table 10: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Number of IAS-USA-Defined NNRTI Substitutions * in the Non-VF Excluded Population of the Pooled TMC125-C206 and TMC125-C216
ENF: enfuvirtide
2008 IAS-USA defined substitutions = 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
# IAS-USA-Defined NNRTI substitutions * EtravirineN=561
Re-used/not used ENF de novo ENF
All ranges 61% (254/418) 76% (109/143)
0 68% (52/76) 95% (20/21)
1 67% (72/107) 77% (24/31)
2 64% (75/118) 86% (38/44)
3 55% (36/65) 62% (16/26)
≥ 4 37% (19/52) 52% (11/21)
All ranges 34% (147/435) 59% (93/157)

Response rates assessed by baseline etravirine phenotype are shown in Table 11. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for INTELENCE. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients.

Table 11: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Phenotype and ENF Use in the Pooled TMC125-C206 and TMC125-C216*
ENF: enfuvirtide
Non-VF excluded analysis
Fold Change EtravirineN=559
Re-used/not used ENF de novo ENF Clinical response range
All ranges 61% (253/416) 76% (109/143) Overall Response
0–3 69% (188/274) 83% (75/90) Higher than Overall Response
> 3–13 50% (39/78) 66% (25/38) Lower than Overall Response
> 13 41% (26/64) 60% (9/15) Lower than Overall Response
All ranges 34% (145/429) 60% (92/154)

The proportion of virologic responders (viral load less than 50 HIV-1 RNA copies/mL) by the phenotypic susceptibility score (PSS) of the background therapy, including ENF, is shown in Table 12.

Table 12: Virologic Response (Viral Load Less Than 50 HIV-1 RNA Copies/mL) at Week 48 by Phenotypic Susceptibility Score (PSS) in the Non-VF Excluded Population of TMC125-C206 and TMC125-C216
PSS * INTELENCE + BRN=559 Placebo + BRN=586
The phenotypic susceptibility score (PSS) was defined as the total number of active antiretroviral drugs in the background therapy to which a subject’s baseline viral isolate showed sensitivity in phenotypic resistance tests. Each drug in the background therapy was scored as a ‘1’ or ‘0’ based on whether the viral isolate was considered susceptible or resistant to that drug, respectively. In the calculation of the PSS, darunavir was counted as a sensitive antiretroviral if the FC was less than or equal to 10; ENF was counted as a sensitive antiretroviral if it had not been used previously. INTELENCE was not included in this calculation.
0 43% (40/93) 5% (5/95)
1 61% (125/206) 28% (64/226)
2 77% (114/149) 59% (97/165)
≥ 3 75% (83/111) 72% (72/100)

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