Mechanism of Action
Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.
Antiviral Activity in Cell Culture
Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510 to 10830 nM) (920 to 3970 ng/mL).
Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).
The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the integrase strand transfer inhibitor raltegravir.
In Cell Culture
Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L.
In Treatment-Naïve Adult Subjects
In the Week 96 pooled resistance analysis of the Phase 3 trials C209 and C215, the emergence of resistance was greater among subjects’ viruses in the EDURANT arm compared to the efavirenz arm, and was dependent on baseline viral load. In the pooled resistance analysis, 58% (57/98) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the EDURANT arm had virus with genotypic and/or phenotypic resistance to rilpivirine compared to 45% (25/56) of the resistance analysis subjects in the efavirenz arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in viruses from 52% (51/98) of the resistance analysis subjects in the rilpivirine arm compared to 23% (13/56) in the efavirenz arm.
Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects’ viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 – 621. The E138K substitution emerged most frequently during rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, T215S/T, or K219E/R) emerged more frequently in rilpivirine resistance analysis subjects compared to efavirenz resistance analysis subjects (see Table 11).
NNRTI- and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses from subjects with baseline viral load of ≤100,000 copies/mL compared to viruses from subjects with baseline viral load of >100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm3 compared to viruses from subjects with baseline CD4+ cell counts <200 cells/mm3: 37% (20/54) compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72% (36/50) of NRTI-resistance substitutions.
|C209 and C215N=1368|
|EDURANT + BRN=686||Efavirenz + BRN=682|
|Subjects who Qualified for Resistance Analysis||15% (98/652)||9% (56/604)|
|Subjects with Evaluable Post-Baseline Resistance Data||87||43|
|Emerging NNRTI Substitutions †|
|Any||62% (54/87)||53% (23/43)|
|V90I||13% (11/87)||2% (1/43)|
|K101E/P/T/Q||20% (17/87)||9% (4/43)|
|K103N||1% (1/87)||40% (17/43)|
|E138K/A/Q/G||40% (35/87)||2% (1/43)|
|E138K+ M184I ‡||25% (22/87)||0|
|V179I/L/D||6% (5/87)||7% (3/43)|
|Y181C/I/S||10% (9/87)||2% (1/43)|
|V189I||8% (7/87)||2% (1/43)|
|Emerging NRTI Substitutions §|
|Any||57% (50/87)||30% (13/43)|
|M184I/V||54% (47/87)||26% (11/43)|
|K65R/N||9% (8/87)||5% (2/43)|
|A62V, D67N/G, K70E, Y115F, T215S/T or K219E/R ¶||21% (18/87)||2% (1/43)|
Site-Directed NNRTI Mutant Virus
Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions had decreased susceptibility to rilpivirine (fold change range of 3.7 – 554) in 38% and 66% of mutants analyzed, respectively.
Treatment-Naïve HIV-1-Infected Adult Subjects
Considering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L.
Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the Week 96 pooled analyses of the Phase 3 TMC278-C209 and TMC278-C215 clinical trials, 50 of the 87 (57%) rilpivirine resistance analysis subjects with post-baseline resistance data had virus with decreased susceptibility to rilpivirine (≥2.5-fold change). Of these, 86% (n=43/50) were resistant to efavirenz (≥3.3-fold change), 90% (n= 45/50) were resistant to etravirine (≥3.2-fold change) and 62% (n=31/50) were resistant to nevirapine (≥6-fold change). In the efavirenz arm, 3 of the 21 (14%) efavirenz resistance analysis subjects’ viruses were resistant to etravirine and rilpivirine, and 95% (n=20/21) were resistant to nevirapine. Virus from subjects experiencing virologic failure on EDURANT developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class compared to virus from subjects who failed on efavirenz.
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