Cabenuva: Package Insert and Label Information (Page 5 of 7)
12.4 Microbiology
Mechanism of Action
Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration that is essential for the HIV replication cycle. The mean 50% inhibitory concentration (IC50 ) value of cabotegravir in a strand transfer assay using purified recombinant HIV-1 integrase was 3.0 nM.
Rilpivirine is a diarylpyrimidine NNRTI of 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
Cabotegravir exhibited antiviral activity against laboratory strains of HIV-1 (subtype B, n = 4) with mean 50 percent effective concentration (EC50 ) values of 0.22 to 1.7 nM in peripheral blood mononuclear cells (PBMCs) and 293 cells. Cabotegravir demonstrated antiviral activity in PBMCs against a panel of 24 HIV-1 clinical isolates (3 in each of group M subtypes A, B, C, D, E, F, and G and 3 in group O) with a median EC50 value of 0.19 nM (range: 0.02 to 1.06 nM, n = 24). The median EC50 value against subtype B clinical isolates was 0.05 nM (range: 0.02 to 0.50 nM, n = 3). Against clinical HIV-2 isolates, the median EC50 value was 0.12 nM (range: 0.10 to 0.14 nM, n = 3).
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 antiviral activity against a broad panel of HIV-1 group M (subtypes A, B, C, D, F, G, and H) primary isolates with EC50 values ranging from 0.07 nM 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 nM to 8.45 nM (1.06 to 3.10 ng/mL).
In cell culture, cabotegravir was not antagonistic in combination with the NNRTI rilpivirine, or the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC), lamivudine (3TC), or tenofovir disoproxil fumarate (TDF).
The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine, or nevirapine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine; the protease inhibitors amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the INSTI raltegravir.
Resistance
Cell Culture: Cabotegravir-resistant viruses were selected during passage of HIV-1 strain IIIB in MT-2 cells in the presence of cabotegravir. Amino acid substitutions in integrase that emerged and conferred decreased susceptibility to cabotegravir included Q146L (fold change: 1.3 to 4.6), S153Y (fold change: 2.8 to 8.4), and I162M (fold change: 2.8). The integrase substitution T124A also emerged alone (fold change: 1.1 to 7.4 in cabotegravir susceptibility), in combination with S153Y (fold change: 3.6 to 6.6 in cabotegravir susceptibility) or I162M (2.8-fold change in cabotegravir susceptibility). Cell culture passage of virus harboring integrase substitutions Q148H, Q148K, or Q148R selected for additional substitutions (C56S, V72I, L74M, V75A, T122N, E138K, G140S, G149A, and M154I), with substituted viruses having reduced susceptibility to cabotegravir of 2.0- to 410-fold change. The combinations of E138K+Q148K and V72I+E138K+Q148K conferred the greatest reductions of 53- to 260‑fold change and 410-fold change, respectively.
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.
Clinical Trials: In the pooled Phase 3 FLAIR (Week 124) and ATLAS (Week 96) analysis, there were 8 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) on cabotegravir plus rilpivirine (8/591, 1.4%) and 8 confirmed virologic failures on current antiretroviral regimen (8/591, 1.4%). Of the 8 confirmed virologic failures in the cabotegravir plus rilpivirine arm, 7 (88%) had treatment-emergent NNRTI resistance-associated substitutions K101E, V106V/A, V108I, E138A, E138G, E138K, H221H/L, or M230L in reverse transcriptase, and 6 of them showed reduced phenotypic susceptibility to rilpivirine (range: 2- to 27-fold). One additional subject in the ATLAS Extension Switch on cabotegravir plus rilpivirine had emergent NNRTI resistance substitution E138A at Week 80 with HIV-1 RNA >50 copies/mL and <200 copies/mL.
Additionally, 5 of the 8 (63%) cabotegravir plus rilpivirine confirmed virologic failures had treatment-emergent INSTI resistance-associated substitutions and reduced phenotypic susceptibility to cabotegravir: Q148R (n = 2; 5- and 9-fold decreased susceptibility to cabotegravir), G140R (n = 1; 7-fold decreased susceptibility to cabotegravir), N155H (n = 1; 3‑fold decreased susceptibility to cabotegravir), or N155H+R263K (n = 1; 9-fold decreased susceptibility to cabotegravir).
There was another confirmed virologic failure subject at Week 112 in FLAIR who had switched to cabotegravir plus rilpivirine direct to injection at Week 100; there were no INSTI resistance‑associated substitutions detected at failure.
In comparison, in the current antiretroviral regimen arm with 8 confirmed virologic failures, 2 of 7 (29%) who had post-baseline resistance data had treatment-emergent resistance substitutions and phenotypic resistance to their antiretroviral drugs; both had treatment-emergent NRTI substitutions, M184V or I, which conferred resistance to emtricitabine or lamivudine in their regimen, and one of them also had the treatment-emergent NNRTI resistance substitution G190S, which conferred resistance to efavirenz in their regimen.
In the ATLAS-2M trial, there were 11 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) through Week 48: 9 subjects (1.7%) in the every-2-month treatment arm and 2 subjects (0.4%) in the monthly treatment arm. Of note, 8 of the 11 (73%) subjects met confirmed virologic failure criteria at or before the Week 24 injection visit.
Four of the 9 confirmed virologic failure subjects in the every-2-month arm transitioned from the oral current antiretroviral regimen arm of ATLAS into this trial.
In the every-2-month treatment arm, 8 of 9 (89%) confirmed virologic failure subjects had NNRTI resistance-associated substitutions (E138E/K+V179V/I, K101E+E138A, A98G+K103N, E138K, V179I+Y188L+P225H, Y188L, K103N+E138A, or K101E) at virologic failure. Decreases in rilpivirine susceptibility for these 8 subject isolates ranged from 2- to 30-fold. Six of the 8 subjects with NNRTI resistance-associated substitutions also had INSTI resistance-associated substitutions (L74I+Q148Q/R+N155N/H (n = 2), L74I+T97A+N155H, L74I+N155H, N155H, or L74I+Q148R) at failure with cabotegravir fold changes ranging from 1- to 9-fold. The INSTI polymorphism L74I was detected at baseline in 5 of the virologic failure subjects by a HIV-1 proviral DNA assay.
In the monthly treatment arm, both of the confirmed virologic failure subjects had NNRTI resistance-associated substitutions (K101E+M230L or Y188F+G190Q) at virologic failure with decreased susceptibility to rilpivirine of 17- and >119.2-fold, respectively. Both subjects also had INSTI resistance-associated substitutions (N155N/H or Q148R+E138E/K) at failure with decreased susceptibility to cabotegravir of 2- and 5-fold, respectively. Neither subject had the L74I integrase polymorphism at baseline.
Genotypic Baseline Factors Associated with Virologic Failure
An increased risk of cabotegravir plus rilpivirine confirmed virologic failure is associated with baseline virological factors: HIV-1 subtype A1, the presence of baseline integrase L74I polymorphism, and archived NNRTI resistance-associated substitutions.
Association of Subtype A1 and Baseline L74I Polymorphism in Integrase with Cabotegravir plus Rilpivirine Virologic Failure
Eight of the 18 (44%) cabotegravir plus rilpivirine confirmed virologic failures in FLAIR, ATLAS, and ATLAS-2M had HIV‑1 subtype A1 with 7 of the 8 subtype A1 failures having the integrase polymorphism L74I detected at baseline and failure timepoints (Table 16). There was no detectable phenotypic resistance to cabotegravir conferred by the presence of L74I at baseline. Subtype A1 is uncommon in the U.S.
The presence of the integrase polymorphism L74I in subtype B commonly seen in the U.S. was not associated with virologic failure. In contrast to FLAIR and ATLAS, where all virologic failures were subtype A, A1, or AG, subtypes of the cabotegravir plus rilpivirine virologic failures in ATLAS-2M included A (n = 1), A1 (n = 3), B (n = 4), C (n = 2), and complex/A1 (n = 1).
Association of Archived Baseline NNRTI Substitutions with Cabotegravir plus Rilpivirine Virologic Failure
The presence of archived NNRTI resistance-associated substitutions at baseline detected using an exploratory HIV-1 proviral DNA assay was associated with a higher virologic failure rate in the every-2-month arm of ATLAS-2M and in the cabotegravir plus rilpivirine arm (monthly) of ATLAS compared to without archived NNRTI resistance-associated substitutions (Table 16). However, in clinical practice, it is unlikely baseline resistance testing will be performed on virologically suppressed patients (HIV-1 RNA <50 copies/mL). Thus, in patients with an incomplete or uncertain NNRTI treatment history, consideration should be given before starting cabotegravir plus rilpivirine treatment.
Table 16. Rate of Confirmed Virologic Failure in FLAIR, ATLAS, and ATLAS-2M: Baselinea Analysis (Subtype Al, Presence of lntegrase Polymorphism L74I, and Presence of Archived NNRTI Resistance-Associated Substitutions
| NNRTI = Non-Nucleoside Reverse Transcriptase Inhibitor, CAB+RPV = Cabotegravir + Rilpivirine, CAR = Current Antiretroviral Regimen, RAS = resistance-associated substitutions, NA = Not available.a Baseline and/or Screening result used.b Per Standard Monogram Nomenclature Reports. Based on June 2020 Los Alamos National Library panel, the majority of HIV-1 subtype A1 was reclassified as HIV-1 subtype A6.c L74I and L74L/I mixture.d Baseline/Screening NNRTI substitutions at L100, K101, K103, V106, V108, E138, V179, Y181, Y188, G190, H221, P225, M230. | ||||||
| FLAIR CAB+RPV N = 283 | FLAIR CAR N = 283 | ATLAS CAB+RPV N = 308 | ATLAS CAR N = 308 | ATLAS-2M Q4W N = 523 | ATLAS-2M Q8W N = 522 | |
| Total confirmed virologic failures | 5 | 4 | 3 | 4 | 2 | 9 |
| Subtype A1b | 4/8 (50%) | 1/4 (25%) | 1/17 (6%) | 0/21 (0%) | 0/30 (0%) | 4/31 (13%) |
| 4/5 (80%) | 1/3 (33%) | 1/16 (6%) | 0/19 (0%) | 2/28 (0%) | 3/26 (12%) |
| 0/3 (0%) | 0/1 (0%) | 0/1 (0%) | 0/2 (0%) | 0/2 (0%) | 1/5 (20%) |
| Other subtypes | 2/268(0.7%) | 3/272(1%) | 2/240(0.8%) | 4/252(1.6%) | 2/409(0.5%) | 5/415(1.2%) |
| 0/49 (0%) | 1/43 (2.3%) | 1/29 (3%) | 1/39 (2.6%) | 0/42 (0%) | 2/48 (4%) |
| 0/219(2.5%) | 2/229(0.9%) | 1/211(0.5%) | 3/213(1.4%) | 2/367(0.5%) | 3/367(0.8%) |
| Missing data | 7 | 7 | 51 | 35 | 84 | 76 |
| With NNRTI RASd | NA | NA | 3/78 (4%) | 2/83 (2%) | 1/128(0.8%) | 7/117 (6%) |
| Without NNRTI RAS | NA | NA | 0/179 (0%) | 2/190(1%) | 1/310(0.3%) | 2/327(0.6%) |
| Missing data | NA | NA | 51 | 35 | 84 | 76 |
Cross-Resistance
Virologic failure isolates from cabotegravir plus rilpivirine treatment in FLAIR, ATLAS, and ATLAS-2M exhibited cross-resistance to INSTIs and NNRTIs. All confirmed virologic isolates with genotypic evidence of cabotegravir resistance had cross-resistance to elvitegravir and raltegravir but retained phenotypic susceptibility to dolutegravir and when tested bictegravir. Virologic failure isolates with rilpivirine resistance had cross-resistance with NNRTIs delavirdine, doravirine, efavirenz, etravirine, and nevirapine.
Cabotegravir: Cross-resistance has been observed among INSTIs. Cabotegravir had reduced susceptibility (>5-fold change) to recombinant HIV-1 strain NL432 viruses harboring the following integrase amino acid substitutions: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K/R, G140C+Q148R, G140S+Q148H/K/R, Y143H+N155H, and Q148R+N155H (range: 5.1- to 81-fold). The substitutions E138K+Q148K and Q148R+N155H conferred the greatest reductions in susceptibility of 81- and 61-fold, respectively.
Cabotegravir was active against viruses harboring the NNRTI substitutions K103N or Y188L, or the NRTI substitutions M184V, D67N/K70R/T215Y, or V75I/F77L/F116Y/Q151M.
Rilpivirine: Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-, 15-, and 12-times fold change to rilpivirine, respectively. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave 3.7- to 554-fold change to rilpivirine in 38% and 66% of substitutions, respectively. 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 and P; E138A, G, K, R, and Q; V179L; Y181C, I, and V; Y188L; H221Y; F227C; M230I and L, and the combination of L100I/K103N.
DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.