RUKOBIA Extended-release tablet Ref.[10095] Active ingredients: Fostemsavir

Cardiac Electrophysiology

At therapeutic doses, RUKOBIA does not prolong the QT interval to any clinically relevant extent. At 4 times the recommended dose, the mean (upper 90% confidence interval) QTcF increase was 11.2 milliseconds (13.3 milliseconds). The observed increase in QTcF was temsavir concentration-dependent [see Warnings and Precautions (5.2)].

Exposure-Response Relationship

In the Phase 3 trial evaluating the recommended dosing regimen of RUKOBIA (600 mg twice daily) in subjects with multidrug resistant HIV-1 infection on their failing regimen, no relationship was observed between plasma temsavir C_trough and change in plasma HIV-1 RNA from Day 1 to Day 8.

Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed (Table 4). Following oral administration, increases in plasma temsavir exposure (C_max and AUC_tau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV‑1–infected subjects.

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of temsavir following administration of RUKOBIA are provided in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5.

Table 4. Pharmacokinetic Properties of Temsavir:

HSA = Human Serum Albumin; UGT = Uridine diphosphate glucuronosyl transferases.
^a Dosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [¹³C] temsavir 100 mcg.
^b Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. High-calorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein.
^c Volume of distribution at steady state (Vss) following IV administration.
^d Apparent clearance.
^e In vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite).
^f Dosing in mass balance study: single-dose administration of [¹⁴C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity.

Table 5. Multiple-Dose Pharmacokinetic Parameters of Temsavir:

CV = Coefficient of Variation; C_max = Maximum concentration; AUC = Area under the time concentration curve; C₁₂ = Concentration at 12 hours.
^a Based on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of RUKOBIA twice daily with or without food in combination with other antiretroviral drugs.

Specific Populations

No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (white, black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown.

The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older.

Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with RUKOBIA indicated age had no clinically relevant effect on the pharmacokinetics of temsavir [see Use in Specific Populations (8.4, 8.5)].

Patients with Renal Impairment

No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe renal impairment. No clinically relevant differences in temsavir pharmacokinetics were observed in patients with end-stage renal disease (ESRD) on hemodialysis compared with the same patients with ESRD off hemodialysis. Temsavir was not readily cleared by hemodialysis with approximately 12.3% of the administered dose removed during the 4-hour hemodialysis session [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C) [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir.

Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites (Table 4) are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP [see Drug Interactions (7.3)].

At clinically relevant concentrations, significant interactions are not expected when RUKOBIA is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results (Table 6).

Drug interaction studies were performed with RUKOBIA and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 6 and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 7.

Dosing recommendations as a result of established and other potentially significant drug-drug interactions with RUKOBIA are provided in Table 3 [see Drug Interactions (7.3)].

Table 6. Effect of Fostemsavir^a on the Pharmacokinetics of Coadministered Drugs:

CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.
AUC = AUC_tau for repeat-dose studies and AUC_(0-inf) for single-dose study.
^a Temsavir is the active moiety.

Table 7. Effect of Coadministered Drugs on the Pharmacokinetics of Temsavir^a Following Coadministration with Fostemsavir:

CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.
AUC = AUC_tau for repeat-dose studies and AUC_(0-inf) for single-dose study.
C_tau = C₁₂ for single-dose study.
^a Temsavir is the active moiety.

Mechanism of Action

Fostemsavir is a prodrug without significant biochemical or antiviral activity that is hydrolyzed to the active moiety, temsavir, which is an HIV-1 attachment inhibitor. Temsavir binds directly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and cellular CD4 receptors, thereby preventing attachment. Additionally, temsavir can inhibit gp120-dependent post-attachment steps required for viral entry into host cells. Temsavir inhibited the binding of soluble CD4 to surface immobilized gp120 with an IC₅₀ value of 14 nM using an enzyme-linked immunosorbent assay (ELISA).

Antiviral Activity in Cell Culture

Temsavir exhibited antiviral activity against 3 CCR5-tropic laboratory strains of subtype B HIV‑1, with EC₅₀ values ranging from 0.4 to 1.7 nM. The range of susceptibility to temsavir was broader for CXCR4-tropic laboratory strains with 2 strains having EC₅₀ values of 0.7 and 2.2 nM and 3 strains having EC₅₀ values of 14.8, 16.2, and >2,000 nM. Antiviral activity of temsavir against HIV-1 subtype B clinical isolates varied depending on tropism with median EC₅₀ values against the CCR5-tropic viruses, CXCR4-tropic viruses, and dual/mixed viruses of 3.7 nM (n=9; range: 0.3 to 345 nM), 40.9 nM (n=4; range: 0.6 to >2,000 nM), and 0.8 nM (n=2; range: 0.3 to 1.3), respectively, showing a broad range of EC₅₀ values for temsavir across the different tropic strains.

Analysis of data from 1,337 clinical samples from the fostemsavir clinical development program (881 subtype B samples, 156 subtype C samples, 43 subtype A samples, 17 subtype A1 samples, 48 subtype F1 samples, 29 subtype BF1 samples, 19 subtype BF samples, 5 CRF01_AE samples, and 139 other) showed temsavir susceptibility is highly variable across subtypes with a wide range in EC₅₀ values from 0.018 nM to >5,000 nM. The majority of subtype B isolates (84%, 740/881) had EC₅₀ values below 10 nM, with 6% of isolates having EC₅₀ values >100 nM. Of all isolates from all subtypes tested, 9% exhibited EC₅₀ values >100 nM. Subtypes BF, F1 and BF1 had higher proportions (21% to 38%) of isolates with EC₅₀ values >100 nM, and all 5 of 5 subtype AE isolates had EC₅₀ values >100 nM. From an additional panel of clinical isolates with non-B subtypes, temsavir EC₅₀ values were greater than the upper limits of the concentrations tested (>1,800 nM) in all subtype E (AE; 3 of 3), Group O (2 of 2), and HIV-2 (1 of 1) isolates, and some subtype D (1 of 4) and subtype G (1 of 3) isolates.

Reduced Antiviral Activity against Subtype AE

Temsavir showed reduced antiviral activity against 14 different subtype AE isolates in peripheral blood mononuclear cell (PBMC) assays and the Phenosense Entry assay indicating that subtype AE (or E) viruses are inherently less sensitive to temsavir. Genotyping of subtype AE viruses identified polymorphisms at amino acid positions S375H and M475I in gp120, which have been associated with reduced susceptibility to fostemsavir. Subtype AE is a predominant subtype in Southeast Asia, but it is not found in high frequencies elsewhere throughout the world.

There were 2 subjects with subtype AE virus at screening in the randomized cohort of the clinical trial. One subject (EC₅₀ fold change >4,747-fold and gp120 substitutions at S375H and M475I at baseline) did not respond to RUKOBIA at Day 8. A second subject (EC₅₀ fold change 298-fold and gp120 substitution at S375N at baseline) received placebo during functional monotherapy. Both subjects were virologically suppressed at Week 96 while receiving OBT (with dolutegravir) plus RUKOBIA.

Antiviral Activity in Combination with Other Antiviral Agents

The antiviral activity of temsavir was not antagonistic in cell culture when combined with the CD4-directed post-attachment HIV-1 inhibitor ibalizumab, the CCR5 co-receptor antagonist maraviroc, the gp41 fusion inhibitor enfuvirtide, integrase strand transfer inhibitors (INSTIs) (dolutegravir, raltegravir), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine, rilpivirine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), or protease inhibitors (PIs) (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir). In addition, temsavir antiviral activity was not antagonistic in cell culture with the anti-HBV drug entecavir and the anti-HCV drug ribavirin.

Resistance in Cell Culture

HIV-1 variants with reduced susceptibility to temsavir were selected following 14 to 49 days passage in cell culture of NL4-3, LAI, and BaL viruses in a T-cell line. Selected viruses exhibited 18- to 159-fold decreased temsavir susceptibility and genotypic analysis identified the following emerging amino acid substitutions in gp120: L116P/Q, L175P, A204D, V255I, A281V, M426L, M434I, and M475I (S375 substitutions were identified based on in vivo data with a related attachment inhibitor). In general, most substitutions mapped to the conserved regions (C1, C2, C4, and C5) of the gp120 envelope, confirming temsavir targets the viral envelope protein during infection.

Single-substitution recombinant viruses at these amino acid positions were engineered into the HIV-1 LAI viral background and the resultant recombinants demonstrated reduced susceptibility to temsavir (L116P [>340-fold], A204D [>340-fold], S375M [47-fold], S375V [5.5-fold], S375Y [>10,000-fold], M426L [81-fold], M426V [3.3-fold], M434I [11-fold], M434T [15-fold], M475I [5-fold], M475L [17-fold], and M475V [9.5-fold]).

Temsavir remained active against laboratory-derived CD4-independent viruses and temsavir-resistant viruses showed no evidence of a CD4-independent phenotype. Therefore, treatment with RUKOBIA is unlikely to promote resistance to temsavir via generation of CD4-independent virus.

Response at Day 8 by Genotype

The effect of the gp120 resistance-associated polymorphisms (RAPs) on response to fostemsavir functional monotherapy at Day 8 was assessed in an as-treated analysis by censoring the subjects who had a >0.4 log₁₀ decline in HIV-1 RNA from screening to baseline or <400 copies/mL at screening (n=47 subjects were censored). The presence of gp120 RAPs at key sites S375, M426, M434, or M475 was associated with a lower overall decline in HIV-1 RNA and fewer subjects achieving >0.5 log₁₀ decline in HIV-1 RNA compared with subjects with no changes at these sites (Table 8). However, the presence of the gp120 RAPs did not preclude some subjects from achieving a response of >0.5 log₁₀ copies/mL at Day 8. Baseline gp120 RAPs most associated with decreased response of <0.5 log₁₀ copies/mL at Day 8 were S375M, M426L, and M475V (Table 8). There was no difference in response rates and median decline in viral load for subjects with more than one gp120 RAP.

Table 8. Outcome of Randomized Fostemsavir Cohort by Presence of Screening gp120 RAPs (As-Treated Analysis^a):

^a Removed subjects who had <400 copies/mL at screening or >0.4 log₁₀ decline from screening to baseline.

Response at Day 8 by Phenotype

The fold change in susceptibility to temsavir for subject isolates at screening was highly variable ranging from 0.06 to 6,651. The effect of screening fostemsavir phenotype on response of >0.5 log₁₀ decline at Day 8 was assessed in the as-treated analysis. The majority of these subjects (55%, 83/151) had a screening temsavir EC₅₀ fold change normalized to a reference virus of <2‑fold. The response rate for fostemsavir phenotypes ≤2 was 80% (66/83) (Table 9). Response rates for fostemsavir phenotypic fold changes of >2 to 200 were moderately decreased to 69% (29/42). Phenotypic fold changes of >200 resulted in lower response rates to fostemsavir (29%, 5/17). Five subjects, despite having >200-fold decreased fostemsavir susceptibility and the presence of screening gp120 RAPs, had over 1 log₁₀ declines in HIV-1 RNA at Day 8. Lack of resistance to background drugs or higher fostemsavir concentrations do not explain the >1 log₁₀ response of these 5 subjects.

Table 9. Response Rate of Randomized Fostemsavir Cohort (>0.5 Log₁₀ Decline Day 8) by Screening Phenotype:

^a Removed subjects who had <400 copies/mL at screening or >0.4 log₁₀ decline from screening to baseline.

Resistance in Clinical Subjects

The percentage of subjects who experienced virologic failure through the Week 96 analysis was 25% (69/272) in the randomized cohort (including 25% [51/203] among subjects who received blinded fostemsavir functional monotherapy and 26% [18/69] among subjects who received blinded placebo during the 8‑day double-blind period) (Table 10). Virologic failure = confirmed ≥400 copies/mL after prior confirmed suppression to <400 copies/mL, ≥400 copies/mL at last available prior to discontinuation, or >1 log₁₀ copies/mL increase in HIV‑1 RNA at any time above nadir level (≥40 copies/mL). Overall, 51% (27/53) of evaluable subjects with virologic failure in the randomized cohorts had treatment-emergent gp120 genotypic substitutions at 4 key sites (S375, M426, M434, and M475) (Table 10).

The median temsavir EC₅₀ fold change at failure in randomized evaluable subject isolates with emergent gp120 substitutions at positions 375, 426, 434, or 475 (n=26) was 1,755-fold. In randomized evaluable subject isolates with no emergent gp120 substitutions at those positions (n=27), the median temsavir EC₅₀ fold change at failure was 3.6-fold.

Thirty percent (21/69) of the virologic failures in the randomized groups combined had genotypic or phenotypic resistance to at least one drug in the OBT at screening, and 48% (31/64) of the virologic failures with post-baseline data had emergent resistance to at least one drug in the OBT.

Rates of virologic failure were higher in the nonrandomized cohort at 51% (50/99) (Table 10). While the proportion of virologic failures with gp120 RAPs at screening was similar between subjects in the randomized and nonrandomized cohorts, the proportion of subjects with emergent gp120 resistance-associated substitutions at the time of failure was higher among nonrandomized subjects (Table 10). The median temsavir EC₅₀ fold change at failure in nonrandomized evaluable subject isolates with emergent substitutions at positions 375, 426, 434, or 475 (n=33) was 4,216-fold and was 767-fold among failure subject isolates without emergent resistance-associated substitutions (n=12). Consistent with the nonrandomized group of subjects having fewer antiretroviral options, 90% (45/50) of the virologic failures in this group had genotypic or phenotypic resistance to at least one drug in the OBT at screening, and 55% (27/49) of the virologic failures with post-baseline data in the nonrandomized group had emergent resistance to at least one drug in the OBT.

Table 10. Virologic Failures in BRIGHTE Trial:

RAPs = Resistance-associated polymorphisms; RAS = Resistance-associated substitutions.

Cross-Resistance

Both the CD4-directed post-attachment inhibitor ibalizumab and the gp120-directed attachment inhibitor fostemsavir develop resistance in gp120. Five of 7 viruses resistant to ibalizumab retained susceptibility to temsavir while the other 2 viruses had reduced susceptibility to both temsavir (>1,400-fold decreased susceptibility) and ibaluzimab. Resistance to the CCR5 coreceptor antagonist maraviroc can also develop in the gp120 envelope. Some CCR5-tropic maraviroc-resistant viruses showed reduced susceptibility to temsavir. Viruses resistant to the gp41 fusion inhibitor enfuvirtide retained susceptibility to temsavir.

Temsavir retained wild-type activity against viruses resistant to the INSTI raltegravir; the NNRTI rilpivirine; the NRTIs abacavir, lamivudine, tenofovir, zidovudine; and the PIs atazanavir and darunavir.

Additionally, ibalizumab, maraviroc, enfuvirtide, the INSTI raltegravir, NNRTIs (efavirenz, rilpivirine), NRTIs (abacavir, tenofovir), and PIs (atazanavir, darunavir) retained activity against site-directed mutants with reduced temsavir susceptibility (S375M, M426L, or M426L plus M475I) or against clinical envelopes that had decreased baseline susceptibility to temsavir.

Carcinogenesis

In a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in transgenic mice, fostemsavir produced no statistically significant increases in tumors over controls. The maximum daily exposures in rats were approximately 5 times (males) and 16 times (females) greater than those in humans at the MRHD.

Mutagenesis

Fostemsavir was not genotoxic in the bacterial reverse mutation assay (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes, and rat bone marrow micronucleus test.

Impairment of Fertility

Oral administration of fostemsavir had no adverse effects on male or female fertility in rats at exposures approximately 10 times (males) and 186 times (females) of those in humans at the MRHD. At higher exposures (>80 times those in humans at the MRHD) in male rats, decreases in prostate gland/seminal vesicle weights, sperm density/motility, and increased abnormal sperm were observed.

The efficacy of RUKOBIA in heavily treatment-experienced adult subjects with HIV-1 infection is based on 96-week data from a Phase 3, partially-randomized, international, double-blind, placebo-controlled trial (BRIGHTE [NCT02362503]).

The BRIGHTE trial was conducted in 371 heavily treatment-experienced subjects with multi-class HIV-1 resistance. All subjects were required to have a viral load ≥400 copies/mL and ≤2 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, contraindication, or other safety concerns. Subjects were enrolled in either a randomized or nonrandomized cohort defined as follows:

• Within the randomized cohort (n=272), subjects had 1, but no more than 2, fully active and available antiretroviral agent(s) at screening which could be combined as part of an efficacious background regimen. Randomized subjects received either blinded RUKOBIA 600 mg twice daily (n=203) or placebo (n=69) in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, randomized subjects received open-label RUKOBIA 600 mg twice daily plus an investigator-selected OBT. This cohort provides primary evidence of efficacy of RUKOBIA.
• Within the nonrandomized cohort (n=99), subjects had no fully active and approved antiretroviral agent(s) available at screening. Nonrandomized subjects were treated with open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward. The use of an investigational drug(s) as a component of the OBT was permitted in the nonrandomized cohort.

Overall, the majority of subjects were male (78%), white (70%), and the median age was 49 years (range: 17 to 73 years). At baseline, the median HIV-1 RNA was 4.6 log₁₀ copies/mL and the median CD4+ cell count was 80 cells/mm³ (100 and 41 cells/mm³ for randomized and nonrandomized subjects, respectively). Seventy-five percent (75%) of all treated subjects had a CD4+ cell count <200 cells/mm³ at baseline (with 30% <20 cells/mm³). Overall, 86% had a history of Acquired Immune Deficiency Syndrome (AIDS) and 8% had a history of hepatitis B and/or C virus co-infection at baseline. Seventy one percent (71%) of subjects had been treated for HIV for >15 years; 85% had been exposed to ≥5 different HIV treatment regimens upon entry into the trial.

Fifty-two percent (52%) of subjects in the randomized cohort had 1 fully active agent within their initial failing background regimen, 42% had 2, and 6% had no fully active agent. Within the nonrandomized cohort, 81% of subjects had no fully active agent(s) in their original regimen and 19% had 1 fully active agent, including 15% (n=15) who received ibalizumab, which was an investigational agent at the time of the BRIGHTE trial start-up.

Randomized Cohort

The primary efficacy endpoint was the adjusted mean decline in HIV-1 RNA from Day 1 to Day 8 with RUKOBIA versus placebo in the randomized cohort. The results of the primary endpoint analysis demonstrated superiority of RUKOBIA compared with placebo, as shown in Table 11.

Table 11. Plasma HIV-1 RNA Log₁₀ (copies/mL) Change from Day 1 to Day 8 (Randomized Cohort) in BRIGHTE Trial – ITT-E Population:

^a Two subjects who received RUKOBIA with missing Day 1 HIV-1 RNA values were not included in the analysis.
^b Mean adjusted by Day 1 log₁₀ HIV-1 RNA.
^c Difference: RUKOBIA minus placebo.
^d P-value <0.0001 for the adjusted and unadjusted mean difference of viral load change from baseline for RUKOBIA compared with placebo.

At Day 8, 65% (131/203) and 46% (93/203) of subjects who received RUKOBIA had a reduction in viral load from baseline >0.5 log₁₀ copies/mL and >1 log₁₀ copies/mL, respectively, compared with 19% (13/69) and 10% (7/69) of subjects, respectively, in the placebo group.

By subgroup analysis, randomized subjects who received RUKOBIA with baseline HIV‑1 RNA >1,000 copies/mL achieved a mean decline in viral load of 0.86 log₁₀ copies/mL at Day 8 compared with 0.20 log₁₀ copies/mL in subjects treated with blinded placebo. Subjects with baseline HIV‑1 RNA ≤1,000 copies/mL achieved a mean decline in viral load of 0.22 log₁₀ copies/mL at Day 8 compared with a mean increase of 0.10 log₁₀ copies/mL in subjects treated with blinded placebo.

Virologic outcomes by ITT-E Snapshot Analysis at Weeks 24 and 96 in the BRIGHTE trial are shown in Table 12 and Table 13 for the randomized cohort. There was considerable variability in the number of antiretrovirals (fully active and otherwise) included in OBT regimens. The majority of subjects (84%) received dolutegravir as a component of OBT, of which approximately half (51% overall) also received darunavir with ritonavir or cobicistat. Virologic outcomes by ITT-E Snapshot Analysis at Week 48 were consistent with those observed at Week 24.

Table 12. Virologic Outcomes (HIV-1 RNA <40 copies/mL) at Weeks 24 and 96 with RUKOBIA (600 mg Twice Daily) plus OBT (Randomized Cohort) in BRIGHTE Trial (ITT-E Population, Snapshot Algorithm):

Table 13. Virologic Outcomes (HIV-1 RNA <40 copies/mL) by Baseline Covariates at Weeks 24 and 96 with RUKOBIA (600 mg Twice Daily) plus OBT (Randomized Cohort) in BRIGHTE Trial (ITT-E Population, Snapshot Algorithm):

DTG = Dolutegravir, DRV = Darunavir.
^a Includes subjects who never initiated OBT, were incorrectly assigned to the randomized cohort, or had 1 or more active antiretroviral agents available at screening but did not use these as part of the initial OBT.
^b Darunavir was coadministered with ritonavir or cobicistat.

In the randomized cohort, HIV-1 RNA <200 copies/mL was achieved in 68% and 64% of subjects at Weeks 24 and 96, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 90 cells/mm³ at Week 24 and 205 cells/mm³ at Week 96. Based on a sub-analysis in the randomized cohort, subjects with the lowest baseline CD4+ cell counts (<20 cells/mm³) had a similar increase in CD4+ cell count over time compared with subjects with higher baseline CD4+ cell count (>200 to <500 cells/mm³).

Nonrandomized Cohort

In the nonrandomized cohort, HIV-1 RNA <40 copies/mL was achieved in 37% of subjects at Weeks 24 and 96. At these timepoints, the proportion of subjects with HIV-1 RNA <200 copies/mL was 42% and 39%, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 41 cells/mm³ at Week 24 and 119 cells/mm³ at Week 96.