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배경 Cabotegravir (CAB) + rilpivirine (RPV) is the first complete long-acting (LA) regimen approved and rec- ommended by treatment guidelines for the maintenance of virologic suppression in people living with HIV-1. To date, limited data are available for those who discontinued CAB+RPV LA and resumed daily oral antiretrovirals (ARVs). Here, we describe results for participants who discontinued CAB+RPV LA during the Phase III/IIIb program and entered 12-month (12M) long-term follow-up (LTFU). 방법 All participants exposed to CAB+RPV LA and discontinued from ATLAS, FLAIR, or ATLAS-2M were included. Demographics, reason(s) for discontinuing LA therapy, and efficacy/safety of subsequent ARV therapy are evaluated 결과 1723 unique participants were randomized across Phase III/IIIb studies, with 150 participants (n=138 from maintenance and extension and n=12 after switch in the extension phase) discontinuing CAB+RPV LA and entering LTFU. The median age in LTFU group was 38 years, 70% were white, and 30% female (Figure 1). Median duration of CAB+RPV LA treatment before discontinuing was 36.7 weeks (0.9-144 weeks). Reasons for entering LTFU included AEs, participant withdrawal, and lack of efficacy (Figure 2). Participants primarily switched to INSTI- (58%) or bPI- (21%) containing regimens; 82% of switches oc- curred within 4-8 weeks of CAB+RPV LA discontinuation. Of 150 entering LTFU, 92 completed M12, 4 withdrew, and 54 are ongoing. At M12, 97% (84/87) with viral load data maintained HIV-1 RNA <50 copies/ml. Thirteen (9%) participants reported drug-related AEs while on oral ARVs, with no AE-related discontinuations. 결론 Through up to 144 weeks, approximately 9% of study participants in Phase III/IIIb trials discontinued CAB+RPV LA and entered LTFU with the majority resuming an INSTI- or bPI-based oral regimen. High rates of suppression were maintained on subsequent ARV, with no efficacy or safety concerns in participants who switched to oral ARVs, regardless of reason for switch. [ABSTRACT FROM AUTHOR]

배경 Cabotegravir (CAB) and rilpivirine (RPV) is the first guideline-recommended complete long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. In Phase 3 studies, oral CAB+RPV given once daily was utilized as an oral lead-in (OLI) for ≥4 weeks prior to initiating LA dosing to assess in- dividual safety and tolerability. The FLAIR extension phase demonstrated that initiating CAB+RPV direct-to-injection (DTI) had comparable safety, tolerability, efficacy, and pharmacokinetics compared with initiating with an OLI, offering a practical treatment simplification strategy. This post hoc analysis com- pares the safety of CAB+RPV during the OLI to LA administration periods across the Phase 3 program. 방법 Week 48 data from participants naive to CAB+RPV in the FLAIR, ATLAS, and ATLAS-2M studies were pooled. Safety outcomes were summarized separately during OLI and LA periods for those randomized at baseline to CAB+RPV, and also for those switching from oral comparator to CAB+RPV (either via DTI or OLI) during the FLAIR extension phase (Week 100-Week 124). 결과 1245 participants were in cluded in the pooled population; 918 and 327 received CAB+RPV LA Q4W and Q8W following an OLI, respectively. Further, 232 FLAIR extension-switch participants received CAB+RPV LA Q4W, either DTI (n=111) or following an OLI (n=121). The OLI period was well tolerated, with few Grade 3/4 AEs (1%, n=15/1245), serious AEs (<1%, n=9/1245), or AEs leading to withdrawal (<1%, n=10/1245); after continuing to LA therapy, AE rates were comparable between participants electing to receive OLI or DTI (Figure). No drug hypersensitivity reactions or other serious AEs occurred during the 4-week OLI that prohibited transition to LA therapy. 결론 A 4-week OLI of CAB+RPV was well tolerated in >1200 participants across the Phase 3 program. The safety profile of CAB+RPV LA dosing was similar regardless of whether participants received OLI or proceeded DTI, supporting optional CAB+RPV DTI as a simplification strategy. Data included in this abstract have been previously presented in full at the 18th European AIDS Conference; October 27-30, 2021; Virtual & London, UK; Poster PE2/75. [ABSTRACT FROM AUTHOR]

배경 Cabotegravir (CAB) + rilpivirine (RPV) is the first guideline-recommended, complete long-acting (LA) injectable regimen for maintenance of HIV-1 virologic suppression. In a post-hoc, multivariable analysis, the presence of ≥2 of 3 baseline (BL) factors (archived RPV resistance-associated mutations [RAMs], HIV-1 subtype A6/A1, or BMI ≥30 kg/m2 ) modestly increased confirmed virologic failure (CVF) risk. Efficacy, safety, and pharmacokinetics of CAB+RPV by BL BMI category among Phase 3/3b trial participants through Week 48 (W48) were evaluated. 방법 Data were pooled from CAB+RPV-naive participants receiving every-4- or 8-week dosing (Q4W or Q8W) in the ATLAS, FLAIR, and ATLAS-2M studies. Baseline characteristics, HIV-1 RNA <50 and ≥50 copies/mL, CVF (2 consecutive HIV-1 RNA ≥200 copies/mL), injection site reaction adverse events (ISR AEs), and plasma CAB and RPV troughs were evaluated through W48 by lower or higher BMI category (<30 or ≥30 kg/m² ). 결과 Among 1245 CAB+RPV LA participants, 213 (17%) had a BL BMI ≥30 kg/m². At W48, 92% vs. 93% of participants with higher vs. lower BMI, respectively, had HIV-1 RNA <50 copies/mL. There were 8 vs. 5 CVFs in the higher vs. lower BMI group. All CVFs in the higher BMI group had at least one other BL risk factor (archived RPV RAMs [n=3], A6/A1 subtype [n=4], both [n=1]). No participant with higher BMI alone developed CVF at W48. Overall safety, including ISR AEs, was comparable between groups. CAB and RPV troughs remained above their respective PA-IC90 values regardless of BMI or dosing arm. 결론 CAB+RPV LA Q4W and Q8W maintained high virologic suppression rates through W48 in Phase 3/3b trials, regardless of BL BMI category. Injections were well-tolerated, with few ISR-related discontinuations. CAB+RPV offers a safe and effective long-acting treatment option in participants across a wide BMI range without need for daily oral dosing. [ABSTRACT FROM AUTHOR]

Background: The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at the time of patient randomisation.Methods: PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.Results: Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimus also prolonged median PFS in patients with PIK3CA H1047R (HR, 0.37) and E545K/E542K mutations (HR=0.30) with a similar magnitude.Conclusions: Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir (CAB) and rilpivirine (RPV) is the first complete long-acting (LA) regimen recommended by treatment guidelines to maintain HIV-1 virologic suppression. Dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) showed noninferior efficacy in Phase 3/3b trials. This post hoc analysis summarizes Asian participant (pt) outcomes through Week (W) 96. Methods: We pooled data from Asian pts naive to CAB+RPV (n=41) randomized to receive Q4W (n=24) or Q8W (n=17) dosing in Phase 3/3b FLAIR (NCT02938520) and ATLAS-2M (NCT03299049). The proportion of pts with HIV-1 RNA ≥50 and <50copies/mL (FDA Snapshot), incidence of confirmed virologic failure (CVF), adherence, and safety through W96 were assessed. Results: Median pt age was 39 years, 4 were female at birth, 1 had a body mass index ≥30 kg/m2; 0 were hepatitis B-reactive (non-reactive, n=12; negative, n=29). Pts enrolled at centers in Asia (59%, n=24), North America (27%, n=11), Europe (10%, n=4), Africa, and Australia (each 2%, n=1). At W96, 83% (n=34/41) of pts maintained HIV-1 RNA <50copies/mL, 0 had HIV-1 RNA ≥50copies/mL, and 17% (n=7/41) had no virologic data due to discontinuation. No pt met CVF criterion. 93% (n=38) of pts had non-injection site reaction [ISR] AEs; 95% (n=36/38) were Grade≤2, and 47% (n=18/38) were deemed drug-related. No pt had a Grade ≥3 drug-related AE. Serious AEs occurred in 12% (n=5/41) of pts. Most injection visits (97%, n=620/642) occurred within the ±7-day dosing window; one injection visit was missed and covered by oral CAB+RPV. The most common ISR was injection site pain (28% of injections, n=378/1360); all Grade≤2 with median 2-day duration. Pts withdrew due to drug-related non-ISR AEs (5%, n=2/41) and injection-related reasons (10%, n=4/41). Conclusion: CAB+RPV LA demonstrated high efficacy, with no pts having CVF, and acceptable safety in Asian pts through W96. These data support CAB+RPV LA as a complete regimen to maintain virologic suppression in Asian pts with HIV-1. [ABSTRACT FROM AUTHOR]

There is continued emphasis from the various worldwide regulatory agencies to ensure that the pharmaceutical industry fully understands the products they are developing. This emphasis is seen via development of quality-by-design (QbD) publications and guidelines generated by the International Committee on Harmonization. The challenge to meet these expectations is primarily associated with the generation of in vivo data (eg, pharmacokinetic data) that is resource intensive. A technique reducing the resources needed to generate this in vivo data permits a more extensive application of QbD principles. This paper presents the application of stable isotopes in pharmacokinetic studies. The data show that the use of stable isotopes can significantly reduce the number of subjects required for a study. This reduction in subjects thus translates into a significant reduction in resources and time needed to generate the required in vivo data to support QbD. [ABSTRACT FROM AUTHOR]