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Rashmi Mehta,1 Joseph Piscitelli,2 Allen Wolstenholme,3 Caifeng Fu,4 Herta Crauwels,5 Brian Wynne,6 Kimberly Adkison7 1GlaxoSmithKline, Research Triangle Park, NC, USA; 2UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA; 3GlaxoSmithKline, Collegeville, PA, USA; 4PAREXEL International, Durham, NC, USA; 5Janssen Pharmaceutical Companies, Beerse, Belgium; 6ViiV Healthcare, Collegeville, PA, USA; 7ViiV Healthcare, Research Triangle Park, NC, USACorrespondence: Kimberly AdkisonViiV Healthcare, 5 Moore Drive, Research Triangle Park, NC 27709, USATel +1 919 483-5867Email kim.k.adkison@viivhealthcare.comAbstract: Dolutegravir 50 mg (DTG) and rilpivirine 25 mg (RPV) are a newly approved 2-drug regimen for the treatment of HIV in virally suppressed patients. A 2-part study evaluated the relative bioavailability and food effect of five experimental fixed-dose combination (FDC) tablet formulations of DTG/RPV. When given with a moderate- or high-fat meal, the absorption of both DTG and RPV was increased, resulting in higher exposures. As per product labelling, DTG/RPV FDC should be taken with a meal.Keywords: food effect, pharmacokinetics, dolutegravir, rilpivirine

Background: Cabotegravir plus rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of human immunodeficiency virus-1 (HIV-1) virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among phase 3/3b trial participants., Methods: Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2M were pooled through week 48. Data beyond week 48 were summarized by study (FLAIR through week 96 and ATLAS-2M through week 152). HIV-1 RNA <50 and ≥50 copies/mL, confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥200 copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30 kg/m2, lower; ≥30 kg/m2, higher)., Results: Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30 kg/m2. At week 48, 92% versus 93% of participants with lower versus higher BMI had HIV-1 RNA <50 copies/mL, respectively. Including data beyond week 48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least 1 other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV-1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories., Conclusions: CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category., Clinical Trials Registration: NCT02938520, NCT02951052, and NCT03299049., Competing Interests: Potential conflicts of interest. E. R. E., J. W. P., P. P., R. D., and J. v. W. are employees of ViiV Healthcare and may be stockholders of GSK. L. G., R. G., V. B., J. R., and S. L. F. are employees and may be stockholders of GSK. S. B. currently performs services for GSK LLC, on behalf of ViiV Healthcare, in connection with the author’s statistical analysis support on the ATLAS-2M study. H. C., R. V. S.-R., E. B., and B. B. are employees of Janssen Research and Development, Pharmaceutical Companies of Johnson & Johnson and may be stockholders of Johnson & Johnson. R. V. S.-R. holds a patent for “Method of treating HIV with cabotegravir and rilpivirine.” All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long-acting (LA) with live births, are presented., Methods: Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare-sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post-last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians., Results: As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non-pregnant women., Conclusion: In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non-pregnant women. Pregnancy surveillance within ViiV Healthcare-sponsored clinical trials is ongoing, with dedicated pregnancy studies planned., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents., Methods: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m 2 ) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC 0-tau ) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment., Findings: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC 0-tau was 148·5 (range 37·2-433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22-6·19) and 1·15 μg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults., Interpretation: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg., Funding: The National Institutes of Health and ViiV Healthcare., Competing Interests: Declaration of interests BMB, KB, PS, AHG, MAM, KC, and PO received IMPAACT Network grant funding from the National Institutes of Health (NIH) to support work on this protocol. AHG and PO's institutions have Clinical Trials Agreements (CTAs) with ViiV Healthcare to support the IMPAACT 2017 study. AHG's institution has a CTA with Janssen to support COVID-19 research and AHG is part of the ViiV Healthcare Pediatric Advisory Board. BMB, KB, MAM, SW, and RM's institution receives funding from ViiV Healthcare. MAM is a consultant for Bio-rad and receives royalties from Elsevier; their institution receives funding from Gilead for industry-sponsored research and funding from the NIH for HIV prevention and microbicide-related research. BMB's institution receives grant funding from Janssen for the study. HC, RMVS-R, and KV are employees of Janssen and have stock and stock options with Johnson & Johnson. ALA received grants or contracts from Gilead, Merck, and ViiV; and is content development faculty for the Simply Speaking HIV Prevention Series, an expert witness, an unpaid Advocates for Youth Board Chair, and an unpaid HIVMA Vice Chair. AC-G is a ViiV Healthcare consultant. CM and CMH are employees at ViiV Healthcare. SLF and JH are employees at GSK. SLF and CM own GSK stock or stock options. EVC is a Data Safety and Management Board member for a paediatric antibacterial study with Melinta Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study., Methods: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m 2 and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had to be willing to continue their pre-study ART during cohort 1. The primary objectives of the study were to confirm doses for oral and injectable cabotegravir and for injectable rilpivirine in adolescents living with HIV. This analysis of participant-reported outcomes included a face scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL) at baseline and week 16 for participants in the USA, South Africa, Botswana, and Thailand. A subset of 11 adolescents and 11 parents or caregivers in the USA underwent in-depth interviews after receipt of one or two injections. This trial is registered at ClinicalTrials.gov, NCT03497676., Findings: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections., Interpretation: High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV., Funding: National Institutes of Health and ViiV Healthcare., Competing Interests: Declaration of interests KC, SB, and DEY received grant funding from the National Institutes of Health (NIH) to support work on this protocol. JC received support to travel and attend a meeting from the IMPAACT Network. AHG's institution has Clinical Trial agreements with ViiV to support work on this study and has a Clinical Trial agreement with Janssen to support other studies; and AHG received payment from ViiV Healthcare to attend a Pediatric Advisory Board meeting. KB, RM, and SW had funds paid to their institution by ViiV Healthcare related to their work on this manuscript. HC and RMVS-R are employees of Janssen and have stock and stock options with Johnson & Johnson. ALA is site principal investigator for multi-site Gilead and Merck studies, a Gilead expert advisory board attendee, a Merck consultant, expert advisory board attendee for ViiV, presenter at a workshop supported by ViiV, part of the Speaker's Bureau for the Simply Speaking HIV Prevention Series, an expert witness, an unpaid Advocates for Youth Board Chair, an unpaid member of the Well Project Board, and an unpaid HIVMA Vice Chair. AC-G is a ViiV Healthcare consultant and has received funds from Merck and Janssen. CCM, VC, and CH are employees at ViiV Healthcare. CCM and VC own GSK stock or stock options. DEY was previously an unpaid technical advisor for the following non-profit institutions: Cover the Globe and Maipelo Trust. JH is an employee at GSK. DEY is an employee of NIH. AA, AB, EDL, RO, CB-M, CS-A, BH, JK, and JDA declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three- or four-drug antiretroviral regimen (CAR) to the two-drug regimen of once-daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV-1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure-efficacy/safety relationships., Methods: Adults with plasma HIV-1 RNA <50 copies/mL were randomized to switch to once-daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV-1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure-response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme-inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated., Results: Although week 2 DTG and RPV C0 were lower in participants switching from enzyme-inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding-adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants., Conclusion: No clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: Cabotegravir + rilpivirine (CAB + RPV) dosed monthly or every 2 months is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virological suppression. This post hoc analysis summarizes outcomes for Asian participants through week 96., Methods: Data from Asian participants naive to CAB + RPV randomized to receive dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) in the FLAIR (NCT02938520) and ATLAS-2M (NCT03299049) phase 3/3b studies were pooled. The proportion of participants with plasma HIV-1 RNA ≥50 and <50 copies/mL (per FDA Snapshot algorithm), incidence of confirmed virological failure (CVF; two consecutive HIV-1 RNA ≥200 copies/mL), pharmacokinetics, safety, and tolerability through week 96 were assessed., Results: Overall, 41 Asian participants received CAB + RPV (Q8W, n = 17; Q4W, n = 24). At week 96, 83% (n = 34/41) of participants maintained HIV-1 RNA <50 copies/mL, none had HIV-1 RNA ≥50 copies/mL, and 17% (n = 7/41) had no virological data. No Asian participant met the CVF criterion. Drug-related adverse events occurred in 44% (n = 18/41) of participants; none were Grade ≥3. All injection site reactions were Grade 1 or 2; median duration was 2 days and most resolved within 7 days (90%, n = 390/435). CAB and RPV trough concentrations remained well above their respective protein-adjusted 90% inhibitory concentrations (CAB, 0.166 μg/mL; RPV, 12 ng/mL) through week 96., Conclusions: CAB + RPV LA demonstrated high efficacy, with no participants having CVF, and an acceptable safety profile in Asian participants through week 96. These data support CAB + RPV LA as a complete regimen for the maintenance of HIV-1 virological suppression in Asian individuals., (© 2023 ViiV Healthcare. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m 2 . One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration., Competing Interests: The authors declare a conflict of interest. K.H., C.L., R.D., and S.L.F. are employees and stockholders of GSK. B.W. is an employee of GSK and a stockholder of GSK and Haleon. H.G. reports no conflicts of interest. J.S.S. and H.C. are employees of Janssen Pharmaceuticals and H.C. is also a stockholder of Johnson and Johnson. G.B., V.C., C.S., R.D'.A., and W.R.S. are employees of ViiV Healthcare and stockholders of GSK.

Cabotegravir (CAB) and rilpivirine (RPV) is the first complete long-acting (LA) injectable regimen recommended by treatment guidelines for the maintenance of HIV-1 virologic suppression in people with HIV-1 who are virologically suppressed on a stable antiretroviral regimen that is administered monthly (Q1M) or every 2 months (Q2M). As an alternative regimen to lifelong daily oral antiretroviral therapy, Q1M or Q2M dosing schedules are associated with increased patient satisfaction and treatment preference. In addition, it may address challenges associated with daily oral dosing, including fear of treatment disclosure or stigma, anxiety related to oral dosing adherence, and the daily reminder of HIV disease status. Cabotegravir + RPV LA is administered by clinical staff as two intramuscular injections dosed Q1M or Q2M. In this review, we share practical dosing guidance for CAB+RPV LA injectable therapy, including how to initiate therapy, schedule injection visits, manage dosing interruptions due to missed or delayed injection visits, manage errors in dosing, and transition to alternative antiretroviral therapy after discontinuation. Practical guidance on the clinical management of CAB+RPV LA dosing, including a detailed discussion using case-based scenarios that may be encountered in clinical practice, is provided. The clinician-administered CAB+RPV LA regimen has dosing management considerations that are flexible and considerate of the patient and has the potential to provide a highly desirable and efficacious alternative to daily oral antiretroviral therapy for many people with HIV-1., (© The Author(s), 2023.)

Background: Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants., Methods: Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination)., Results: Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses., Conclusions: The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA., Competing Interests: Potential conflicts of interest . C. O. reports personal fees and grants from ViiV Healthcare, GSK, Gilead Sciences, MSD, and Janssen; grants from AstraZeneca; travel support from Gilead Sciences and ViiV Healthcare; and is the president of the Medical Women's Federation (UK) and a governing council member of the International AIDS Society. J. M. S. reports personal consulting fees, honoraria, travel support, participation on a Data Safety Monitoring or Advisory Board, and nonfinancial support from Gilead Sciences, Merck, ViiV Healthcare, Pfizer, Moderna, GSK, Teva, and AbbVie. C. F. P. reports consulting fees and payment or honoraria from Gilead Sciences, ViiV Healthcare, GSK, AstraZeneca, Janssen, and Merck; and participation on a Data Safety Monitoring or Advisory Board for ViiV Healthcare, Gilead Sciences, Merck, and Janssen. D. R. K. has received grants from ViiV Healthcare, Gilead Sciences, Merck, and the National Institutes of Health; reports payment for expert testimony from Gilead Sciences; consulting fees from Gilead Sciences, GSK, Janssen, AbbVie, Merck, and ViiV Healthcare; payment or honoraria from Gilead Sciences and Janssen; and participation on a Data Safety Monitoring or Advisory Board for GSK and ViiV Healthcare. P. P., Y. W., C. L. L., M. S. C., J. W. P., R. D’A., H. P. G., A. Z., W. R. S., J. v. W., and A. G. C. are employees of ViiV Healthcare and stockholders of GSK. R. D., D. D., K. H., and S. L. F. are employees and stockholders of GSK. H. C., S. V., and K. V. are employees and may be stockholders of Janssen, Pharmaceutical Companies of Johnson & Johnson. V. V. E. is an employee and may be a stockholder of Janssen, Pharmaceutical Companies of Johnson & Johnson, and has a pending patent for HIV infection treatment in children., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Long-acting (LA) intramuscular injections of cabotegravir (CAB) and rilpivirine (RPV) have been developed as an alternative to daily oral dosing for HIV-1. The Phase 3 FLAIR study (NCT02938520) demonstrated [...]

Background: Cabotegravir (CAB) + rilpivirine (RPV) dosed intramuscularly monthly or every 2 months is a complete, long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Here, we report the antiretroviral therapy as long acting suppression (ATLAS)-2M study week 152 results., Methods: ATLAS-2M is a phase 3b, randomized, multicenter study assessing the efficacy and safety of CAB+RPV LA every 8 weeks (Q8W) versus every 4 weeks (Q4W). Virologically suppressed (HIV-1 RNA <50 copies/mL) individuals were randomized to receive CAB+RPV LA Q8W or Q4W. Endpoints included the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL and <50 copies/mL, incidence of confirmed virologic failure (CVF; 2 consecutive measurements ≥200 copies/mL), safety, and tolerability., Results: A total of 1045 participants received CAB+RPV LA (Q8W, n = 522; Q4W, n = 523). CAB+RPV LA Q8W demonstrated noninferior efficacy versus Q4W dosing, with 2.7% (n = 14) and 1.0% (n = 5) of participants having HIV-1 RNA ≥50 copies/mL, respectively, with adjusted treatment difference being 1.7% (95% CI: 0.1-3.3%), meeting the 4% noninferiority threshold. At week 152, 87% of participants maintained HIV-1 RNA <50 copies/mL (Q8W, 87% [n = 456]; Q4W, 86% [n = 449]). Overall, 12 (2.3%) participants in the Q8W arm and 2 (0.4%) in the Q4W arm had CVF. Eight and 10 participants with CVF had treatment-emergent, resistance-associated mutations to RPV and integrase inhibitors, respectively. Safety profiles were comparable, with no new safety signals observed since week 48., Conclusions: These data demonstrate virologic suppression durability with CAB+RPV LA Q8W or Q4W for ∼3 years and confirm long-term efficacy, safety, and tolerability of CAB+RPV LA as a complete regimen to maintain HIV-1 virologic suppression., Competing Interests: Potential conflicts of interest. E. T. O. has received research support to their institution during the conduct of this study and has served as a consultant for Merck and ViiV Healthcare, outside of the submitted work. E. T. O. joined ViiV Healthcare after the conclusion of the week 152 analysis. G. Richmond received grants for clinical trials from Gilead, TaiMed, Insmed, and ViiV Healthcare, outside the submitted work. G. Rizzardini has received payment/honoraria from Gilead, GSK, MSD, and ViiV Healthcare, outside of the submitted work, and reports participation on a Data Safety Monitoring Board or Advisory Board for ViiV, GSK, and Gilead. A. T. has served as a consultant on advisory boards for GSK and received payment for presentations by GSK and ViiV Healthcare (Nordic countries), outside of the submitted work. S. N. reports consulting fees and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or education events from Gilead Sciences, MSD, Janssen, and ViiV Healthcare and support for attending meetings and/or travel from Gilead Sciences, Janssen, and ViiV Healthcare. N. P. reports payment of honoraria for educational events not related to this manuscript. A. W. reports grants and personal fees and honoraria for lectures and presentations from Gilead, Merck, and ViiV Healthcare, outside the submitted work. S. S. reports payments to their institution for clinical trial participation for the submitted work from ViiV Healthcare, salary support for research from the National Institutes of Health (NIH), and participation on a Data and Safety Monitoring Board for NIH. J. R. reports personal fees from Gilead (consulting and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), Janssen (payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), Merck (payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), Theratechnologies (payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), and ViiV Healthcare (consulting and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events) and support for attending meetings and/or travel from Gilead and Pfizer, outside of the submitted work. C. H., C. L., R. D., K. Y. S., C. A., and W. R. S. are employees of ViiV Healthcare and stockholders of GSK. K. Y. S. also reports a role as ViiV Employee-Head of Research and Development and as a member of the ViiV Leadership Team. C. M. E., A. A., Y. W., S. L. F., and S. T. are employees and stockholders of GSK. S. L. F. also reports that GSK provides support for travel and registration to conferences as relevant and a patent application with GSK (author is named as an inventor on the patent application for a Method of Treating HIV with Cabotegravir and Rilpivirine). S. T. also reports stocks in Haleon. H. C., V. v. E., R. V. S.-R., and K. V. are employees and stockholders of Janssen, Pharmaceutical Companies of Johnson & Johnson. V. v. E. also reports the following: the US application or Patent Cooperation Treaty international application number 62/870,413 filed on 3 July 2019 (TIP1068USPSP1 Methods of Treating HIV. The disclosure is directed to the use of rilpivirine, or a salt thereof, to treat HIV infections in pediatric subjects). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented., Methods and Design: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm). Endpoints assessed at W 96 included proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, incidence of confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/ml), safety and tolerability, pharmacokinetics, and patient-reported outcomes., Results: Most participants completing the Maintenance Phase transitioned to ATLAS-2M (88%, n = 502/572). Overall, 52 participants were included in the W 96 analysis of ATLAS; of these, 100% (n = 23/23) and 97% (n = 28/29) in the Long-acting and Switch arms had plasma HIV-1 RNA less than 50 copies/ml at W 96, respectively. One participant had plasma HIV-1 RNA 50 copies/ml or higher in the Switch arm (173 copies/ml). No participants met the CVF criterion during the Extension Phase. No new safety signals were identified. All Switch arm participants surveyed preferred long-acting therapy to their previous daily oral regimen (100%, n = 27/27)., Conclusion: In this subgroup of ATLAS, 98% (n = 51/52) of participants at the Extension Phase W 96 analysis maintained virologic suppression with long-acting therapy. Safety, efficacy, and participant preference results support the therapeutic potential of long-acting CAB+RPV treatment for virologically suppressed people living with HIV-1., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing., Methods: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing., Findings: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred., Interpretation: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1., Funding: ViiV Healthcare and Janssen., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean C max (144.3 ng/mL) and AUC inf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median t max and mean t 1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUC inf in Japanese subjects was within the range of AUC tau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients., Competing Interests: Declaration of competing interest This study was sponsored by Janssen Pharmaceutical K.K, Japan. Kentaro Ohta, Nobuko Matsushima and Hiromi Tanii are employees of Janssen Pharmaceutical K.K., Japan, and Herta Crauwels is an employee of Janssen Pharmaceutica NV, Belgium., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: Previous work established non-inferiority of switching participants who were virologically suppressed from daily oral standard of care to monthly long-acting intramuscular injections of cabotegravir plus rilpivirine over 96 weeks following a cabotegravir plus rilpivirine oral lead-in. Here, we report an evaluation of switching participants from standard of care oral regimens to long-acting cabotegravir plus rilpivirine via direct-to-injection or oral lead-in pathways., Methods: This study reports the week 124 results of the FLAIR study, an ongoing phase 3, randomised, open-label, multicentre (11 countries) trial. Antiretroviral therapy (ART)-naive participants who were virologically suppressed (HIV-1 RNA <50 copies per mL) during the 20-week induction phase with standard of care were randomly assigned (1:1) to continue the standard of care oral regimen or switch to long-acting cabotegravir plus rilpivirine (283 per group) in the 100-week maintenance phase. Randomisation was stratified by sex at birth and baseline (pre-induction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL). Participants randomly assigned to long-acting therapy at baseline received a cabotegravir (30 mg) plus rilpivirine (25 mg) once daily oral lead-in for at least 4 weeks before first injection and could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw. At week 100, participants in the oral comparator ART group, in discussion with the investigator, could elect to switch to long-acting therapy (extension switch population), either direct-to-injection or with a 4 week oral lead-in (oral lead-in group), or withdraw. Week 124 endpoints included plasma HIV-1 RNA 50 or more copies per mL and less than 50 copies per mL (US Food and Drug Administration [FDA] Snapshot), confirmed virological failure (two consecutive HIV-1 RNA ≥200 copies per mL), and safety and tolerability. The study is registered at ClinicalTrials.gov, NCT02938520., Findings: Screening occurred between Oct 27, 2016, and March 24, 2017. At week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 [48%] in the direct-to-injection group and 121 [52%] in the oral lead-in group; extension switch population). 243 (86%) of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. One (<1%) participant in each extension switch group had 50 or more HIV-1 RNA copies per mL; 110 (99%) participants in the direct-to-injection group and 113 (93%) participants in the oral lead-in group remained suppressed (HIV-1 RNA <50 copies per mL) at the week 124 Snapshot. The lower suppression rates in the oral lead-in group were driven by non-virological reasons. For participants in the randomly assigned long-acting group, 227 (80%) of 283 participants remained suppressed; at the week 124 Snapshot, 14 (5%) participants had HIV-1 RNA 50 or more copies per mL, including five additional participants since the week 96 analysis. The remaining 42 (15%) participants in the randomly assigned long-acting group had no virological data. Adverse events leading to withdrawal were infrequent, occurring in three (1%) participants in the extension switch population (one in the direct-to-injection group and two in the oral lead-in group) after 24 weeks of cabotegravir plus rilpivirine therapy, and 15 (5%) participants in the randomly assigned long-acting group up to 124 weeks of therapy. No deaths occurred in the extension phase. Overall, cabotegravir plus rilpivirine adverse event type, severity, and frequency were similar across all groups. Injection site reactions were the most common adverse event, occurring after 914 (21%) of 4442 injections in the extension switch population and 3732 (21%) of 17 392 injections in the randomly assigned long-acting group. Injection site reactions were mostly classified as mild-to-moderate in severity and decreased in incidence over time. Four (2%) of 232 participants in the extension switch population and seven (2%) of 283 in the randomly assigned long-acting group withdrew due to injection-related reasons., Interpretation: After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-injection approach. The week 124 results for participants randomly assigned originally to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable maintenance therapy with a favourable safety profile., Funding: ViiV Healthcare and Janssen Research & Development., Competing Interests: Declaration of interests CO reports grants, personal fees, non-financial support, and travel sponsorship during the study from ViiV Healthcare; and grants, personal fees, non-financial support, speaker's bureau, and travel sponsorship from GlaxoSmithKline, Gilead Sciences, Merck Sharp & Dohme, Janssen, and ViiV Healthcare, outside the submitted work. EBM reports grants from ViiV Healthcare, during the study; and grants, personal fees, and non-financial support from Gilead Sciences, Janssen, ViiV Healthcare, and Merck Sharp & Dohme, outside the submitted work. DHST reports grants from the Canada Research Chairs Program, during the study; grants from Gilead Sciences, ViiV Healthcare, and AbbVie; and DHST participated as a site principal investigator in a trial sponsored by GlaxoSmithKline, outside of the submitted work. H-JS reports personal fees from ViiV Healthcare during the study; personal fees from Gilead Sciences, Janssen-Cilag, Theratechnologies, and Merck Sharp & Dohme, outside of the submitted work. RD, ST, and SLF are employees and stockholders of GlaxoSmithKline. SG, PP, AC, KYS, MSC, WRS, and RD'A are employees of ViiV Healthcare and stockholders of GlaxoSmithKline. RVS-R, HC, KV, and EBi are employees and stockholders of Janssen. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Long-acting cabotegravir and rilpivirine administered monthly or every 2 months might address the challenges associated with daily oral antiretroviral therapy. The ATLAS-2M week 48 results showed non-inferiority of long-acting cabotegravir and rilpivirine administered every 8 weeks compared with that of every 4 weeks. In this study, we report the efficacy, safety, and tolerability results from the week 96 analysis., Methods: ATLAS-2M is a randomised, multicentre, open-label, phase 3b, non-inferiority trial conducted in 13 countries, evaluating the safety and efficacy of maintenance treatment with intramuscular injections of long-acting cabotegravir and rilpivirine, administered every 8 weeks versus every 4 weeks, to people living with HIV-1. Virologically suppressed adults with HIV-1, either already receiving intramuscular long-acting cabotegravir and rilpivirine every 4 weeks (ie, ATLAS study rollover participants) or oral standard of care, were randomly assigned (1:1), in an unblinded fashion, to receive either intramuscular long-acting cabotegravir (600 mg) and rilpivirine (900 mg) every 8 weeks (ie, the every 8-week dosing group) or intramuscular long-acting cabotegravir (400 mg) and rilpivirine (600 mg) every 4 weeks (ie, the every 4-week dosing group). Randomisation was generated using the GlaxoSmithKline-validated randomisation software RANDALL NG (version 1.3.3). The primary endpoint at week 48 was the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (ie, the US Food and Drug Administration [FDA] Snapshot algorithm), which has been published previously. Here, we present the week 96 results: the proportion of participants with plasma HIV-1 RNA measurements of less than 50 copies per mL (FDA Snapshot algorithm), with a non-inferiority margin of -10%; the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (FDA Snapshot algorithm), with a non-inferiority margin of 4%; the proportion of participants with protocol-defined confirmed virological failure (ie, two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL); safety; pharmacokinetics; and tolerability. This study is registered with ClinicalTrials.gov, number NCT03299049, and is currently ongoing., Findings: Between Oct 27, 2017, and May 31, 2018, a total of 1149 participants were screened; of whom, 1049 (91%) were randomly assigned and 1045 (91%) initiated treatment (522 in the every 8-week dosing group and 523 in the every 4-week dosing group). The median age was 42 years (IQR 34-50). 280 (27%) of 1045 participants were assigned female at birth and 764 (73%) were white. At week 96 (FDA Snapshot algorithm), 11 (2%) of 522 participants in the every 8-week dosing group and six (1%) of 523 in the every 4-week dosing group had an HIV-1 RNA measurement of 50 copies per mL or more, with an adjusted treatment difference of 1·0 (95% CI -0·6 to 2·5), meeting the prespecified non-inferiority threshold of 4%; 475 (91%) of 522 participants in the every 8-week dosing group and 472 (90%) of 523 in the every 4-week dosing group maintained an HIV-1 RNA measurement of less than 50 copies per mL, with an adjusted treatment difference of 0·8 (95% CI -2·8 to 4·3), which met the prespecified non-inferiority threshold of -10%. One participant in the every 8-week dosing group met the confirmed virological failure criterion since the week 48 analysis at week 88, resulting in a total of nine participants in the every 8-week dosing group and two in the every 4-week dosing group having confirmed virological failure. No new safety signals were identified, and no treatment-related deaths occurred. Injection site reactions were the most common adverse event, occurring in 412 (79%) of 522 participants in the every 8-week dosing group and 400 (76%) of 523 in the every 4-week dosing group. Most injection site reactions were grade 1 or 2 (7453 [99%] of 7557 in both groups), with a median duration of 3 days (IQR 2-5)., Interpretation: Long-acting cabotegravir and rilpivirine dosed every 8 weeks had non-inferior efficacy compared with that of every 4 weeks through the 96-week analysis, with both regimens maintaining high levels of virological suppression. These results show the durable safety, efficacy, and acceptability of dosing long-acting cabotegravir and rilpivirine monthly and every 2 months as maintenance therapy for people living with HIV-1., Funding: ViiV Healthcare and Janssen Research & Development., Competing Interests: Declaration of interests HJ reports non-financial support from GlaxoSmithKline during the conduct of the study; and personal fees and non-financial support from AbbVie, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, TAD Pharma, and ViiV Healthcare, outside the submitted work. ETO reports funding from ViiV Healthcare to do research at his institution, during the conduct of the study; consultant fees from Theratechnologies, outside of the submitted work; consultant fees and research support from ViiV Healthcare and Gilead Sciences; and research support from Merck Sharp & Dohme, outside of the submitted work. GRic reports grants from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, Johnson & Johnson, Taimed, Merck Sharp & Dohme, and Insmed, outside of the submitted work. GRiz has received personal fees from ViiV Healthcare, Angelini, and Janssen; personal fees and non-financial support from Gilead Sciences and AbbVie; and personal fees and fees for participation on a Data Safety Monitoring Board and Advisory Board from Merck Sharp & Dohme, outside of the submitted work. AOH reports non-financial support from PPD, during the conduct of the study; and grants from ViiV Healthcare, and Gilead Sciences, outside of the submitted work. AT reports funding of study costs from ViiV Healthcare and Janssen, during the conduct of the study; and personal fees from GlaxoSmithKline, ViiV Healthcare, and Gilead Sciences, outside of the submitted work. YW, CME, and SLF are employees and stockholders of GlaxoSmithKline. VvE is an employee of Janssen and has a pending patent. HC, RVS-R, and SV are employees and stockholders of Janssen. DAM was an employee of ViiV Healthcare and is a shareholder of GlaxoSmithKline, and has a pending patent. PDB, KJH, CLT, KYS, and WRS are employees of ViiV Healthcare and stockholders of GlaxoSmithKline. JFA-V, RM, EB, and FA declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc., Design and Methods: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination., Results: Overall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated (P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35)., Conclusion: CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings., Methods: FLAIR is a randomised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 mL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or more assessed as per the US Food and Drug Administration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520., Findings: Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0·0 (95% CI -2·9 to 2·9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14 [5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase., Interpretation: The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1., Funding: ViiV Healthcare and Janssen Research and Development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1., Setting: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies., Methods: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints., Results: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm., Conclusion: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Background: Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection., Methods: We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm)., Results: At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48., Conclusions: Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence., Methods: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm., Results: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group., Conclusions: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression., Objectives: To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352)., Methods: Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays., Results: Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF., Conclusions: A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Rilpivirine (RPV, TMC278, Edurant®) is a next‐generation non‐nucleoside reverse transcriptase inhibitor (NNRTI), which demonstrated high virologic response rates and non‐inferiority versus efavirenz in two Phase III trials in HIV‐infected patients through 96 weeks [1,2]. RPV has been shown to inhibit P‐glycoprotein (P‐gp) in vitro with an apparent IC[sub.50] of 9.2 µM (3.4 µg/mL). This study evaluated the in‐vivo effect of steady‐state RPV 25 mg once daily (qd) on the single‐dose pharmacokinetics of the probe P‐gp substrate digoxin. This was a Phase I, open‐label, randomised, crossover trial in 22 HIV‐negative volunteers. Participants received in one session a single 0.5 mg dose of digoxin, and in another session RPV 25 mg qd for 16 days with a single 0.5 mg dose of digoxin in the morning of Day 11. All study drugs were taken with a breakfast. Pharmacokinetic profiles of digoxin in plasma and urine were determined over 144 hours after dosing in each session. Steady‐state RPV 24‐hour pharmacokinetic profiles in plasma were determined on Day 11. Plasma and urine samples were analysed using validated LC‐MS/MS methods. Pharmacokinetic parameters were calculated with non‐compartmental methods. The least square (LS) means and associated 90% confidence intervals (CI) of treatment ratios were calculated based on log‐transformed pharmacokinetic parameters. Safety and tolerability were assessed throughout the trial. Digoxin pharmacokinetic parameters and statistical results are summarised in Table 1. The plasma and urine digoxin pharmacokinetics were unaffected by co‐administration of steady‐state RPV. The 90% CIs of the LS means ratios of the main pharmacokinetic parameters were contained within the 0.80‐1.25 boundaries of no effect. The terminal elimination half‐life of digoxin was similar in the absence or the presence of steady‐state RPV. RPV pharmacokinetic parameters were comparable to those in previous clinical trials in healthy volunteers. Administration of digoxin and RPV was generally safe and well tolerated. There were no discontinuations due to adverse events. In conclusion, RPV does not affect the pharmacokinetics of the probe P‐gp substrate digoxin. In vivo, at the recommended RPV dose of 25mg qd, the observed in‐vitro inhibition of P‐gp by RPV is not clinically relevant., References Cohen C, Andrade‐Villaneuva J, Clotet B, Fourie J, Johnson MA, Ruxrungtham K, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment‐naïve adults [...]

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm-transformed) for each component were compared using linear mixed-effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [C max ] and area under the plasma concentration-time curve [AUC last ]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine C max ; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for C max and AUC last , respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent., (© 2018, The American College of Clinical Pharmacology.)

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma ( C max variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and C max variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and C max (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% ( n = 5) and 3% ( n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.)., (Copyright © 2018 Mehta et al.)

Sheet metal working remains an important industry. It is argued that, to be competitive, the complete production chain needs to be optimised. Therefore, this article focuses on the optimisation of the production plan. The sheet metal shop is configured as a two-stage flow shop with laser cutting and air bending. In the literature, theoretical production planning models can be found for both individual processes. Unfortunately, those planning models have a low applicability in sheet metal working small and medium sized enterprises (SMEs) due to the fact that they only focus on one single production step while in reality the planning decisions taken at the cutting stage affect the production plan for the air bending stage. An integrated production planning methodology is proposed to overcome this problem of individual optimisation by taking into account relevant bending information already at the cutting stage. An integer program is presented, incorporating some important practical requirements: (1) the planning model is suited for normal workpieces, rush orders, special workpieces and multiple-machine sheet metal shops and (2) the computational times to generate the production plan are limited. Ten real-life industrial test cases are used to evaluate the proposed methodology. The integrated production planning methodology results in schedules with a reduced makespan and a reduced set-up time at the press brake compared to the current way of planning. All planning models are developed in close cooperation with sheet metal working SMEs to facilitate the implementation process. [ABSTRACT FROM AUTHOR]