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Objective: International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent hepatitis B virus (HBV) mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the 2 regimens are lacking., Design: In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to 31 March 2024 and extracted data from cohort studies and randomized controlled trials (RCTs) in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups., Results: We included 31 studies with 2588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6-12 months (risk ratio: 0.10, 95% confidence interval [CI] .07-.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval .16-7.61). Network meta-analysis showed equal efficacy of the 2 regimens in reducing MTCT (risk ratio: 1.09, 95% CI .15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: .77 vs .72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens., Conclusions: Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers., Competing Interests: Potential conflicts of interest . C. Q. P. received an institutional research grant from Gilead Sciences. A. S. Y. serves as a speaker for Gilead Sciences, Inc. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Antiretroviral therapy (ART)-related weight gain is of particular concern in people with HIV (PWH). Although weight gain was observed among PWH receiving tenofovir alafenamide (TAF), little is known about the potential reversibility after TAF discontinuation. We evaluated weight and metabolic changes 12 months after TAF discontinuation in the Swiss HIV Cohort Study., Methods: We included participants who received at least 6 months of TAF-containing ART between January 2016 and March 2023. Using multivariable mixed-effect models, changes in weight and lipid levels were compared between individuals who continued TAF and those who switched to one of the following TAF-free regimens: (1) tenofovir disoproxil fumarate (TDF)-based ART, (2) dolutegravir/lamivudine (DTG/3TC), or (3) long-acting cabotegravir/rilpivirine (CAB/RPV)., Results: Of 6555 participants (median age 54 years, 24.3% female, 13% Black), 5485 (83.7%) continued, and 1070 (16.3%) stopped TAF. Overall, discontinuing TAF was associated with an adjusted mean weight change of -0.54 kg (95% confidence interval [CI] -.98 to -.11) after 12 months. In stratified analyses, switching from TAF to TDF led to an adjusted mean weight decrease of -1.84 kg (95% CI -2.72 to -.97), and to a decrease in mean total cholesterol (-0.44 mmol/L) and triglycerides (-0.38 mmol/L) after 12 months. Switching from TAF-based ART to DTG/3TC (-0.17 kg, 95% CI -.82 to .48) or long-acting CAB/RPV (-0.64 kg, 95% CI -2.16 to .89) did not lead to reductions in weight., Conclusions: Replacing TAF with TDF in PWH led to a decrease in body weight and an improved lipid profile within 1 year. Weight changes were not observed among individuals who switched to DTG/3TC or long-acting CAB/RPV., Competing Interests: Potential conflicts of interest . P. E. T. received grants, and educational and advisory fees to institution from Gilead, MSD, and ViiV outside the submitted work. O. N. T.’s institution received expenses compensation for expert opinion from ViiV Healthcare. K. E. A. D.'s institution has received research grants from Gilead Sciences and travel grants and lecture fees from Gilead and MSD. B. S. reports support to his institution for travel grants from Gilead Sciences and ViiV healthcare. G. W. reports unrestricted research grants from Gilead Sciences and Roche Diagnostics, as well as travel grants and advisory board/lecture fees from ViiV, Gilead Sciences and MSD, all paid to his institution. M. C.’s institution received research grants and payment for expert testimony from Gilead, MSD, and ViiV. E. B.'s institution received research grants from MSD, consulting fees from Moderna, payment for lectures from Pfizer AG as well as fees for the participation of E. B. to advisory boards and/or travel grants from Gilead Sciences, ViiV, MSD, Abbvie, Pfizer, AstraZeneca, Moderna, and Ely Lilly. C. B. reports participation on the Gilead advisory board on Bulevirtide. K. D. reports grants, payment for lectures, and support for meetings and/or travel from Gilead Sciences, as well as payment for expert testimony from MSD. C. A. F. reports grants from Gilead, as well as Advisory Board attendance support from Gilead, Menarini, Moderna, MSD, and ViiV. M. S. reports support for meetings and/or travel from Gilead, participation on an advisory board for Gilead Sciences, Moderna, MSD, and ViiV Healthcare. O. N. T. reports payment or honoraria for lectures from ViiV Healthcare. C. M. reports speaker honoraria from Gilead, ViiV, and MSD. P. T. reports grants and payment for lectures from Gielad, ViiV, and MSD. D. H. reports grants from Abbvie, AstraZeneka, Gilead, GSK, ViiV, MDF, and Pfizer, consulting fees from AstraZeneca, Gilead, ViiV Healthcare, and Bavarian Nordic, support for travel and/or meetings from Gilead, and payment for leadership or fiduciary role from PFMD and Positive Council. D. L. B. reports payment for lectures, consulting fees,and participation on advisory board from Gilead, ViiV, MSD, Pfizer, and consulting fees from AstraZeneka, support for attending meetings from Gilead. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aims: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]., Methods: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (C min , C max and AUC) and oestradiol concentrations (C min , C 4h, C max and AUC) at month 2., Discussion: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT., Methods: The study evaluated stored blood samples and dried blood spot cards from TGD adults without HIV who took ≥12 weeks of TDF/FTC and then switched to ≥12 weeks of TAF/FTC for pre-exposure prophylaxis., Results: Thirty-nine individuals met the study inclusion criteria. Regardless of sex assigned at birth and the use of GAHT, there were no significant differences in hormone concentrations when individuals taking GAHT were taking TDF/FTC and then switched to TAF/FTC. Further, there was no significant difference in intraerythrocytic tenofovir diphosphate concentrations between users and nonusers of GAHT., Conclusion: There are no bidirectional effects between hormone and intraerythocytic tenofovir diphosphate concentrations when switching from TDF/FTC to TAF/FTC in TGD users/nonusers of GAHT., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Hepatitis B virus (HBV) infection is a contagious condition posing a major public health risk in various nations, including Vietnam. In 2019, the Ministry of Health introduced tenofovir alafenamide (TAF) to treat patients with chronic HBV infection and reduce the long-term toxicity of tenofovir disoproxil fumarate (TDF). This study aimed to assess the effectiveness and safety of these 2 medications in individuals with hepatitis B e antigen (HBeAg)-positive chronic HBV., Methods: This retrospective cohort study included data collected from the medical records of patients with chronic HBV who visited the Liver Clinic at University Medical Center Ho Chi Minh City between 2018 and 2020., Results: After 2 years of treatment, the proportion of HBeAg loss in the TAF group was twice that of the TDF group (22.4% vs 11.2%), indicating a statistically significant difference in the probability of HBeAg loss (adjusted hazard ratio = 2.22; 95% confidence interval [CI] 1.43-3.42; P < 0.01). In addition, there was a statistically significant difference in the rate and ability of antiviral response between patients treated with TAF and TDF (65% vs 54.5%, respectively; adjusted hazard ratio = 1.34; 95% CI 1.08-1.69; P < 0.01). A total of 93.9% of patients achieved the goal of restoring alanine aminotransferase to normal, a higher percentage compared with the 81.2% in the TDF group, and the likelihood of achieving normal alanine aminotransferase levels with TAF was greater compared with those on TDF (adjusted hazard ratio = 1.67; 95% CI 1.38-2.01; P < 0.01). Moreover, there was a statistically significant difference in the variation in renal function between the TAF and TDF groups. Serum creatinine levels in the TAF group increased less than those in the TDF group by 0.03 mg/dL every 6 months (95% CI -0.04 to -0.01, P < 0.01), and the estimated glomerular filtration rate in the TAF group was higher than that in the TDF group every 6 months by 2.78 mL/min/1.73 m 2 (95% CI 0.98-4.57, P < 0.01). However, there was no statistically significant difference in the likelihood of HBeAg seroconversion between patients with chronic hepatitis B treated with TAF or TDF (adjusted hazard ratio = 1.79; 95% CI 0.91-3.53; P = 0.09), nor in the risk of adverse events between the 2 groups (adjusted odds ratio = 1.34; 95% CI 0.88-2.05; P = 0.17). In addition, although the HBsAg concentration in the TAF group was lower than in the TDF group by an average of 0.05 log 10 IU/mL every 6 months (95% CI -0.15 to 0.05), this difference also did not reach statistical significance ( P = 0.35)., Discussion: TAF has been demonstrated to achieve some therapeutic efficacy goals and reduce nephrotoxicity better than TDF. However, no differences were found in seroconversion or adverse events between the patient groups., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Liposils, synthesized via the liposome templating method, offer a promising strategy for enhancing liposome stability by employing a silica coating. This study focuses on the development of nanocarriers utilizing silica-coated nanoliposomes for encapsulating the poorly water-soluble drug, ibrutinib. Ibrutinib-loaded nanoliposomes were meticulously formulated using the reverse-phase evaporation technique, serving as templates for silica coating, resulting in spherical liposils with an average size of approximately 240 nanometers. Comprehensive characterization of the liposil's physical and chemical properties was conducted using various analytical methods, including dynamic light scattering, transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction analysis. Liposils demonstrated superior performance compared to ibrutinib-loaded nanoliposomes, showing sustained drug release profiles in simulated intestinal fluids and resistance to simulated gastric fluid, as confirmed by dissolution studies. Moreover, ibrutinib liposils exhibited a significant increase in half-life (4.08-fold) and notable improvement in bioavailability (3.12-fold) compared to ibrutinib suspensions, as determined by pharmacokinetic studies in rats. These findings underscore the potential of liposils as nanocarriers for orally delivering poorly water-soluble drugs, offering enhanced stability and controlled release profiles, thereby improving bioavailability prospects and therapeutic efficacy. This approach holds promise for addressing challenges associated with the oral administration of drugs with limited solubility, thereby advancing drug delivery technologies and clinical outcomes in pharmaceutical research and development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ashar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We evaluated hair tenofovir (TFV) concentrations as an adherence metric for HIV preexposure prophylaxis during pregnancy and postpartum and compared hair levels with TFV-diphosphate levels in dried blood spots (DBSs). Overall 152 hair samples from 102 women and 36 hair-DBS paired samples from 29 women were collected from a subset of women in a cluster-randomized trial. Having a partner with HIV was associated with higher hair TFV levels (P < .001). Hair TFV concentrations were strongly correlated with DBS TFV-diphosphate levels (r = 0.76, P < .001), indicating hair as a promising cumulative adherence metric for perinatal preexposure prophylaxis assessment., Competing Interests: Potential conflicts of interest. J. M. B. is an employee of Gilead Sciences outside of the present work. P. L. A. received personal fees from Gilead, Merck, and ViiV not related to this work and research/contract work from Gilead Sciences paid to his institution. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally., Methods: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant., Results: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively)., Discussion: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420., Competing Interests: Potential conflicts of interest. S. A. R. received research grants from Gilead Sciences and Merck. P. L. A. received research contracts from Gilead Sciences paid to his institution. S. L. H. received research grants and consulting fees from Merck. G. F. D. received research grants from Gilead Sciences. C. W. H. has received clinical research funding from Gilead Sciences and Merck; he is a coinventor of 2 issued US patents related to microbicides; and is founder of Prionde BioPharma, LLC, a microbicide company. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy., Methods: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle., Results: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively., Conclusion: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing., Trial Registration: NCT04446962., (© 2024. The Author(s).)

Introduction: Rapid initiation of ART after HIV diagnosis is recommended for individual and public health benefits. However, certain clinical and ART-related considerations hinder immediate initiation of therapy., Methods: An open-label, single-arm, single-centre 48-week prospective clinical trial involving ART-naïve HIV-diagnosed adults who started bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) within a week from the first hospital visit, before the availability of baseline laboratory and genotype results. The primary aim was to determine the proportion of people with at least one condition that would hinder immediate initiation of any recommended ART regimen other than BIC/FTC/TAF. Clinicaltrials.gov: NCT04416906., Results: We included 100 participants: 79% men, 64% from Latin America, median age 32 years. According to European AIDS Clinical Society (EACS) and US Department of Health and Human Services 2023 guidelines, 11% (95%CI 6; 19) of participants had at least one condition that made any ART different from BIC/FTC/TAF less appropriate for a rapid ART strategy. Seventy-nine percent of the people started BIC/FTC/TAF within the first 48 hours of their first hospital visit. There were 16 early discontinuations (11 lost to follow-up). By week 48, 92% (95%CI 86; 98) of the participants of the ITT population with observed data achieved viral suppression. Eight grade 3-4 adverse events (AEs), five serious AEs and six ART-related AEs were identified. Adherence remained high., Conclusions: BIC/FTC/TAF is an optimal treatment for rapid initiation of ART. However, additional strategies to improve retention in care must be implemented., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: This phase II clinical trial evaluated the combination of ibrutinib with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in patients with nongerminal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL)., Patients and Methods: The IBDCL trial (NCT02692248) included patients with histologic diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem-cell transplantation. Patients received an induction treatment consisting of six or eight cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate after four cycles., Results: Sixty-four patients were included, 72% of them refractory to the last regimen. The overall response rate and complete remission rate after the fourth cycle were 53% [95% confidence interval (CI), 41-65] and 34% (95% CI, 24-46), respectively. Twenty-four (37%) patients started maintenance, and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4-48.6), the estimated 2-year progression-free survival and overall survival were 18% (95% CI, 8-28) and 26% (95% CI, 14-37), respectively. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (44%), neutropenia (30%), and anemia (14%). Grade ≥3 infectious and cardiovascular treatment-related adverse events were reported in 6 (9%) and 1 (2%) patient, respectively., Conclusions: Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL., (©2024 American Association for Cancer Research.)

Increased consumption of folic acid is prevalent due to its beneficial effects, but growing evidence emphasizes the side effects pointing to excessive dietary folate intake. The effects of excessive paternal folic acid consumption on offspring and its transgenerational inheritance mechanism have not been elucidated. We hypothesize that excessive folic acid consumption will alter sperm DNA N6-methyladenine (6mA) and 5-methylcytosine (5mC) methylation and heritably influence offspring metabolic homeostasis. Here, we fed roosters either folic acid-control or folic acid-excess diet throughout life. Paternal chronic folic acid excessive supplementation increased hepatic lipogenesis and lipid accumulation but reduced lipolysis both in the roosters and their offspring, which was further confirmed to be induced by one-carbon metabolism inhibition and gene expression alteration associated with the Peroxisome proliferator-activated receptor pathway. Based on the spermatozoal genome-wide DNA methylome identified by Nanopore sequencing, multi-omics association analysis of spermatozoal and hepatic DNA methylome, transcriptome, and metabolome suggested that differential spermatozoal DNA 6mA and 5mC methylation could be involved in regulating lipid metabolism-related gene expression in offspring chickens. This model suggests that sperm DNA N6-methyladenine and 5-methylcytosine methylation were involved in epigenetic transmission and that paternal dietary excess folic acid leads to hepatic lipid accumulation in offspring., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: We measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Methods: A total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 μL of 50% methanol and 400 μL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 μm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 μL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05-12.5 ng/punch., Results: We determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration., Conclusions: A multiplex LC-MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Abstract: In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background and Aim: Our study evaluated the outcomes of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). We assessed viral and biochemical responses as well as changes in the estimated glomerular filtration rate (eGFR) and bone mineral density (BMD)., Methods: This retrospective multicenter study included CHB patients who achieved virologic response (VR) (HBV DNA < 20 IU/mL) while on TDF and were subsequently switched to TAF between April 2018 and October 2021., Results: This study included 309 patients with a median age of 59 years, and 42.1% were male. The mean duration of TDF and TAF administration were 54.0 and 37.5 months, respectively. All patients maintained VR after switching to TAF. Alanine aminotransferase (ALT) normalization rate significantly increased 6 months after switching (74.8%-83.5%; P = 0.008). Adjusted eGFR significantly improved at 6 months (+5.55 ± 10.52 mL/min/1.73 m 2 ; P < 0.001) and 12 months (+6.02 ± 10.70 mL/min/1.73 m 2 ; P < 0.001) after switching. In the subgroup of patients with renal impairment (eGFR < 60 mL/min/1.73 m 2 ), significant improvement in renal function was observed at 6 months (+0.6 ± 10.5 mL/min/1.73 m 2 ; P < 0.001) and 12 months (+1.0 ± 10.7 mL/min/1.73 m 2 ; P < 0.001) after switching to TAF. In patients with osteoporosis (n = 182), switching to TAF resulted in significant improvement in spine and hip BMD at 12 months, with increases of 9.7% (95% CI: 7.0-12.5) and 9.4% (95% CI: 7.0-11.8), respectively., Conclusion: In this real-world study, switching to TAF was effective and safe in patients, with notable improvements in ALT levels, renal function, and BMD., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The use of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is based on the results of robust clinical trials., Objectives: To assess the effectiveness and safety of BIC/FTC/TAF in treatment-naïve (TN) and treatment-experienced (TE) people with HIV using available real-world cohort studies., Methods: Systematic review and meta-analysis of publications and communications identified via Boolean search in Medline, PubMed and Embase, and conference abstracts reporting retrospective real-world use of BIC/FTC/TAF, published until 31 January 2024. The primary endpoint was the proportion of TN and TE people with HIV with viral load (VL) < 50 copies/mL at 48 weeks while on treatment., Results: Of the 38 identified publications and conference abstracts, for the present analysis we included 12 publications (comprising 792 TN and 6732 TE individuals). For the three publications including 507 TN participants reporting the primary outcome, VL suppression was 97% [95% confidence intervals (CI): 89-100]. For the nine publications including 4946 TE participants reporting the primary outcome, VL suppression was 95% (95% CI: 94-96), with suppression >93% in all studies. Total discontinuations at 48 weeks in TE individuals were 3% (95% CI: 2-5), 1% (95% CI: 0-2) due to side effects. A total of four publications with 151 TE individuals with previous presence of M184V substitution were identified, reporting a suppression rate at 48 weeks of 95% (95% CI: 88-100)., Conclusions: Real-world studies demonstrate low discontinuation rates and high rates of virologic suppression in individuals treated with BIC/FTC/TAF, both TN and TE with and without previous detection of M184V substitution., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up., Methods: The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing., Findings: Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (β2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide., Interpretation: Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities., Funding: Gilead Sciences., Competing Interests: Declaration of interests DAW has received grants, consulting fees, and speaker honoraria from Gilead Sciences; grants from Merck; consulting fees and speaker honoraria from ViiV Healthcare; and consulting fees and speaker honoraria from Janssen Pharmaceuticals. CDS has received funding, grants, consulting fees, and non-financial support from Gilead Sciences; grants and speaker honoraria from AbbVie; grants and personal fees from Janssen-Cilag; grants and personal fees from MSD, ViiV Healthcare, BioNtech, and Eli Lilly; grants from Cepheid; grants, personal fees, and non-financial support from B Braun Melsungen; consulting fees from AstraZeneca; personal fees, non-financial support, and other support outside the submitted work from Apeiron Biologics; and personal fees from GSK, Formycon, Moderna, Molecular Partners, Novartis, Roche, Sobi, and Pfizer. JF, PJR, and RMG have received research funding from Gilead Sciences. CBH has received research grant support from Gilead Sciences. SD-L has received research grant support (paid to their institution) from Gilead Sciences and Merck. J-MM has received grants (paid to their institution) from Gilead Sciences and Merck; consulting fees from Gilead Sciences, Merck, and ViiV Healthcare; and payments for participation on an advisory board from AELIX Therapeutics. AM has received research funding (paid to their institution) from Gilead Sciences, ViiV Healthcare, Merck, GSK, AbbVie, and TaiMed Biologics; speaker honoraria from Gilead Sciences, ViiV Healthcare, and EMD Serono; and payments for participation on an advisory board from Gilead Sciences and ViiV Healthcare. CB has received funding and speaker honoraria from Gilead Sciences; speaker honoraria from ViiV Healthcare; and support for attending principal investigator meetings from Gilead Sciences, ViiV Healthcare, GSK, PPD (Thermo Fisher Scientific), Merck, Viking Therapeutics, Syneos Health, Novo Nordisk, AbbVie, Regeneron Pharmaceuticals, Janssen, and Shionogi. MR has received funding and speaker and consulting fees from Gilead Sciences, speaker and consulting fees from ViiV Healthcare, consulting fees from MSD and Abbott, and speaker honoraria from AbbVie and Janssen. AC has received advisory boards fees from Gilead Sciences, ViiV Healthcare, MSD, and Theratechnologies; funding for clinical trials (paid to their institution) from Gilead Sciences, MSD, GSK, ViiV Healthcare, and Pfizer; speaker fees from MSD; and support for congress attendance from Gilead Sciences and ViiV Healthcare. GC has received research funding (paid to their institution) from Gilead Sciences for conducting research discussed in this manuscript. CM has received funding and speaker fees from Gilead Sciences and grants and speaker fees from ViiV Healthcare and Theratechnologies. CC, SC, JCH, YS, MD, AK, and JMB are shareholders and employees of Gilead Sciences. KMo has received funding from Gilead Sciences; speaker fees and advisory board fees from Gilead Sciences, ViiV Healthcare, Janssen Therapeutics, Theratechnologies, and Epividian; and funding for clinical trials (paid to their institution) from Gilead Sciences, ViiV Healthcare, and Janssen Therapeutics. KMa has received research funding from Gilead Sciences, and unrestricted grants and advisory board fees from Gilead Sciences and Merck., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Liposomes being a promising colloidal system facilitates delivery of drugs with limited pharmacokinetic properties to achieve desirable clinical applications. However, development of a stable liposomal system is always challenging due to multiple complexities involved. Aqueous instability of liposomes and impact of various process and formulation parameters can lead to serious alteration of its therapeutic performance. In the proposed work, the authors aim to develop stable Ibrutinib-loaded liposomes using lyophilization and Quality-by-Design and assess their long-term stability. Ibrutinib-loaded liposomes were developed and optimized using Quality-by-Design technique and were further PEGylated and characterized for the same. Effect of cryoprotectants during lyophilization and other parameters are evaluated to obtain a robust formulation. The stability studies were conducted upto 6 months at various storage conditions to evaluate the effect of lyophilization. The impact of formulation, processing and lyophilization parameters on physicochemical properties of developed liposomal systems were evaluated and are critically discussed. Liquid dispersion exhibited a %degradation of 16-36% at 25 °C/60% RH which was reduced for less than 1% in lyophilized formulation for 6 months. Critical analysis and assessment of various parameters lead to identification of optimum conditions to manufacture this drug product and also opens way forward for further evaluation and translational possibilities., (© 2024. Controlled Release Society.)

Objective: This article examined the cost-effectiveness of zanubrutinib and ibrutinib for managing relapsed and refractory chronic lymphocytic leukemia from the viewpoint of payers in China and the US., Methods: Markov models were employed to conduct comparisons. Baseline characteristics and clinical data were extracted from the ALPINE study. The cost-effectiveness outcome indicators encompassed cost, quality-adjusted life years, and the incremental cost-effectiveness ratio., Results: The Markov model analysis revealed that the zanubrutinib group incurred an incremental cost per patient of $-24,586.53 compared to the ibrutinib group. The zanubrutinib group exhibited an incremental utility per capita of 0.28 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $-88,068.16 per quality-adjusted life year, which is lower than the payment threshold in China. The willingness-to-pay value in China for 2022 was three times the country's gross domestic product per capita. In the US, patients in the zanubrutinib group experienced per capita incremental costs of $-79,421.56, per capita incremental utility of 0.28 quality-adjusted life years, and an incremental cost-effectiveness ratio of $-284,485.45 per quality-adjusted life year., Conclusion: For Chinese payers, zanubrutinib exhibited superior cost-effectiveness compared to ibrutinib. Zanubrutinib proved to be a more affordable option for US payers when considering the payment threshold.

Human immunodeficiency virus (HIV) continues to pose a serious threat to global health. Oral preexposure prophylaxis (PrEP), considered highly effective for HIV prevention, is the utilisation of antiretroviral (ARV) drugs before HIV exposure in high-risk uninfected individuals. However, ARV drugs are associated with poor patient compliance and pill fatigue due to their daily oral dosing. Therefore, an alternative strategy for drug delivery is required. In this work, two dissolving microneedle patches (MNs) containing either bictegravir (BIC) or tenofovir alafenamide (TAF) solid drug nanoparticles (SDNs) were developed for systemic delivery of a novel ARV regimen for potential HIV prevention. According to ex vivo skin deposition studies, approximately 11% and 50% of BIC and TAF was delivered using dissolving MNs, respectively. Pharmacokinetic studies in Sprague Dawley rats demonstrated that BIC MNs achieved a long-acting release profile, maintaining the relative plasma concentration above the 95% inhibitory concentration (IC 95 ) for 3 weeks. For TAF MNs, a rapid release of drug and metabolism of TAF into TFV were obtained from the plasma samples. This work has shown that the proposed transdermal drug delivery platform could be potentially used as an alternative method to systemically deliver ARV drugs for HIV PrEP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL R ) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail., Methods: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination., Results: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h -1 vs. 5.18 h -1 ) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K m ) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V max ) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min., Conclusion: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K m value suggests that assessing renal OAT1 activity by CL R has no relevant misspecification error with the cocktail doses used., (© 2024. The Author(s).)

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m 2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study., (© 2024. The Author(s).)

Objective: We assessed the association and concordance between self-reported oral pre-exposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations., Design: AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020)., Methods: Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48 months and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6 weeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250 fmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa., Results: Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration ( β  = 0.77, 95% CI = 0.70-0.84, P  < 0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate ( κ  = 0.44, 95% CI = 0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect ( κ  = 0.83, 95% CI 0.76-0.90)., Conclusion: Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown., Methods: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles., Results: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively., Conclusions: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.)., (Copyright © 2024 Massachusetts Medical Society.)

Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20 mg) and elvitegravir (EVG, 16 mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women., Competing Interests: Potential conflicts of interest. J. G. G.-L. and W. H. are named in US government patents on “Inhibition of HIV infection through chemoprophylaxis” (US patents 9,044,509 B2; 9,579,333 B2; 9,937,191 B2 and 10,335,423 B2) and “HIV post-exposure prophylaxis” (US patent 11,191,763 B2), and the US government patent application on “HIV preexposure prophylaxis.” (US 2022/0265689 A1). M. M. P., V. A., G. F. D., and M. R. C. are named in patent applications US 2021/0379089 A1 on “Pharmaceutical compositions and methods of making on-demand solid dosage formulations,” inventions that were developed under a USAID-funded cooperative agreement. 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., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens., Methods: In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG)., Results: The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events., Conclusions: BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes., Trial Registration: The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 )., (© 2024. The Author(s).)

Objectives: To assess the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among people poorly represented in clinical trials and potentially at higher risk of suboptimal response to ART., Methods: Observational cohort study on persons with HIV (PWH) enrolled in ICONA who started BIC/FTC/TAF as initial therapy or as switching regimen while virologically suppressed. Primary endpoint was time to treatment failure (TF): new AIDS/death or virological failure (VF) or discontinuation for toxicity/failure. Secondary endpoints were time to treatment discontinuation for toxicity (TDT) and to VF. Groups of interest were those aged >50 years, female sex, and advanced HIV disease at first ART start. Probability of the events overall and according to groups and adjusted HR for every endpoint were calculated by Kaplan-Meier curves and Cox regression models., Results: Nine hundred and thirty-three ART-naive and 1655 ART-experienced PWH initiated BIC/FTC/TAF. Over a median follow-up of 69.8 weeks, 89 (9.6%) PWH at their first regimen experienced TF. PWH aged >50 years had 1.83-fold (95% CI: 1.19-2.83) higher risk of TF; PWH with advanced HIV disease had 2.21-fold (95% CI: 1.53-3.82) higher risk; there were no differences in TF according to sex.Over a median follow-up of 146.3 weeks, 109 (6.6%) out of 1655 switching PWH experienced TF; no differences were found in the risk of TF, TDT and VF according to groups of interest., Conclusions: Overall, BIC/FTC/TAF is well tolerated and virologically effective in the real-world scenario for ART-naive and -experienced PWH. Older ART-naive PWH and those with advanced HIV disease may respond less well as the burden of diseases might compromise treatment efficacy., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available., Methods: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m 2 , days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m 2 , days 1-3) and intravenous cyclophosphamide (250 mg/m 2 , days 1-3). Intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment., Findings: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy)., Interpretation: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination., Funding: AbbVie, Janssen, and F Hoffmann-La Roche., Competing Interests: Declaration of interests MF reports research funding from AbbVie, AstraZeneca, BeiGene, Janssen, and Roche, and honoraria from AbbVie. JvT reports honoraria from AbbVie, BeiGene, Amgen, AstraZeneca, Janssen, Lilly, and Roche; travel grants from AbbVie, AstraZeneca, BeiGene, Roche, Lilly, and Janssen; and has received consulting fees from and participated on advisory boards for AbbVe, BeiGene, Amgen, and AstraZeneca. MG has received honoraria for participation in symposia and advisory boards from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb (BMS)/Celgene, GSK, Novartis, Incyte, Janssen-Cilag, Jazz, Roche, Pfizer, Sanofi, and Servier; travel support from AbbVie, BeiGene, Pfizer, and Roche; all fees went to their institution. GJ has received honoraria from Astellas and AbbVie and participated on advisory boards for AbbVie and Servier. M-DL reports travel grants from AbbVie and Janssen. CdC-B reports consulting fees from Janssen, honoraria for lectures from Octapharma, support for attending meetings from AbbVie and Octapharma, and participation on advisory boards for Janssen, BeiGene, and AstraZeneca. CSchn reports speakers fees from AstraZeneca and AbbVie, travel support from AbbVie, and participation on an advisory board for Janssen. RB reports travel support from BeiGene, Janssen, and AbbVie, and honoraria for participation on an advisory board from AbbVie. TN reports honoraria for lectures or presentations and has participated at advisory boards from AbbVie, Roche, AstraZeneca, Gilead, BeiGene, and Janssen. CBP is the chairman of the Danish CLL group. HF reports research funding from Sanofi, Novartis, and Alexion and honoraria for lectures from Sanofi. NK reports research funding from AstraZeneca; honoraria from AbbVie, AstraZeneca, Kite/Gilead, BMS, and Lilly; and travel support from AbbVie, AstraZeneca, BeiGene, Lilly, and Janssen; and participation on advisory boards for AstraZeneca and Janssen. JD reports consulting fees, honoraria, and travel support from AbbVie and Janssen. SB reports honoraria from and participation on speakers bureaus for Roche, Janssen, AbbVie, AstraZeneca, and Sanofi; travel support from Janssen, BeiGene, and Roche; and research funding from Janssen and Miltenyi. FS reports speakers fees from AstraZeneca, travel support from Lilly, and research funding from AstraZeneca. A-MF reports research funding and honoraria from AstraZeneca and travel support from AbbVie. KF reports research grants from AbbVie and Roche, honoraria for advisory boards from AstraZeneca, and travel support from Roche. K-AK reports consulting fees, participation on speakers bureaus, and research funding from Roche, AbbVie, and Janssen. MR reports honoraria from Janssen, Roche, and AstraZeneca; consulting fees from Roche, Janssen, AstraZeneca, and AbbVie; research funding from AbbVie and Roche, and travel support from AstraZeneca. MBr reports research funding and consulting fees from Amgen; honoraria for speakers bureaus from Amgen, Becton Dickinson, Janssen, and Pfizer; travel support from Janssen; and participation on advisory boards for Incyte and Amgen. ET reports participation on advisory boards and honoraria from AbbVie, Janssen-Cilag, and BeiGene, AstraZeneca, and Roche; and travel support from AstraZeneca, AbbVie, BeiGene, Janssen. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; research funding from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; travel support from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis; and speaker fees from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis. MH reports consulting fees from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca and honoraria from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca. APK reports honoraria from AbbVie, AstraZeneca, BMS, Janssen, LAVA, and Roche/Genentech; travel grants from AbbVie and Janssen; research funding from AstraZeneca, Janssen, Roche/Genentech, AbbVie, and BMS. CUN reports research funding from Octapharma and AstraZeneca; consultancy and speaker fees from AbbVie, AstraZeneca, Janssen, Genmab, BeiGene, Octapharma, CSL Behring, Takeda, Lilly, and MSD; and participation on advisory boards for AstraZeneca, MSD, Genmab, and Janssen. BE reports consulting fees fromJanssen, AbbVie, Gilead, AstraZeneca, MSD, BeiGene, and Lilly; participation on speakers bureau for Roche, AbbVie, BeiGene, AstraZeneca, and MSD; honoraria from Roche, AbbVie, AstraZeneca, BeiGene, and MSD; research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; and travel support from BeiGene. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1., Methods: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791., Findings: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per μL) and total lymphocyte counts (mean change -0·20 × 10 9 /L) were decreased at 48 weeks., Interpretation: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg)., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests F-HS, SOK, KE, RMP, TC (former), and MCF are or were employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, who might own stock, hold stock options, or both in the company. AMM has received research funding from AbbVie, Gilead Sciences, Merck, Taimed, GSK, and ViiV Healthcare; honoraria from Gilead Sciences, ViiV Healthcare, and EMD Serono; and served on advisory boards for Gilead Sciences and ViiV Healthcare. GR has received honoraria from MSD, Gilead Sciences, GSK, and ViiV Healthcare and meeting or travel support from Gilead Sciences. MNR has received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare and honoraria from AbbVie, Gilead Sciences, Janssen, and ViiV Healthcare. OOO has received honoraria from Gilead Sciences and ViiV Healthcare. JRB has received consulting fees from Gilead Sciences, MSD, Pfizer, and ViiV Healthcare and honoraria from AbbVie, Gilead Sciences, MSD, Pfizer, AstraZeneca, GSK, Janssen, ViiV Healthcare, and NovoNordisk. DPH has received research funding from Gilead Sciences, MSD, ViiV Healthcare, GSK, Janssen; honoraria for speakers bureau from Gilead Sciences and ViiV Healthcare; meeting or travel support from Gilead Sciences, ViiV Healthcare, GSK, and MSD; and served on advisory boards for and received consulting fees from Gilead Sciences, ViiV Healthcare, and Janssen. RP has served on advisory boards for and received consulting fees from Pfizer, MSD, Gilead Sciences, ViiV Healthcare, GSK, Roche, Atea, and Lilly and has received research funds (awarded to institution) from MSD, Gilead Sciences, and ViiV Healthcare. JR has received honoraria from MSD, Gilead Sciences, ViiV Healthcare, and Theratechnologies, outside the submitted work; meeting or travel support from Gilead Sciences; and has served on advisory boards for MSD, Gilead Sciences, and ViiV Healthcare. JKR has received consulting fees from AbbVie, Boehringer, Gilead Sciences, Merck, and ViiV Healthcare; honoraria from Gilead, Merck, Janssen, and ViiV; has served on advisory board for Abivax; and is a member of the governing board of the European AIDS Clinical Society. AC has received research funding from MSD and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD, and ViiV Healthcare., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25 mg Film Tablet", which contains 25 mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT., Methods: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m 2 on day 1, intravenous doxorubicin 50 mg/m 2 on day 1, intravenous vincristine 1·4 mg/m 2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m 2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m 2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m 2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258., Findings: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238)., Interpretation: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined., Funding: Janssen and Leukemia & Lymphoma Society., Competing Interests: Declaration of interests MD reports research grants for clinical studies from AbbVie, Bayer, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche; speakers' honoraria from AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; travel support from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, Lilly/Loxo Oncology, Novartis, and Roche. JDo reports payment for expert testimony (once Advisory Board) from Lilly. EG reports grants from Janssen; honoraria (educational lecture) from Genmab, Gilead, Janssen, and Lilly; support for attending meetings or travel from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Gilead/Kite and Miltenyi Biotec. MJ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead/Kite, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Gilead/Kite, Janssen, and Pierre Fabre. JW reports grants to his institution from GlaxoSmithKline/Novartis and Roche; honoraria for lectures from AbbVie, Amgen, Gilead, Novartis, Roche, Servier, and Takeda; participation on an Advisory Board from AbbVie, Gilead, Novartis, Roche, and Takeda. MHu reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda. UM reports travel support from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche; Advisory Board role for Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda; participation in national Guideline committee for the German-Swiss-Austrian Guideline for Mantle Cell Lymphoma. JR reports participation on an Advisory Board for AstraZeneca. VV reports consulting fees from AbbVie, BeiGene, Gilead, Lilly, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Janssen; payment for expert testimony from Gilead and Roche; support for attending meetings or travel from AbbVie and Gilead. MGdS reports a research grant from AstraZeneca; payment for Advisory Boards from AbbVie, Gilead, Janssen-Cilag, Roche, and Takeda; payment or honoraria for educational events from Gilead and Janssen-Cilag; support for attending meetings or travel from AbbVie, Janssen-Cilag, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for Roche; leadership in a scientific society (Sociedade Portuguesa de Hematologia); administration board on a patient advocacy group (Associação Portuguesa Contra a Leucemia). SL reports grants or contracts to her institution from Bristol-Myers Squibb/Celgene, Genmab, HUTCHMED, Novartis, and Roche; consulting fees from AbbVie, Genmab, Gilead, Novartis, ORION Pharma, Roche, and Swedish Orphan Biovitrum (sobi); payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead, Incyte, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Incyte. StS reports grants or contracts from any entity from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; consulting fees from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; support for attending meetings or travel from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; receipt of equipment, materials, drugs, medical writing, gifts, or other services from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem. AK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol-Myers Squibb/Celgene, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; support for attending meetings or travel from AbbVie, BeiGene, EUSA Pharma, Swedish Orphan Biovitrum (sobi), and Takeda. RJ reports travel support for meeting attendance from BeiGene; meeting fee from Janssen. GH reports grants or contracts for clinical research from AbbVie, Gilead/Kite, Incyte, Janssen, MorphoSys, Pfizer, and Roche; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi Biotec, Novartis, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche; support for attending meetings or travel from Gilead/Kite and Janssen; participation on a Data Safety Monitoring Board or Advisory Board for Miltenyi Biotec. CV reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead/Kite, Incyte, Istituto Gentili, Janssen, Lilly, Novartis, Pfizer, Roche, and Servier; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Bristol-Myers Squibb, Incyte, Janssen, Lilly, Pfizer, and Roche. TvM reports payment or honoraria for educational lectures from Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Lilly; participation on a Data Safety Monitoring Board or Advisory Board for GE HealthCare and Gilead/Kite. SW reports payment to his institution from AbbVie, Stemline Therapeutics, and Takeda; payment for expert testimony from Stemline Therapeutics; support for attending meetings or travel from AbbVie and BeiGene; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Astra Zeneca, Roche, and Stemline Therapeutics. PLZ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda. UN reports consulting fees to his institution from AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to his institution from Bristol-Myers Squibb/Celgene, Gilead, Novartis, and Takeda; support for attending meetings or travel from Janssen, Gilead, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda. CH reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol-Myers Squibb, Janssen, and Pfizer; support for attending meetings or travel from AbbVie and Janssen. MHa reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation, Gilead, Novartis, and Swedish Orphan Biovitrum (sobi); payment for expert testimony from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen, Novartis, Pizer, Roche, Sanofi-Aventis, and Swedish Orphan Biovitrum (sobi). WK reports research grants provided to his institution from Amgen, Janssen, Roche, and Takeda. DG reports support for attending meetings and travel from Janssen. CS reports consulting fees from Bristol-Myers Squibb and Janssen; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and Bristol-Myers Squibb; support for attending meetings or travel from Gilead/Kite. MU reports institutional funding of the TRIANGLE trial from Janssen. ML reports consulting fees from AstraZeneca, BeiGene, Janssen, and Lilly; honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Janssen, and Lilly; participation on a Data Safety Monitoring Board with Acerta. All other authors (MT, OS, LJ, MC, LA, PH, FB, KS, JDi, CP, and EH) declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg., Methods: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUC tau ) and concentration at the end of the dosing interval (C tau ) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320., Findings: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUC tau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); C tau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48., Interpretation: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg., Funding: Gilead Sciences., Competing Interests: Declaration of interests CAR received grant support to their institution from Gilead, GSK, and ViiV Healthcare during the study and outside the submitted work; and support for meeting travel from Gilead outside the submitted work. RS reports grant support to their institution from Gilead, GSK, Merck, and Penta outside the submitted work; and support for meeting travel from Gilead outside the submitted work. CKC and PK report grant support to their institution from Gilead for the conduct of this study. MK, RL, JTH, VAV, and KK are employed by Gilead and hold stocks in Gilead. MFC reports grant support to their institution from Gilead for the conduct of this study. AHG reports clinical trial agreement to their institution from Gilead for the conduct of this study; and is Chair of the Data Safety and Monitoring Board for a study sponsored by the National Institute of Dental and Craniofacial Research. All other authors declare no competing interests., (© 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Objective: Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together., Methods: Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (C max ) of each compound were within 0.70-1.43, we considered this as no clinically relevant PK interaction., Results: A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC 0-∞ and C max fell outside our acceptance criteria of 0.70-1.43., Conclusions: Although TAF AUC and C max 90% CIs fell outside the pre-defined criteria (0.62-1.11 and 0.65-1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study., (© 2024. The Author(s).)

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1., Methods: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires., Results: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers., Conclusion: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years., Trial Registration: ClinicalTrials.gov Identifier: NCT04006704., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SVH, EVL, VH, and SV are or were employees of Janssen Pharmaceuticals and may hold stock / stock options in Johnson & Johnson.

Introduction: The results from 2 phase 3 studies, through 2 years, in chronic hepatitis B infection showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. We report updated results through 5 years., Methods: Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B infection with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, and serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses., Results: Of 1,298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA <29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median estimated glomerular filtration rate (by using Cockcroft-Gault) declined <2.5 mL/min, and mean declines of <1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF., Discussion: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma., Methods: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed., Results: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group., Conclusions: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.)., (Copyright © 2022 Massachusetts Medical Society.)

Despite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P < .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL., (© 2022 by The American Society of Hematology.)

Ferroptosis was reported to be involved in the occurrence and development of asthma. However, the potential mechanism underlying the role of ferroptosis in asthma remains unclear. In this study, we established the mouse asthma model following the ovalbumin (OVA) method in C57BL/6 mice and the cell model with IL-13 induction in bronchial epithelial cells (BEAS-2B cells). Treatment of ferrostatin-1 (Ferr-1) and 3-methyladenine (3-MA) decreased iron deposition in IL-13-induced BEAS-2B cells and lung tissues of asthma mice, opposite to that in bronchoalveolar lavage fluid (BALF). Meanwhile, excessive lipid peroxidation asthma model in vivo and in vitro was alleviated by Ferr-1 or 3-MA treatment. In addition, Ferr-1 and 3-MA inhibited the expression of LC-3 in these cells and lung tissues of mice. Moreover, Ferr-1 and 3-MA also suppressed the production of inflammatory cytokines (IL-1 β , IL-6, and TNF- α ) and oxidative stress factors (ROS and MDA), while promoting the level of SOD, in vivo and in vitro . Furthermore, application of Ferr-1 exhibited a greater inhibitory effect on iron release and lipid peroxidation in IL-13-induced BEAS-2B cells and asthma mice than 3-MA, accompanied with a weaker effect on ferritinophagy than 3-MA. Collectively, Ferr-1 and 3-MA ameliorated asthma in vivo and in vitro through inhibiting ferroptosis, providing a new strategy for the clinical treatment of asthma., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Nan Yang and Yunxiao Shang.)

Objective: To evaluate temporal trends in survival and causes of death in patients with chronic lymphocytic leukemia (CLL) in a nationwide study., Methods: The cohort consisted of 13,009 Swedish CLL patients diagnosed 1982-2013. Relative survival (RS) and excess mortality rate ratios (EMRR) with 95% confidence intervals (95% CIs) were estimated using flexible parametric survival models. Cause-specific hazard ratios (HRs) were estimated for the linear effect of 10-year increase in year of diagnosis., Results: The excess mortality decreased comparing 2003-2013 to 1982-1992 (EMRR = 0.53, 95% CI 0.48-0.58). The 5-year RS increased between 1982 and 2012 for patients >51 years at diagnosis and improved for patients ≤51 years after 2002. The rate of CLL-specific deaths decreased over time (HR = 0.78, 95% CI 0.75-0.81). Compared to patients with no comorbidity, patients with 1 and 2+ Charlson Comorbidity Index points had HR = 1.35 (95% CI 1.25-1.45) and HR = 1.47 (95% CI 1.37-1.57) for CLL-related mortality, respectively., Conclusion: Survival in CLL patients improved in the era of chemoimmunotherapy, and this was largely explained by reduced CLL-related mortality. The increased rate of CLL-related mortality in patients with comorbidities emphasizes the importance of the newer and better tolerated targeted therapy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Therapy of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with drugs such as ibrutinib and rituximab is often associated with immune suppression, opportunistic infections, and reactivation of virus infections such as hepatitis B virus (HBV). This risk is especially important in geographical regions like Asia where many potential therapy recipients have HBV infection. Also, whether safety and efficacy of ibrutinib in Asians and Europeans with advanced CLL/SLL are similar is unknown. We determined the safety and efficacy of ibrutinib compared with rituximab in advanced CLL/SLL including persons with HBV infection. We compared outcomes with data published from trials in persons of European descent., Methods: This is a post hoc analysis of a multicenter, phase-3 trial (NCT01973387). Subjects with advanced CLL/SLL were randomized 2:1 to receive ibrutinib, 420 mg/day, or rituximab, 500 mg/mE + 2, for 6 cycles. Subjects with resolved HBV infection were included. Endpoints were progression-free survival (PFS), overall response rate (ORR), survival, and adverse events including resolved HBV reactivation., Results: 131 subjects received ibrutinib (N = 87) or rituximab (N = 44) including 53 with resolved HBV infection. Median follow-up was 31 months (95% confidence interval: 28, 32 months). ORR was 61% (50, 71%) versus 7% (2, 18%; p < 0.001). Median PFS was not reached in the ibrutinib cohort but must be >40 months versus 8 months (7, 9 months; p < 0.0001) in the rituximab cohort. Median survival was not reached but must be >40 months versus 27 months (17 months, NE; p = 0.0006). In multivariable analyses, receiving ibrutinib increased PFS (hazard rate [HR] for failure = 0.12 [0.06, 0.23]; p < 0.001) and decreased risk of death (HR = 0.31 [0.15, 0.63]; p < 0.001). Median duration of exposure to ibrutinib was significantly longer than exposure to rituximab (28 vs. 5 months). The safety profile of ibrutinib was consistent with that observed in previous studies with no new safety signal. No subject receiving ibrutinib had HBV reactivation versus 2 receiving rituximab, despite much greater use of drugs to prevent HBV reactivation in the rituximab cohort. Outcomes were like those reported in persons of European descent, except ORR which, was unreliably correlated with PFS in Asians., Conclusion: Ibrutinib is safe and effective in persons with advanced CLL/SLL and better than rituximab in all therapy outcomes including risk of HBV reactivation. Outcomes with ibrutinib in Chinese were like those reported in persons of predominately European descent., (© 2021 S. Karger AG, Basel.)