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Introduction: Human immunodeficiency virus HIV causes a well-known global disease, acquired immunodeficiency syndrome (AIDS), which has a high disease burden in Africa. HIV infection is known to be associated with oxidative stress, which may contribute to disease severity. However, the effect of HAART is equivocal, and requires more studies. 8-hydroxy-2-deoxyguanosine (8-OHdG), a useful biomarker to assess oxidative DNA damage in biological fluids, was therefore measured in this study., Objectives: The study measured 8-OHdG in HIV seronegative and seropositive participants and correlated it with the duration of HAART., Research Question: Does HIV infection have an effect on oxidative DNA damage? Does HAART have an effect on oxidative DNA damage? Does HAART duration have an effect on oxidative DNA damage?, Methods: This was a cross-sectional study consisting of 99 participants in 4 strata: 20 HIV seronegative, 25 HAART naïve, 26 on HAART <5 years, and 28 on HAART >5 years. Those on HAART were all on Tenofovir, Lamivudine, and Dolutegravir (TLD) combination. The questionnaires were administered, and blood samples were collected from all the participants. The serum 8-OHdG was measured with enzyme-linked immunosorbent assay in all the participants. The universal biosafety standards were strictly adhered to. The data were collected and analyzed with SPSS 2016 version., Results/discussion: The serum levels of 8-OHdG of the participants were shown below. Our findings showed higher 8-OHdG in HIV patients than the Controls and is much higher in HAART naïve when compared with those on HAART (p = 0.005). The serum 8-OHdG and HAART duration were compared and showed a statistically significant negative correlation (r = - 0.331, p= 0.014)., Conclusion: This study found that HIV infection causes oxidative DNA damage which is more in patients who have not started HAART than those on HAART. This showed that the TLD-HAART regimen reduces HIV-associated oxidative stress over time, though not completely. This finding further supports a critical role of oxidative stress in HIV infection, a protective effect of HAART, and a potential role of antioxidants that requires further research., Competing Interests: The Authors declare that no competing interest exists, (Copyright © 2024 by West African Journal of Medicine.)

There is clearly a need for novel antifungal agents, not only concerning spectrum, but also oral bioavailability, tolerability, and drug-drug interactions. There is growing concern for antifungal resistance for current available antifungals, mainly driven by environmental fungicide use or long-term exposure to antifungals, in the setting of mould-active prophylaxis or for chronic antifungal infections, such as chronic pulmonary aspergillosis. Moreover, the incidence of breakthrough infections is increasing, because of the introduction of (mould-active) prophylaxis (1-4). There is emergence of difficult to treat invasive fungal infections, such as those caused by Lomentospora prolificans, cryptic species of Aspergillus, Scedosporium and Coccidioides. Olorofim (F901318) is the first-in class of the orotomides, a novel antifungal class targeting dihydroorotate dehydrogenase (DHODH), a key enzyme in the biosynthesis of pyrimidines. Olorofim shows good in vitro and in vivo activity against Aspergillus species, rare and difficult to treat moulds and endemic dimorphic fungi, including azole- and amphotericin-resistant isolates. It lacks activity against yeasts and the Mucorales species. It is only orally available and shows very promising results in ongoing clinical trials. In this review we will describe the mechanism of action of olorofim, the spectrum of activity in vitro and in vivo, pharmacokinetics, pharmacodynamics, drug-drug interactions, resistance, and clinical outcomes., (© 2024. The Author(s).)

GDC-6036 is a covalent KRAS G12C inhibitor that demonstrates high potency and selectivity. Structurally, GDC-6036 consists of several motifs that make the analytical characterization of this molecule challenging, including a highly basic pyrrolidine motif bonded to a quinazoline ring via an ether bond and an atropisomeric carbon-carbon bond between functionalized pyridine and quinazoline groups. Structurally, the desired atropisomer was synthesized via an atroposelective Negishi coupling with very high yield. However, having a direct way to analyze and confirm the presence of the atropisomeric species remained challenging in routine analytical workflows. In this study, both variable temperature nuclear magnetic resonance (VT-NMR) and two different approaches of in-line ion mobility coupled to liquid chromatography mass spectrometry (LC-MS) workflows were evaluated for the characterization of GDC-6036 and its undesired atropisomer (Compound B) to support synthetic route development. Briefly, both VT-NMR and traveling wave ion mobility spectrometry (TWIMS) enabled by structures for lossless ion manipulation (SLIM) technology coupled to high resolution MS (HRMS) are able to elucidate the structures of the atropisomers in a complex mixture. Drift tube IMS (DTIMS) was also evaluated, but lacked the resolving power to demonstrate separation between the two species in a mixture, but did show slight differences in their arrival times when multiplexed and injected separately. The determined resolving power ( R p ) by multiplexing the ions via DTIMS was 67.3 and 60.5 for GDC-6036 and Compound B, respectively, while the two peak resolving power ( R pp ) was determined to be 0.41, indicating inadequate resolution between the two species. Alternatively, the SLIM-IM studies showed R p of 103.8 and 99.4, with a R pp of 2.64, indicating good separation between the atropisomers. Furthermore, the CCS/z for GDC-6036 and Compound B was determined to be 231.2 Å 2 /z and 235.0 Å 2 /z, respectively. Quantitative experiments demonstrate linearity ( R 2 >0.99) for both GDC-6036 and Compound B while maintaining separation via SLIM-IM. Spike recoveries of one atropisomer relative to the other yielded strong recoveries (98.7% to 102.5%) while maintaining reproducibility (<7% RSD). The study herein describes the analytical process for evaluating new technologies and strategies for implementation in routine biopharmaceutical characterization workflows.

It is debated whether CNS involvement begins during acute human immunodeficiency virus (HIV) infection in persons without meningitis/encephalitis and whether specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir; darunavir; or both) during primary HIV infection were enrolled. Serum and CSF were collected at baseline and at 12 and 48 (serum only) weeks after treatment initiation. Single molecule array was used to measure neurofilament light chain (NFL), total tau protein (Tau), brain-derived neurotrophic factor, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase. We assessed the longitudinal change in biomarkers over time, in addition to the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/ml if 5-18 years, 10 pg/ml if 18-51 years, 15 pg/ml if 51-61 years, 20 pg/ml if 61-70 years and 35 pg/ml if >70 years). Serum was available from 47 participants at all time points, and CSF was available from 13 participants at baseline and 7 at Week 12. We observed a significant direct serum-to-CSF correlation for NFL (ρ = 0.692, P = 0.009), GFAP (ρ = 0.659, P = 0.014) and brain-derived neurotrophic factor (ρ = 0.587, P = 0.045). Serum (ρ = 0.560, P = 0.046) and CSF NFL (ρ = 0.582, P = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (P = 0.006) and GFAP (P = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and four participants (30.8%), respectively; considering serum NFL, this proportion was lower at Weeks 12 (31.9%, P = 0.057) and 48 (27.7%, P = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. 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: Several important vaccines differ in immunogenicity and efficacy between populations. We hypothesised that malaria suppresses responses to unrelated vaccines and that this effect can be reversed-at least partially-by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings., Methods: We conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine on vaccine responses among schoolchildren aged 9-17 years in Jinja district, Uganda. Participants were recruited from two schools and did not have exposure to vaccines of interest after the age of 5 years, with the exception of human papillomavirus (HPV). Computer-generated 1:1 randomisation was implemented in REDCap. 3-day courses of dihydroartemisinin-piperaquine (dosage by weight) or placebo were administered monthly, including twice before the first vaccination. Trial participants were vaccinated with the live parenteral BCG vaccine (Serum Institute of India, Pune, India) at week 0; yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France); live oral typhoid vaccine (Ty21a; PaxVax, London, UK), and quadrivalent virus-like particle HPV vaccine (Merck, Rahway, NJ, USA) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated, and a tetanus-diphtheria booster was given after completion of the trial at week 52. Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, at week 52, and analysis was done in the intention-to-treat population. Malaria parasite prevalence at enrolment and during follow-up was determined retrospectively by PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN62041885) and is complete., Findings: Between May 25 and July 14, 2021, we assessed 388 potential participants for eligibility. We enrolled and randomly allocated 341 participants to the two groups (170 [50%] to dihydroartemisinin-piperaquine and 171 [50%] to placebo); 192 (56%) were female and 149 (44%) participants were male. 145 (85%) participants in the dihydroartemisinin-piperaquine group and 140 participants (82%) in the placebo group were followed up until the week 52 endpoint. At enrolment, 109 (64%) of all participants in the dihydroartemisinin-piperaquine group and 99 (58%) of 170 participants in the placebo group had malaria; this reduced to 6% or lower at all follow-up visits in the dihydroartemisinin-piperaquine group. There was no effect of dihydroartemisinin-piperaquine versus placebo on primary outcomes: BCG-specific IFNγ ELISpot response had a geometric mean ratio (GMR) of 1·09 (95% CI 0·93-1·29), p=0·28; yellow fever neutralising antibody was 1·19 (0·91-1·54), p=0·20 for plaque reduction neutralising reference tests (PRNT 50 ) titres (the reciprocal of the last plasma dilution that reduced by 50%) and 1·24 (0·97-1·58), p=0·09 for PRNT 90 titres (reciprocal of the last plasma dilution that reduced by 90%); and IgG to Salmonella enterica serovar Typhi O-lipopolysaccharide was 1·09 (0·81-1·46), p=0·58, HPV-16 was 0·72 (0·44-1·77), p=0·19, HPV-18 was 0·71 (0·47-1·09), p=0·11; tetanus toxoid was 1·22 (0·91-1·62), p=0·18, and diphtheria toxoid was 0·97 (0·83-1·13), p=0·72. There was some evidence that dihydroartemisinin-piperaquine reduced waning of the yellow fever response., Interpretation: IPT for malaria with dihydroartemisinin-piperaquine did not improve peak vaccine responses, despite reducing malaria prevalence. Possible longer-term effects on response waning should be further explored., Funding: UK Medical Research Council., Translation: For the Luganda translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests GN reports funding from the EDCTP2 programme supported by the EU, and from the Wellcome Trust. AME, PK and SC report funding from the UK Medical Research Council (MRC) for conduct of the study; AME reports funding from UK National Institute of Health and care Research (NIHR), Science for Africa Foundation, and DELTAS Africa, outside the submitted work. AME and SC further report support from the Serum Institute of India and Emergent BioSolutions; AME reports support from Uganda National Expanded Program on Immunization; SC reports support from Bliss GVS Pharma, India, for conduct of the study. 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: Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses., Methods: We analysed data from 633 infants born to mothers enrolled in a randomised trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs. sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0 to 12 months of age. Using generalised linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anaemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrolment, maternal age, maternal parasitaemia at enrolment, education, and wealth., Findings: SP increased mean LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased mean WLZ by 0.11-0.28 Z from 2 to 8 months compared to SP among infants of multigravidae; at these ages, confidence intervals for mean differences excluded 0. We did not observe differences among primigravida. Mediators of SP included birth weight, birth length, maternal stem cell factor, and DNER. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery., Interpretation: In high malaria transmission settings, this exploratory study suggests different IPTp regimens may influence infant growth among multigravidae, potentially through distinct pathways, in the exclusive breastfeeding period, when few other interventions are available., Funding: Stanford Center for Innovation in Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests Anna Nguyen is the recipient of a grant from them National Institute of Allergy and Infectious Diseases (F31AI179107) focused on evaluating the causal effects of anti-malarial chemoprevention in pregnancy and childhood on growth outcomes using a different dataset. The other authors declare no further potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chemotherapy-induced peripheral neuropathy (CIPN) used to treat cancer, is a significant side effect with a complex pathophysiology, and its mechanisms remain unclear. Recent research highlights neuroinflammation, which is modulated by the endocannabinoid system (ECS) and associated with glial activation, and the role of toll-like receptor 4 (TLR4) in CIPN. This study aimed to investigate the effects of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and explore the connection between cannabinoid receptors and TLR4 in glial cells. A CIPN animal model was developed using cisplatin-injected male C57BL/6 mice. Mechanical and cold allodynia were assessed through von Frey and acetone tests. Western blot analysis was used to examine the expression of catabolic enzymes, cannabinoid receptors, glial cells, and neuroinflammatory factors in the dorsal root ganglia (DRGs) and spinal cord. Immunohistochemistry was used to investigate the colocalization of cannabinoid receptors and TLR4 in glial cells. JZL195 alleviated pain by inhibiting FAAH/MAGL, modulating the ECS and neuroinflammatory factors, and suppressing glial cell activity. Additionally, cannabinoid receptors and TLR4 colocalized with astrocytes and microglia in the spinal cord. This study highlights the therapeutic potential of JZL195 in modulating the ECS and suggests a correlation between cannabinoid receptors and TLR4 in spinal glial cells, providing insight into alleviating pain and neuroinflammation in CIPN., 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 Masson SAS.. All rights reserved.)

Postoperative pain management is challenging. We used mice with a transverse laparotomy to study tactile allodynia measured by the von Frey test, pain at rest measured by facial pain expressions detected by an artificial intelligence algorithm, and movement-induced pain measured by reductions in exploratory activity. The standard analgesics morphine and ibuprofen induced distinct patterns of outcome-dependent effects. Whereas morphine was more effective in reversing pain at rest compared to tactile allodynia, it was unable to alter movement-induced pain. Ibuprofen showed comparable effects across the three outcomes. Administered together, the compounds induced synergistic effects in the three aspects of postoperative pain, mirroring the known advantages of multimodal analgesia used in clinical practice. We explored the impact of neuroimmune interactions using a neutrophil depletion strategy. This reversed pain at rest and movement-induced pain, but did not alter cutaneous sensitivity. Non-peptidergic (IB4+) and peptidergic (CGRP+) nociceptors are segregated neuronal populations in the mouse. We tested the effects of gefapixant, an antitussive drug targeting non-peptidergic nociceptors through P2X3 antagonism, and olcegepant, an antimigraine drug acting as a CGRP antagonist. Both compounds reversed tactile allodynia, while only gefapixant reversed pain at rest, and none of them reversed movement-induced pain. In conclusion, tactile allodynia, pain at rest, and movement-induced pain after surgery have different pharmacological profiles, and none of the three aspects of postoperative pain can predict the effects of a given intervention on the other two. Combining these measures provides a more realistic view of postoperative pain and has the potential to benefit analgesic development., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients. Illustration of the oncogenic pathway regulated by SUV39H1 in NB., (© 2024. The Author(s).)

The present study utilized Analytical Quality by Design (AQbD) approach to develop a stability-indicating high-performance liquid chromatography (HPLC) method for estimating evogliptin tartrate using design expert software. The key parameters were methodically optimized, contours were plotted, and stability was evaluated using various forced degradation conditions. Using an Agilent HPLC system with a photo diode array (PDA) detector along with Fortis C18 column (250 × 4.6 mm, 5 μm) effectively separated the drug from its degradants. The mobile phase used was methanol: water (pH adjusted to 3.0, 76:24; v/v) at 0.8 mL/min flow rate. Evogliptin was eluted at 2.98 min, at a detection wavelength of 267 nm. The proposed method was found to be specific, precise, linear and robust. The drug was sensitive to acidic, basic, oxidative, thermal, and photodegradation resolving six degradation products. Thus, the developed AQbD-based stability-indicating HPLC method is applicable in analyzing evogliptin in bulk, tablet dosage form and stability samples., (© 2024 John Wiley & Sons Ltd.)

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC 0-24h divided by DTG AUC 0-24h ) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination., Patients and Methods: In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level., Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups., Conclusion: Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Potential associations between periconception dolutegravir (DTG) exposure and neural tube defects (NTDs) reported in 2018 caused shifting international and national antiretroviral treatment (ART) guidelines. They sometimes required women to use contraception prior to initiating DTG. To better understand the tensions between ART and family planning (FP) choices, and explore the decision-making processes of women living with HIV (WLHIV) and their healthcare providers (HCPs) employed, we conducted interviews with WLHIV exposed to DTG and their providers in western Kenya from July 2019 to August 2020. For the interviews with WLHIV, we sampled women at varying ages who either continued using DTG, switched to a different ART, or became pregnant while using DTG. We utilized inductive coding and thematic analysis. We conducted 44 interviews with WLHIV and 10 with providers. We found four dominant themes: (1) a range of attitudes about birth defects, (2) nuanced knowledge of DTG and its potential risk of birth defects, (3) significant tensions at the intersection of DTG and FP use with varying priorities amongst WLHIV and their providers for navigating the tensions, and (4) WLHIV desiring autonomy, and provider support for this, in such decision-making. Variations in beliefs were noted between WLHIV and HCPs. WLHIV highlighted the impact of community and social beliefs when discussing their attitudes while HCPs generally reported more medicalized views towards DTG utilization, potential adverse outcomes, and FP selection. Decisions pertaining to ART and FP selection are complex, and HIV treatment guidelines need to better support women's agency and reproductive health justice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sotorasib is a small molecule drug that specifically and irreversibly inhibits the KRAS p.G12C mutant protein. This analysis investigated the impact of a high-calorie high-fat meal on the pharmacokinetics, safety, and tolerability of sotorasib in both healthy volunteers and patients with KRAS G12C advanced solid tumors. Each subject received a single oral dose of 360 or 960 mg of sotorasib under fasted conditions or with a high-fat meal (fed conditions). The geometric least squares means (GLSM) ratios (fed/fasted) for 360 mg of sotorasib C max and AUC inf were 1.03 and 1.38, respectively, in healthy volunteers (N = 14). The GLSM ratios (fed/fasted) for C max and AUC 0-24h were 1.38 and 1.75, respectively, with 360 mg of sotorasib in cancer patients (N = 2). The GLSM ratios (fed/fasted) for C max and AUC 0-24h were 0.660 and 1.25, respectively, with 960 mg of sotorasib in cancer patients (N = 8). Sotorasib was well tolerated in fast and fed conditions. The impact of a high-fat meal on sotorasib exposure is less than a 2-fold increase or decrease in C max and AUCs., (© 2024, The American College of Clinical Pharmacology.)

Purpose of Review: Universal antiretroviral (ART) coverage and virological suppression are fundamental to ending AIDS in children by 2030. Availability of new paediatric dolutegravir (DTG)-based ART formulations is a major breakthrough and will undoubtedly help achieve this goal, but treatment challenges still remain., Recent Findings: Paediatric formulations remain limited compared to those for adults, especially for young children, those unable to tolerate DTG or with DTG-based first-line ART failure. Tenofovir alafenamide is virologically superior to standard-of-care backbone drugs in second-line, but paediatric formulations are not widely available. The roles of resistance testing and recycling of backbone drugs following first-line ART failure remain to be determined. Results of trials of novel treatment strategies including dual therapy and long-acting agents are awaited. Although numbers are currently small, safe and effective ART options are urgently required for children developing DTG resistance., Summary: The antiretroviral treatment gap between adults and children persists. The potential benefits from rollout of new paediatric DTG-based fixed-dose combination ART for first-line treatment are considerable. However, children remain disadvantaged when DTG-based first-line ART fails or cannot be used. Research efforts to address this inequity require prioritisation in order to ensure health outcomes are optimised for all ages in all settings., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Acute stress normally engages descending brain pathways to produce an antinociceptive response, known as stress-induced analgesia. Paradoxically, these descending pain modulatory pathways are also involved in the maintenance of the abnormal pain associated with chronic neuropathic pain. It remains unclear how stress-induced analgesia is affected by neuropathic pain states. We therefore examined the impact of a chronic constriction nerve-injury (CCI) model of neuropathic pain on restraint stress-induced analgesia in C57BL/6 mice. Thirty minutes of restraint stress produced analgesia in the hotplate thermal nociceptive assay that was less in CCI compared to control mice who underwent a sham-surgery. In sham but not CCI mice, stress-induced analgesia was reduced by the opioid receptor antagonist naltrexone. The cannabinoid CB 1 receptor antagonist AM281 did not affect stress-induced analgesia in either sham or CCI mice. Low-dose pre-treatment with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195 increased stress-induced analgesia in CCI but not sham mice. The JZL195 enhancement of stress-induced analgesia in CCI mice was abolished by AM281 but was unaffected by naltrexone. These findings indicate that the acute opioid-mediated analgesic response to a psychological stressor is disrupted in a nerve-injury model of neuropathic pain. Importantly, this impairment of stress-induced analgesia was rescued by blockade of endocannabinoid breakdown via a cannabinoid CB 1 receptor dependent mechanism. These findings suggest that subthreshold treatment with endocannabinoid degradation blockers could be used to alleviate the disruption of endogenous pain control systems in a neuropathic pain state., (© 2024 International Society for Neurochemistry.)

Background: Bruton's tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B-lymphocyte and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, BTK inhibitors have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain-penetrant, small-molecule BTK inhibitors may also address compartmentalized neuroinflammation, which is proposed to underlie MS disease progression. BTK is expressed by microglia, which are the resident innate immune cells of the brain; however, the precise roles of microglial BTK and impact of BTK inhibitors on microglial functions are still being elucidated. Research on the effects of BTK inhibitors has been limited to rodent disease models. This is the first study reporting effects in human microglia., Methods: Here we characterize the pharmacological and functional properties of fenebrutinib, a potent, highly selective, noncovalent, reversible, brain-penetrant BTK inhibitor, in human microglia and complex human brain cell systems, including brain organoids., Results: We find that fenebrutinib blocks the deleterious effects of microglial Fc gamma receptor (FcγR) activation, including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by fenebrutinib treatment. In contrast, fenebrutinib had no significant impact on human microglial pathways linked to Toll-like receptor 4 (TLR4) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) signaling or myelin phagocytosis., Conclusions: Our study enhances the understanding of BTK functions in human microglial signaling that are relevant to MS pathogenesis and suggests that fenebrutinib could attenuate detrimental microglial activity associated with FcγR activation in people with MS., (© 2024. The Author(s).)

Objective: To investigate the effect of human colorectal fibroblast (CCD-18Co)-conditioned medium (CCD18-Co-CM) on biological behaviors of colorectal cancer (CRC) cells and explore the possible molecular mechanisms., Methods: Real-time cellular analysis (RTCA), clone formation assay and wound healing assay were used to analyze the changes in proliferation, clone formation, and migration abilities of CRC cell lines HCT116 and Caco-2 treated with CCD18-Co-CM. Western blotting was used to detect the changes in ATK, ERK and STAT3 signaling pathways in the CRC cells activated by CCD18-Co-CM. The effect of CCD18-Co-CM on spheroidization ability of the cells was assessed with sphere-formation assay, and the changes in expressions of CRC stemness markers were detected using RT-PCR., Results: CCD-18Co-CM significantly promoted proliferation, colony formation, and migration of HCT116 and Caco-2 cells, enhanced sphere-forming ability and expressions of CRC stemness markers, and increased ERK phosphorylation in the cells. Treatment with SCH772984 effectively inhibited CCD-18Co-CM-induced ERK signaling pathway activation, suppressed the malignant phenotype, and lowered the sphere-forming ability and expression of stemness markers of the two CRC cells., Conclusion: Colorectal fibroblasts promote malignant phenotype of CRC cells by activating the ERK signaling pathway.

HIV-1 drug resistance (HIVDR) impedes treatment and control of HIV-1, especially in high-prevalence settings such as KwaZulu-Natal (KZN) province, South Africa. This study merged routine HIV-1 genotypic resistance test (GRT) data with Geographic Information Systems coordinates to assess patterns and geographic distribution of HIVDR in KZN, among ART-experienced adults with virological failure. We curated 3133 GRT records generated between 1 January 2018 and 30 June 2022, which includes the early phase of dolutegravir (DTG) rollout, of which 2735 (87.30%) had HIVDR. Of the 2735, major protease, nucleoside, and non-nucleoside reverse transcriptase inhibitor mutations were detected in 41.24%, 84.97% and 88.08% of GRTs, respectively. Additional genotyping of HIV-1 integrase for 41/3133 (1.31%) GRTs showed that 17/41 (41.46%) had integrase strand transfer inhibitor resistance. Notably, of 26 patients on DTG with integrase genotyping, 9 (34.62%) had DTG-associated resistance mutations. Dual- or triple-class resistance was observed in four of every five GRTs. The odds of HIVDR increased significantly with age, with ≥60 years having 5 times higher odds of HIVDR compared to 18-29 years ( p = 0.001). We identified geospatial differences in the burden of HIVDR, providing proof of concept that this could be used for data-driven public health decision making. Ongoing real-time HIVDR surveillance is essential for evaluating the outcomes of the updated South African HIV treatment programme.

Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers and thus have been a target of intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors have finally reached clinical practice. Sotorasib (AMG-510) was the first FDA-approved covalent inhibitor to treat KRAS(G12C)-positive nonsmall cell lung cancer (NSCLC), followed soon by adagrasib (MRTX849). Both drugs target the GDP-bound state of KRAS(G12C), exploiting the strong nucleophilicity of acquired cysteine. Here, we evaluate the similarities and differences between sotorasib and adagrasib in their RAS SII-P binding by applying biochemical, cellular, and computational methods. Exact knowledge of SII-P engagement can enable targeting this site by reversible inhibitors for KRAS mutants beyond G12C. We show that adagrasib is strictly KRAS- but not KRAS(G12C)-specific due to its strong and unreplaceable interaction with H95. Unlike adagrasib, sotorasib is less dependent on H95 for its binding, making it a RAS isoform-agnostic compound, having a similar functionality also with NRAS and HRAS G12C mutants. Our results emphasize the accessibility of SII-P beyond oncogenic G12C and aid in understanding the molecular mechanism behind the clinically observed drug resistance, associated especially with secondary mutations on KRAS H95 and Y96.

Background: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for tuberculosis prevention in people with human immunodeficiency virus (HIV). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. AIDS Clinical Trials Group A5372 evaluated the effect of 1HP on the pharmacokinetics of twice-daily dolutegravir., Methods: A5372 was a multicenter, pharmacokinetic study in people with HIV (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA <50 copies/mL. Participants received daily rifapentine/isoniazid (600 mg/300 mg) for 28 days as part of 1HP. Dolutegravir was increased to 50 mg twice daily during 1HP, and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment., Results: Thirty-two participants (41% female; 66% Black/African; median [Q1, Q3] age, 42 [34, 49] years) were included in the pharmacokinetic analysis; 31 had HIV RNA <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 versus 1987 ng/mL (1331, 2278) on day 28 (day 28:day 0 geometric mean ratio, 1.05 [90% confidence interval, .93-1.2]; P = .43). No serious adverse events were reported., Conclusions: Dolutegravir trough concentrations with 50 mg twice-daily dosing during 1HP treatment were greater than those with standard-dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice-daily dolutegravir use in combination with 1HP for tuberculosis prevention., Clinical Trials Registration: NCT04272242., Competing Interests: Potential conflicts of interest. A.F.L. has contracts for clinical research unrelated to this work from Gilead, ViiV, and Merck; consulting fees from ViiV. A.A. reports grants from Gilead, ViiV, Roche, GSK and MSD unrelated to this work. S.S. reports grants from ViiV unrelated to the present work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© 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.)

Aims: Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signalling in AS are not known. In the present study, we investigated fibroblast growth factor receptor 1 (FGFR1) signalling in AS development and progression., Methods and Results: Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2., Conclusion: Our study provides evidence of a new FGFR1-PLCγ-NF-κB axis in macrophages in inflammatory AS, supporting FGFR1 as a potentially therapeutic target for AS-related diseases., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. 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: Human Immunodeficiency Virus (HIV) and type 2 diabetes (T2D) are amongst the leading causes of death in South Africa. The preferred first-line anti-retroviral treatment contains dolutegravir (DTG), shown to increase body weight, may compound the already high rates of obesity and associated risk for T2D. South Africa has widespread food insecurity, making traditional dietary strategies difficult to implement. Time-restricted eating (TRE) may be an appropriate intervention in resource-limited communities., Methods: This article outlines the development and feasibility testing of a TRE intervention to inform the design of a TRE randomised controlled trial in women (20-45 years old) living with overweight/obesity and HIV, receiving DTG-based treatment from a resource-limited community in Cape Town, South Africa. Factors influencing TRE adoption were identified using the Capability, Opportunity, Motivation - Behaviour model and the Theoretical Domains Framework, combining in-depth interviews (IDIs) and focus group discussions. Participants from the IDIs went on to participate in a single arm 4-week TRE pilot trial where feasibility was explored in terms of reach, acceptability, applicability, and implementation integrity. An iterative, thematic analysis approach was employed to analyse the qualitative data., Results: Participants included 33 isiXhosa-speaking women (mean age 37.1 years, mean BMI 35.9 kg/m 2 ). Thematic analysis identified psychological capability (knowledge of fasting), social influences (cultural preferences, family support), and reflective motivation (awareness of weight, health impact, motivation for TRE) as key factors influencing adoption of TRE for weight management. In a 4-week TRE pilot trial (n = 12), retention was 100%. Positive outcomes perceived included improved energy, appetite control and weight loss. TRE was perceived as acceptable, easy, and enjoyable. Family support facilitated adherence, while habitual and social eating and drinking practices were barriers. Compliance was high, aided by self-selected eating times, reminders, and weekly calls. Recommendations included the incorporation of dietary education sessions and text messages to provide additional support and reminders., Conclusions: This study indicates that TRE is a feasible weight management strategy in women living with overweight/obesity and HIV, receiving DTG-based treatment in a resource-limited community. These findings will ensure that the forthcoming TRE randomised controlled trial is adapted and optimised to the local South African context., (© 2024. The Author(s).)

Background: The increasing incidence and prevalence of breast cancer alongside diagnostic and treatment technology advances have produced a debate about the financial burden cancer places on the healthcare system and concerns about access., Methods: This study was conducted at 51 hospitals belonging to the Breast Cancer Study Group of the Japan Clinical Oncology Group using a web-based survey. The survey period conducted from July 2021 to June 2022. The study population included patients with metastatic breast cancer who received the related treatment as their first-line therapy. The proportion of patients who selected that regimen as their first-line treatment was tabulated. The total cost increase for each current standard therapy in comparison to conventional treatments was calculated., Results: A total of 702 patients (pts) were surveyed. Of those enrolled, 342 (48.7%) received high-cost treatment [estimated monthly drug costs exceeding ~500 000 Japanese Yen (JPY)]. Of these, 16 pts (4.7%) were receiving very high-cost treatment, amounting to more than 1 000 000 JPY per month. Fifty three (15.5%) of the patients who received high-cost treatment were 75 years of age or older. Of these, 1 pt (0.3%) were receiving very high-cost treatment. Analyses of incremental costs by current drugs showed that abemaciclib was costly with total additional cost of 6 365 670 JPY per patient. The total additional cost of the regimen per patient that included palbociclib was the second highest at 4011248 JPY, followed by atezolizumab at 3209033 JPY., Conclusions: The findings indicate that evaluating the financial implications of high-cost treatments requires considering not only drug prices but also analysis of total cost increase., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Surveillance studies of Transmitted Drug Resistance (TDR) are crucial in tracking the evolution of HIV epidemiology. Our aim was to investigate TDR to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), as well as to new drugs: lenacapavir, fostemsavir. Predictive sensitivity was evaluated for maraviroc and broadly neutralizing antibodies (bNAbs) (zinlirvimab and teropavimab). Between 2020 and 2023, 85 people with HIV (PWH) were diagnosed with primary HIV-1 infection (PHI). Pol and env sequences were analyzed and TDR was characterized according to the French ANRS algorithm. The genotypic-based prediction of bNAbs sensitivity was based on HIV env amino acid signatures I108, I201, F353 for teropavimab and N325, N332, H330 for zinlirvimab. TDR to NRTIs, NNRTIs, PIs and INIs was evidenced in 8.2%, 12.9%, 4.7%, and 5.9% strains, respectively. Ten viruses were CXCR4/dual mix. All viruses were susceptible to lenacapavir (100%) and 52% harbored resistance to fostemsavir. The genotypic profile was associated with a predictive positive value (PPV) > 83% of susceptibility to both teropavimab and zinlirvimab for 23 viruses (31%), while 22 (29%) had a PPV between 62% and 75%, suggesting reduced susceptibility to both bNAbs as soon as primary infection. The surveillance of TDR evidenced at the time of PHI is important with regard to new strategies for HIV patients with virological failure and global implementation of PrEP using NRTI, INI such as recently approved injectable cabotegravir, and future long-acting drugs such as lenacapavir and bNAbs., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Objectives: KRAS (G12C) inhibitors (sotorasib and adagrasib) have approved treatment in patients with KRAS (G12C)-mutated non-small cell lung cancer (NSCLC). The post-marketing data concerning KRAS (G12C) inhibitors remain limited, and the outcomes of relevant studies are yet to yield conclusive evidence supporting the long-term safety of KRAS (G12C) inhibitors., Materials and Methods: This investigation comprehensively assessed adverse events (AEs) attributed to KRAS (G12C) inhibitors by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The dataset encompasses the period from the first quarter of 2021 to the first quarter of 2024. A disproportionality analysis was conducted to quantify the correlation between KRAS (G12C) inhibitors and AEs. The metrics employed for the evaluation of disproportionality comprise the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayesian geometric mean (EBGM)., Results: A total of 2,253 and 486 reports were identified as related to sotorasib and adagrasib, with the identification of 51 and 26 preferred terms, respectively. The most frequent AEs of sotorasib comprised diarrhoea (ROR 5.27), hepatotoxicity (ROR 38.09), alanine aminotransferase increased (ROR 17.41), aspartate aminotransferase increased (ROR 20.88), and hepatic function abnormal (ROR 19.88). The most common AEs of adagrasib included diarrhoea (ROR 4.21), nausea (ROR 3.84), vomiting (ROR 5.36), decreased appetite (ROR 4.79), and dehydration (ROR 7.00). A relatively reduced risk of hepatotoxicity but a increased risk of serious AEs in adagrasib compared to sotorasib (P < 0.001)., Conclusion: Our findings would provide valued evidence for healthcare professionals to recognize AEs associated with KRAS (G12C) inhibitors and differences between sotorasib and adagrasib, and guide their clinical practice., 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 Elsevier B.V. All rights reserved.)

Background: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have emerged as a significant advancement in the treatment of HR+/HER2- metastatic breast cancer (MBC). Despite the clinical efficacy of CDK 4/6 inhibitors in HR+/HER2- metastatic breast cancer, there remains a significant gap in understanding their cost-effectiveness, particularly regarding the long-term economic impact and the key drivers of costs, when used in combination with endocrine therapy. This study aims to systematically review and conduct a meta-analysis of cost-effectiveness studies evaluating CDK4/6 inhibitors in treatment of HR+/HER2- advanced breast cancer and identify key drivers of costs of CDK4/6 inhibitors in combination with endocrine therapy., Methods: A comprehensive search of PubMed and Embase was conducted to identify peer-reviewed studies from February 2015 to March 2022 reporting cost-effectiveness of CDK4/6 inhibitors in MBC treatment. Incremental net benefits (INBs) were estimated, and meta-analysis was conducted. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: We identified 120 articles, of which 18 were eligible for systematic review and 16 for meta-analysis. None of the three CDK4/6 inhibitors had positive INB compared to endocrine/aromatase inhibitors therapy alone. The pooled INB was estimated at -$149,266.87 (95% Confidence Interval (CI) = -$196,961.54, -$101,572.20)., Conclusion: The combination of CDK4/6 inhibitors and letrozole/endocrine therapy for the treatment of postmenopausal patients with advanced HR+/HER2 - MBC was not cost-effective.

Background: In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL)., Methods: In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m 2 intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes., Results: Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12)., Conclusions: Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC., Competing Interests: Declaration of competing interest David M. Waterhouse received consulting fees from Bristol Myers Squibb (BMS), Amgen, Janssen, Merck, Fresenius Kabi, and Novartis; received honoraria from BMS, AstraZeneca, Amgen, Janssen, EMD Serono, Fresenius Kabi, and Sanofi; received support to attend meetings and/or travel from BMS and Amgen; and participated on a data safety monitoring board or advisory board for BMS, AstraZeneca, AbbVie, Amgen, Janssen, Eisai, EMD Serono, Merck, Pfizer, Fresenius Kabi, Sanofi, Astellas, Gilead, Takeda, Daiichi, and Bayer. Sacha Rothschild received grants or research support from AstraZeneca, Merck Serono, Roche Pharma, and Amgen; received consulting fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck KG, MSD, Novartis, Otsuka, Pfizer, PharmaMar, Roche Pharma, Roche Diagnostics, Sanofi Aventis, and Takeda; received honoraria from Roche Pharma, BMS, AstraZeneca, Amgen, MSD Oncology, Novartis, Roche Diagnostics, and Takeda; received payment for expert testimony from Roche, AstraZeneca, and BMS; received support for attending meetings and/or travel from Roche Pharma, Eli Lilly, BMS, Amgen, AstraZeneca, and MSD; participated on a data safety monitoring board or advisory board for Roche Pharma; and is the vice president of the Swiss Group for Clinical Cancer Research (SAKK) and elected member of the Swiss Federal Drug Commission (Federal Health Office). Christophe Dooms has nothing to disclose. Bertrand Mennecier received honoraria from Amgen, Roche, AstraZeneca, Pharma Mar, Eli Lilly, BMS, MSD, Sanofi, Takeda, and Pfizer; and received support for attending meetings and/or travel from MSD, Roche, BMS, AstraZeneca, and Takeda. Farastuk Bozorgmehr received grant/research support from Roche and AstraZeneca; received honoraria from Novocure, Daiichi Sankyo, GSK, and AstraZeneca, received support for attending meetings and/or travel from Janssen; and participated in a data safety monitoring board or advisory board for Amgen, AstraZeneca, Daiichi Sankyo, and Janssen. Margarita Majem received consulting fees from AstraZeneca, Roche, MSD, Janssen, and Sanofi; received honoraria from MSD, Roche, AstraZeneca, Casen Recordati, Takeda, and Helsinn; received support for attending meetings and/or travel from MSD, Pfizer, Roche, and AstraZeneca, and is the vice president of ICAPEM and a board member of AEC Barcelona. Michel M. van den Heuvel participated on a data safety monitoring board or advisory board for Amgen. Helena Linardou received payment or honoraria for lectures and/or speakers bureaus from Roche, AstraZeneca, Pfizer, BMS, MSD, Novartis, Amgen, and GSK; received support for attending meetings and/or travel from Pfizer and Roche; participated on a data safety monitoring board or advisory board for Roche, AstraZeneca, MSD, BMS, Novartis, Pfizer, and Amgen; and held unpaid positions in non-profit organizations, including president of a scientific committee in the Hellenic Cooperative Oncology Group and board member for Hellenic Foundation of Cancer Research, FairLife Lung Cancer, and W4O-Hellas. Byoung Chul Cho received grant/research support from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridge Biotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS BIO, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG. Rachel Roberts-Thomson received royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; received consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, MedPacto, Blueprint Medicines, RaND Bio, and Hanmi; received honoraria from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer; participated on a scientific advisory board for Kanaph Therapeutics, Bridge Biotherapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, and Amgen; was a board member for J INTS BIO; owned stock in TheraCanVac Inc, Gencurix Inc, Bridge Biotherapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., and J INTS BIO; was employed by Yonsei University Health System and is a founder of DAAN Biotherapeutics. Kentaro Tanaka received consulting fees from Pfizer and received honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Takeda Pharmaceutical, Novartis, Ono Pharmaceutical, Daiichi Sankyo, Merck, MSD, and BMS. Normand Blais received consulting and speakership fees from Amgen. Gustavo Schvartsman received consulting fees from AstraZeneca, BMS, Merck, Sharp & Dome, and Daiichi Sankyo; received honoraria from Roche, Amgen, Adiu, and Pfizer; and received support for attending meetings and/or travel from Merck, Sharp & Dome and Daiichi Sankyo. Karin Holmskov Hansen participated in clinical trial safety meetings for MSD and Incyte (not paid) and was head of the Danish Oncology Group until February 2023 (not paid) and a member of the Expert Committee under the Danish Medicines Council (not paid). Izabela Chmielewska received consulting honoraria from Amgen; and received speakership fees from Amgen, BMS, Takeda, Roche, and MSD. Martin D. Forster received grant/research support from Cancer Research UK Early Detection Committee Program Grant, Bristol Myers Squibb Research Grant, NIHR RfPB Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, Merck Educational Grant, MSD Educational Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, MRC BMC:DPFS Grant Award, and Boehringer Ingelheim Educational Grant and received consulting fees from Amgen and participated in an Advisory Board for Amgen. Christina Giannopoulou is an employee of Amgen Europe GmbH and holds stock in Amgen. Björn Stollenwerk is an employee of Amgen Europe GmbH and holds stock in Amgen. Cynthia C. Obiozor is an employee of and holds stock in Amgen. Yang Wang is an employee of and holds stock in Amgen.Silvia Novello received honoraria from AstraZeneca, Amgen, Thermo Fisher, MSD, Novartis, Sanofi, Roche, Pfizer, Takeda, and Janssen and participated on a data safety monitoring board or advisory board from Pfizer, AstraZeneca, Sanofi, Jannsen, and Daiichi., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: High-level resistance to sulfadoxine-pyrimethamine threatens the efficacy of WHO-recommended intermittent preventive treatment in pregnancy (IPTp) with single-dose sulfadoxine-pyrimethamine to prevent malaria. Monthly IPTp with dihydroartemisinin-piperaquine, a 3-day regimen, is an emerging alternative, but this regimen poses potential implementation and adherence challenges. We aimed to assess adherence to a multiday IPTp with dihydroartemisinin-piperaquine regimen and its delivery effectiveness in routine antenatal care settings in western Kenya., Methods: We conducted a pragmatic, three-armed, open-label, cluster-randomised trial in antenatal clinics in 18 health-care facilities (six facilities per group) in Kisumu County and Homa Bay County in western Kenya. Clusters were facilities offering routine antenatal care services provided by trained Ministry of Health staff with 100 or more antenatal clinic attendances per month between July, 2018, and June, 2019. Private or mission hospitals, dispensaries, referral hospitals, and trial sites were excluded. Individuals in their first trimester, living with HIV, or who were not attending a scheduled antenatal clinic visit were excluded. The 18 antenatal clinics were grouped into matched triplets stratified by location and clinics in each matched triplet were randomly assigned to one of the three study groups (1:1:1). Masking was not possible. Two groups were given IPTp with dihydroartemisinin-piperaquine (one group with a targeted information transfer intervention and one group without any additional interventions) and one group was given the standard of care (ie, IPTp with sulfadoxine-pyrimethamine). The primary endpoint, adherence, was defined as the proportion of participants completing their most recent 3-day IPTp with dihydroartemisinin-piperaquine regimen. This completion was verified by pill counts during home visits no more than 2 days after participants' 3-day regimens ended. The secondary endpoint, delivery effectiveness, was defined as the proportion of participants who received the correct number of IPTp tablets and correctly repeated dosing instructions (ie, correctly recalled the instructions they received about self-administered dihydroartemisinin-piperaquine doses and the number of sulfadoxine-pyrimethamine tablets they had received) at their exit from the antenatal clinic. Individuals receiving treatment for malaria, visiting a clinic for registration only, or interviewed during IPTp drug stock-outs were excluded from analyses. We used generalised linear mixed models to compare endpoints among the IPTp with dihydroartemisinin-piperaquine groups. This trial was registered with ClinicalTrials.gov, NCT04160026, and is complete., Findings: 15 facilities (five per group) completed the trial, with 1189 participants having exit interviews (377 in the IPTp with sulfadoxine-pyrimethamine group, 408 in the IPTp with dihydroartemisinin-piperaquine only group, and 404 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) and 586 participants having home visits (267 in the IPTp with dihydroartemisinin-piperaquine only group and 319 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) from Sept 8 to Dec 10, 2020. Relative to the IPTp with dihydroartemisinin-piperaquine only group, adherence was 16% higher in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group (266 [83%] of 319 participants vs 196 [73%] of 267 participants; adjusted relative risk [RR] 1·16, 95% CI 1·03-1·31; p=0·0140). Delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group was not significantly different from that in the IPTp with sulfadoxine-pyrimethamine group (352 [87%] of 403 participants vs 335 [89%] of 375 participants; adjusted RR 0·97, 95% CI 0·90-1·05; p=0·4810). However, delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine only group was significantly lower than in the IPTp with sulfadoxine-pyrimethamine group (300 [74%] of 404 participants vs 335 [89%] of 375 participants; 0·84, 0·75-0·95; p=0·0030)., Interpretation: Targeted information transfer interventions to health-care providers and pregnant individuals boost antenatal care delivery adherence to a multiday regimen with dihydroartemisinin-piperaquine., Funding: European and Developing Countries Clinical Trials Partnership 2, UK Joint Global Health Trials Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust; and Swedish International Development Cooperation Agency., Competing Interests: Declaration of interests We 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: Both efavirenz and dolutegravir have been associated with neuropsychiatric side-effects and cognitive impairment. Furthermore, cerebrospinal fluid (CSF) HIV RNA escape has not been comprehensively studied in African populations. We aimed to examine changes in cognition, neuropsychiatric symptoms, and CSF viral control associated with the widespread switch from efavirenz-based to dolutegravir-based antiretroviral therapy (ART)., Methods: This prospective cohort study of people with HIV and people without HIV recruited adults with HIV (aged 18-55 years) from the Gugulethu Community Health Centre in a low-income periurban area of Cape Town, South Africa. Eligible participants had been receiving efavirenz-based ART for at least 1 year and were identified by the clinic to switch to dolutegravir-based ART as part of the national programmatic switch. Participants were studied at baseline and followed up at 1 year after switch to dolutegravir. People without HIV were recruited from the same area, matched for age and gender, and followed up at the same time interval. People with HIV and people without HIV underwent comprehensive cognitive testing over seven domains and measures of functioning, mood, anxiety, and sleep. People with HIV had CSF sampling for HIV RNA quantification., Findings: Between Aug 12, 2019, and Sept 16, 2022, we recruited 178 people with HIV and 95 people without HIV. 145 (81%) of 178 people with HIV and 40 (66%) of 60 people without HIV who were offered underwent follow-up. Global cognitive performance was 2·57 T score points lower in people with HIV than in people without HIV at baseline (p=0·0008). At follow-up, cognition in people with HIV improved more than practice effects observed in people without HIV (coefficient 1·40, 95% CI 0·48-2·32, p=0·0028) and no significant difference in cognitive performance between groups was apparent (51·43 vs 52·73; p=0·22). Sleep quality improved following the switch (risk ratio 0·90, 95% CI 0·84-0·95; p=0·0002), driven mainly by indicators of disturbed sleep. There were nine incident cases of depression, although baseline differences were present. There was one case (1%) of CSF escape at baseline and three cases (4%) at follow-up; all were at low levels or resolved with repeated sampling., Interpretation: Improvements in cognition and sleep are probably related to switching from efavirenz. However, the possible increase in depression warrants further examination. Cognitive performance in virally supressed African people with HIV receiving dolutegravir-based therapy is similar to people without HIV. CSF escape is uncommon on both efavirenz-based and dolutegravir-based therapy., Funding: South African Medical Research Council and UK Medical Research Council, Newton Fund., Competing Interests: Declaration of interests AW reports research grants paid to his institution from ViiV Healthcare, Gilead, and MSD, and lecture honoraria from ViiV Healthcare, Gilead, Janssen, and MSD. PS reports grants paid to her institution from the South African Medical Research Council. SK reports awards for research and drug interactions website paid to their institution from ViiV Healthcare and Merck, an unrestricted grant paid to their institution from Gilead, consulting fees (advisory board) from ViiV Healthcare and Pfizer, lecture honoraria from Pfizer, and receipt of study drug from Merck and GSK. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Dolutegravir (DTG) is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric subjects aged at least 4 weeks. The present work aimed to characterize the viral response based on a pooled analysis of exposure-response (E-R) from five studies in treatment-experienced and integrase-resistant (INI-r) patients infected with HIV-1. Importantly, model-based simulations of the E-R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub-population with Q148-driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation-containing products) factors expected to influence the DTG E-R relationship. Model-based post hoc exposure metrics (C min and C avg ) were incorporated into a mechanistic population viral dynamic model describing the short-term effect of DTG on log10 HIV-1 RNA viral load over 8 or 10 days. In addition, the impact of DTG in combination with background ARTs on the 24-week HIV RNA response was also assessed using logistic regression. There was good concordance between model-based predictions and observed virologic response on day 10 and week 24. The E-R model-based simulations exploring the potential impact of a higher dose (100 mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50 mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50 mg b.i.d. in the integrase inhibitor-resistant (INI-r) population., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non-Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data., Objectives: Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital., Materials and Methods: Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific)., Results: A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25-0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (n = 10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4->8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species., Conclusions: Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus, L. prolificans, Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava., (© 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.)

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Meningioma and schwannoma are common tumours of the nervous system. They occur sporadically or as part of the hereditary NF2-related schwannomatosis syndrome. There is an unmet need for new effective drug treatments for both tumour types. In this paper, we demonstrate overexpression/activation of TAM (TYRO3/AXL/MERTK) receptors (TAMs) and overexpression/release of ligand GAS6 in patient-derived meningioma tumour cells and tissue. For the first time, we reveal the formation of MERTK/TYRO3 heterocomplexes in meningioma and schwannoma tissue. We demonstrate the dependence of AXL and TYRO3 expression on MERTK in both tumour types, as well as interdependency of MERTK and AXL expression in meningioma. We show that MERTK and AXL contribute to increased proliferation and survival of meningioma and schwannoma cells, which we inhibited in vitro using the MERTK/FLT3 inhibitor UNC2025 and the AXL inhibitor BGB324. UNC2025 was effective in both tumour types with superior efficacy over BGB324. Finally, we found that TAMs are expressed by tumour-associated macrophages in meningioma and schwannoma tumours and that UNC2025 strongly depleted macrophages in both tumour types., (© 2024. he Authors.)

The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development., Competing Interests: Declaration of competing interests J.H.L.: Participation on Advisory or Steering Committees for Grifols, Octapharma, Takeda, and Werfen. J.R.S.: In-kind laboratory support from Diagnostica Stago. L.A.C.: L.A.C.’s research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier. L.A.C. holds a Tier 2 Research Chair from the University of Ottawa. J.M.C.: Participation on Scientific Advisory Boards and consulting for Abbott, Anthos, BMS, Pfizer, Roche, Sanofi, and Werfen; research funding from CSL Behring to the institution. J.D.: Serves on advisory committees for Pfizer, Sanofi, Leo Pharma, Bristol-Myers Squibb, and Janssen. E.L-L.: Lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Portola, CSL Behring, Norgine, Roche, Leo, AstraZeneca, and Aspen; institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Werfen, and CSL Behring. B.R.: Consultant for AbocaSRL on medical devices; Advisory Committee for Bayer AG. C.M.S.: Advisory for Norgine Pharma. D.S.: Honoraria for educational presentations and advisory fees paid indirectly to research institute from AstraZeneca, BMS-Pfizer, Roche, Servier. D.S. is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. J.I.W.: Consultant or member of Advisory Boards or Steering Committees for Anthos, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson and Johnson, Merck, and Regeneron., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Polo-like kinase 1 (PLK1) inhibitors have had limited antitumor efficacy as single agents, and focus of current efforts is on combination therapies. We initially confirmed that the PLK1-specific inhibitor onvansertib (ONV) could enhance responses to a PARP inhibitor (olaparib) in prostate cancer xenografts. To identify more effective combinations, we screened a library of bioactive compounds for efficacy in combination with ONV in LNCaP prostate cancer cells, which identified a series of compounds including multiple AKT inhibitors. We confirmed in vitro synergy between ONV and the AKT inhibitor ipatasertib (IPA) and found that the combination increased apoptosis. Mechanistic studies showed that ONV increased expression of the antiapoptotic protein SURVIVIN and that this was mitigated by IPA. Studies in three PTEN-deficient prostate cancer xenograft models showed that cotreatment with IPA and ONV led to significant tumor growth inhibition compared with monotherapies. Together, these in vitro and in vivo studies demonstrate that the efficacy of PLK1 antagonists can be enhanced by PARP or AKT inhibition and support further development of these combination therapies., (©2024 American Association for Cancer Research.)

Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-G i complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR's structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery., (© 2024. The Author(s).)

Background: Malaria and HIV infection overlap geographically in sub-Saharan Africa and share risk factors. HIV infection increases malaria's severity, especially in pregnant women. The World Health Organization (WHO) recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for pregnant women living in areas of stable malaria transmission. However, HIV-positive women on daily cotrimoxazole prophylaxis (recommended for prevention of opportunistic infections in people with HIV) cannot receive SP due to adverse drug interactions, so malaria prevention in this vulnerable population currently relies on daily cotrimoxazole prophylaxis alone. This review is based on a new protocol and provides an update to the 2011 Cochrane Review that evaluated alternative drugs for IPTp to prevent malaria in HIV-positive women., Objectives: To compare the safety and efficacy of intermittent preventive treatment regimens for malaria prevention in HIV-positive pregnant women., Search Methods: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trial registries to 31 January 2024. To identify relevant additional studies or unpublished work, we checked references and contacted study authors and other researchers working on malaria and HIV., Selection Criteria: We included randomized controlled trials (RCTs) comparing any intermittent preventive treatment regimen for preventing malaria in HIV-positive pregnant women against daily cotrimoxazole prophylaxis alone, placebo, current or previous standard of care, or combinations of these options. By 'standard of care' we refer to the country's recommended drug regimen to prevent malaria in pregnancy among HIV-positive women, or the treatment that a trial's research team considered to be the standard of care., Data Collection and Analysis: Review authors, in pairs, independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias in included trials, and extracted data. We contacted trial authors when additional information was required. We presented dichotomous outcomes using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes as mean differences (MDs). We presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach for what we considered to be the main comparisons and outcomes., Main Results: We included 14 RCTs, with a total of 4976 HIV-positive pregnant women initially randomized. All trials assessed the efficacy and safety of one antimalarial used as IPTp (mefloquine, dihydroartemisinin/piperaquine, SP, or azithromycin) with or without daily cotrimoxazole, compared to daily cotrimoxazole alone, placebo, or a standard of care regimen. We grouped the trials into nine comparisons. Our main comparison evaluated the current standard of care (daily cotrimoxazole) with another drug regimen (mefloquine or dihydroartemisinin/piperaquine) versus daily cotrimoxazole with or without placebo. In this comparison, two trials evaluated mefloquine and three evaluated dihydroartemisinin/piperaquine. We conducted meta-analyses that included trials evaluating dihydroartemisinin/piperaquine plus cotrimoxazole, and trials that evaluated mefloquine plus cotrimoxazole, as we considered there to be no qualitative or quantitative heterogeneity among trials for most outcomes. We considered drug-related adverse events and HIV-related outcomes to be drug-specific. Daily cotrimoxazole prophylaxis plus another drug regimen (mefloquine or dihydroartemisinin/piperaquine) probably results in lower risk of maternal peripheral parasitaemia at delivery (RR 0.62, 95% CI 0.41 to 0.95; 2406 participants, 5 trials; moderate-certainty evidence). It results in little or no difference in maternal anaemia cases at delivery (RR 0.98, 95% CI 0.90 to 1.07; 2417 participants, 3 trials; high-certainty evidence). It probably results in a decrease in placental malaria measured by blood smear (RR 0.54, 95% CI 0.31 to 0.93; 1337 participants, 3 trials; moderate-certainty evidence), and probably results in little or no difference in low birth weight (RR 1.16, 95% CI 0.95 to 1.41; 2915 participants, 5 trials; moderate-certainty evidence). There is insufficient evidence to ascertain whether daily cotrimoxazole prophylaxis plus another drug regimen affects the risk of cord blood parasitaemia (RR 0.27, 95% CI 0.04 to 1.64; 2696 participants, 5 trials; very low-certainty evidence). Daily cotrimoxazole prophylaxis plus another drug regimen probably results in little or no difference in foetal loss (RR 1.03, 95% CI 0.73 to 1.46; 2957 participants, 5 trials; moderate-certainty evidence), and may result in little or no difference in neonatal mortality (RR 1.21, 95% CI 0.68 to 2.14; 2706 participants, 4 trials; low-certainty evidence). Due to the probability of an increased risk of mother-to-child HIV transmission and some adverse drug effects noted with mefloquine, we also looked at the results for dihydroartemisinin/piperaquine specifically. Dihydroartemisinin/piperaquine plus daily contrimoxazole probably results in little to no difference in maternal peripheral parasitaemia (RR 0.59, 95% CI 0.31 to 1.11; 1517 participants, 3 trials; moderate-certainty evidence) or anaemia at delivery (RR 0.95, 95% CI 0.82 to 1.10; 1454 participants, 2 trials; moderate-certainty evidence), but leads to fewer women having placental malaria when measured by histopathologic analysis (RR 0.67, 95% CI 0.50 to 0.90; 1570 participants, 3 trials; high-certainty evidence). The addition of dihydroartemisinin/piperaquine to daily cotrimoxazole probably made little to no difference to rates of low birth weight (RR 1.13, 95% CI 0.87 to 1.48; 1695 participants, 3 trials), foetal loss (RR 1.14, 95% CI 0.68 to 1.90; 1610 participants, 3 trials), or neonatal mortality (RR 1.03, 95% CI 0.39 to 2.72; 1467 participants, 2 trials) (all moderate-certainty evidence). We found low-certainty evidence of no increased risk of gastrointestinal drug-related adverse events (RR 1.42, 95% CI 0.51 to 3.98; 1447 participants, 2 trials) or mother-to-child HIV transmission (RR 1.54, 95% CI 0.26 to 9.19; 1063 participants, 2 trials)., Authors' Conclusions: Dihydroartemisinin/piperaquine and mefloquine added to daily cotrimoxazole seem to be efficacious in preventing malaria infection in HIV-positive pregnant women compared to daily cotrimoxazole alone. However, increased risk of HIV transmission to the foetus and poor drug tolerability may be barriers to implementation of mefloquine in practice. In contrast, the evidence suggests that dihydroartemisinin/piperaquine does not increase the risk of HIV mother-to-child transmission and is well tolerated., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Tenofovir/lamivudine/dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen for people with HIV (PWH), including those who were previously virologically suppressed on nonnucleoside reverse transcriptase inhibitors (NNRTIs). We sought to estimate the real-world effectiveness of the TLD transition in Ugandan public-sector clinics., Methods: We conducted a prospective cohort study of PWH aged ≥18 years who were transitioned from NNRTI-based ART to TLD. Study visits were conducted on the day of TLD transition and 24 and 48 weeks later. The primary end point was viral suppression (<200 copies/mL) at 48 weeks. We collected blood for retrospective viral load (VL) assessment and conducted genotypic resistance tests for specimens with VL >500 copies/mL., Results: We enrolled 500 participants (median age 47 years; 41% women). At 48 weeks after TLD transition, 94% of participants were in care with a VL <200 copies/mL (n = 469/500); 2% (n = 11/500) were lost from care or died; and only 2% (n = 9/500) had a VL >500 copies/mL. No incident resistance to DTG was identified. Few participants (2%, n = 9/500) discontinued TLD due to adverse events., Conclusions: High rates of viral suppression, high tolerability, and lack of emergent drug resistance support use of TLD as the preferred first-line regimen in the region., Clinical Trials Registration: NCT04066036., Competing Interests: Potential conflicts of interest. V. C. M. received investigator-initiated research grants and consultation fees from Eli Lilly, Bayer, Gilead Sciences, Merck, and ViiV Healthcare. 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.)

Objectives: To assess the efficacy and safety of a two-drug regimen (2DR) with dolutegravir (DTG) and lamivudine (3TC) in maintaining viral suppression during pregnancy and breastfeeding, and to evaluate its potential as an alternative to the recommended three-drug regimen (3DR) in preventing mother-to-child transmission (MTCT) of HIV., Methods: We present a case of a 34-year-old pregnant woman who, after discontinuing 3DR due to side effects and poor adherence, was switched to DTG/3TC at gestational week 23. Maternal viral load (VL) and infant HIV status were monitored throughout pregnancy and a ten-month breastfeeding period. Data on pharmacokinetic changes in pregnancy and the risks associated with 2DR were reviewed., Results: The patient's VL remained suppressed (<20 copies/mL) from gestational week 23 until the end of the breastfeeding period. A healthy HIV-negative baby was born at 39 weeks, and the child remained HIV-negative after ten months of breastfeeding. The 2DR was well-tolerated, improved adherence, and reduced fetal drug exposure. Despite limited experience with 2DR in pregnancy, no viral rebound occurred, and no adverse effects were observed., Conclusions: Although 3DR remains the preferred therapy during pregnancy and breastfeeding, this case indicates that DTG/3TC may be an effective alternative for patients experiencing intolerance or poor adherence to 3DR. Further studies are needed to explore the impact of pharmacokinetic changes in pregnancy on 2DR efficacy and to confirm its safety and role in preventing MTCT., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Migraine is among the most prevalent and burdensome neurological disorders in the United States based on disability-adjusted life years. Cortical spreading depolarization (SD) is the most likely electrophysiological cause of migraine aura and may be linked to trigeminal nociception. We previously demonstrated, using a minimally invasive optogenetic approach of SD induction (opto-SD), that opto-SD triggers acute periorbital mechanical allodynia that is reversed by 5HT 1B/1D receptor agonists, supporting SD-induced activation of migraine-relevant trigeminal pain pathways in mice. Recent data highlight hypothalamic neural circuits in migraine, and SD may activate hypothalamic neurons. Furthermore, neuroanatomical, electrophysiological, and behavioral data suggest a homeostatic analgesic function of hypothalamic neuropeptide hormone, oxytocin. We, therefore, examined the role of hypothalamic paraventricular nucleus (PVN) and oxytocinergic (OXT) signaling in opto-SD-induced trigeminal pain behavior., Methods: We induced a single opto-SD in adult male and female Thy1-ChR2-YFP transgenic mice and quantified fos immunolabeling in the PVN and supraoptic nucleus (SON) compared with sham controls. Oxytocin expression was also measured in fos-positive neurons in the PVN. Periorbital mechanical allodynia was tested after treatment with selective OXT receptor antagonist L-368,899 (5 to 25 mg/kg i.p.) or vehicle at 1, 2, and 4 h after opto-SD or sham stimulation using von Frey monofilaments., Results: Opto-SD significantly increased the number of fos immunoreactive cells in the PVN and SON as compared to sham stimulation (p < 0.001, p = 0.018, respectively). A subpopulation of fos-positive neurons also stained positive for oxytocin. Opto-SD evoked periorbital mechanical allodynia 1 h after SD (p = 0.001 vs. sham), which recovered quickly within 2 h (p = 0.638). OXT receptor antagonist L-368,899 dose-dependently prolonged SD-induced periorbital allodynia (p < 0.001). L-368,899 did not affect mechanical thresholds in the absence of opto-SD., Conclusions: These data support an SD-induced activation of PVN neurons and a role for endogenous OXT in alleviating acute SD-induced trigeminal allodynia by shortening its duration., (© 2024. The Author(s).)

Background: Cardiovascular events following anti-malarial treatment are reported infrequently; only a few studies have reported adverse outcomes. This case presentation emphasizes cardiological assessment of Brugada syndrome, presenting as life-threatening arrhythmia during anti-malarial treatment. Without screening and untreated, this disease may lead to sudden cardiac death., Case Presentation: This is a case of 23-year-old male who initially presented with palpitations followed by syncope and shortness of breath with a history of malaria. He had switched treatment from quinine to dihydroartemisinin-piperaquine (DHP). Further investigations revealed the ST elevation electrocardiogram pattern typical of Brugada syndrome, confirmed with flecainide challenge test. Subsequently, anti-malarial treatment was stopped and an Implantable Cardioverter Defibrillator (ICD) was inserted., Conclusions: Another possible cause of arrhythmic events happened following anti-malarial consumption. This case highlights the possibility of proarrhytmogenic mechanism of malaria infection and anti-malarial drug resulting in typical manifestations of Brugada syndrome., (© 2024. The Author(s).)

Background: Medical therapy for aortic stenosis (AS) remains an elusive goal., Objectives: This study sought to establish whether evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce AS progression., Methods: A total of 228 patients (age 67 ± 11 years; 33% women) with AS were randomly assigned to receive placebo (n = 75), evogliptin 5 mg (n = 77), or evogliptin 10 mg (n = 76). The primary endpoint was the 96-week change in aortic valve calcium volume (AVCV) on computed tomography. Secondary endpoints included the 48-week change in active calcification volume measured using 18 F-sodium fluoride positron emission tomography ( 18 F-NaF PET)., Results: There were no significant differences in the 96-week changes in AVCV between evogliptin 5 mg and placebo (-5.27; 95% CI: -55.36 to 44.82; P = 0.84) or evogliptin 10 mg and placebo (-18.83; 95% CI: -32.43 to 70.10; P = 0.47). In the placebo group, the increase in AVCV between 48 weeks and 96 weeks was higher than that between baseline and 48 weeks (136 mm 3 ; 95% CI: 108-163 vs 102 mm 3 ; 95% CI: 75-129; P = 0.0485). This increasing trend in the second half of the study was suppressed in both evogliptin groups. The 48-week change in active calcification volume on 18 F-NaF PET was significantly lower in both the evogliptin 5 mg (-1,325.6; 95% CI: -2,285.9 to -365.4; P = 0.008) and 10-mg groups (-1,582.2; 95% CI: -2,610.8 to -553.5; P = 0.0038) compared with the placebo group., Conclusions: This exploratory study did not demonstrate the protective effect of evogliptin on AV calcification. Favorable 18 F-NaF PET results and possible suppression of aortic valve calcification with longer medication use in the evogliptin groups suggest the need for larger confirmatory trials. (A Multicenter, Double-blind, Placebo-controlled, Stratified-randomized, Parallel, Therapeutic Exploratory Clinical Study to Evaluate the Efficacy and Safety of DA-1229 in Patients With Calcific Aortic Valve Disease; NCT04055883)., Competing Interests: Funding Support and Author Disclosures This is a sponsor-initiated trial, and the DongA ST company (Seoul, South Korea), which produces evogliptin, provided the research funding. Dr Song works as the chief medical officer of REDNVIA, a venture company dedicated to the development of drugs for the medical treatment of calcific aortic valve disease. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This article provides a narrative review of recent developments in mood-stabilizing drugs, considering their mechanism of action, efficacy, safety, and therapeutic potential in the treatment of mood disorders, particularly bipolar disorder and schizophrenia. The review focuses on the mechanism and clinical aspects of second-generation antipsychotic medications; aripiprazole, classified as a third-generation antipsychotic medication; lamotrigine, as a representative of antiepileptic drugs; and lurasidone, a novel second-generation antipsychotic medication. Moreover, the article refers to one of the newest and most highly effective normothymic drugs, cariprazine. The potential of new mood stabilizer candidates lumateperone and brexpiprazole is also presented. Covered topics include the clinical efficacy of new drugs in reducing manic and depressive symptoms during acute episodes, as well as their role in preventing relapse. In addition, we analyzed the incidence of adverse effects of each drug. Many of the new drugs have strong potential to be beneficial and safe in cases of many comorbidities, as they do not cause many adverse effects and do not require high doses of use. The results underscore the importance of ongoing and future research to better understand the action and efficacy of these mood stabilizers and their implications in the treatment of mood disorders, aiming to achieve euthymia and improve the quality of life of affected patients. In this article, we aim to review current drug treatments for the management of mood disorders, including bipolar disorder and schizophrenia.

Objective: This study examined the prevalence, severity and risk factors of anaemia among adult people living with HIV attending an antiretroviral therapy centre in Woreta Primary Hospital, Woreta town, Ethiopia., Design: Hospital-based retrospective cross-sectional study., Setting: Public health facility that provides HIV care in Woreta town., Participants: A total of 289 medical records of adults living with HIV/AIDS on highly active antiretroviral therapy from February 2019 to September 2023 at government hospital were reviewed using a systematic sampling method. The data were entered using Epi-info V.7 and exported to SPSS V.23 for data analysis. The data were analysed using bivariate and then multivariate logistic regression models in order to identify variables associated with anaemia. At the 95% CI level, variables having a p value of <0.05 were deemed to be statistically significant predictors., Primary Outcome: Prevalence and severity of anaemia and its predictors among adult patients living with HIV on antiretroviral therapy in Woreta Primary Hospital., Results: The total prevalence of anaemia was 31.5% (95% CI 28.9 to 33.8). The prevalence of mild, moderate and severe anaemia was 20.42%, 10.38% and 0.70%, respectively. Predictors independently linked with anaemia were female sex (adjusted OR (AOR) 1.08), age ≥40 years (AOR 1.21), lived with HIV >10 years (AOR 2.31), CD4 counts <200 cells/µL (AOR 3.81), non-suppressed viral load (AOR 1.28), history of opportunistic infections (AOR 1.54), WHO clinical stages III and IV (AOR 1.37 and 2.23, respectively) and history of parasitic infestation (AOR 2.81)., Conclusions: A sizeable proportion of participants were found anaemic. Female sex, older age, longer periods lived with the virus, lower CD4 count, non-suppressed viral load, history of opportunistic infections, WHO clinical stages III and IV and history of parasitic infestation were the contributing factors. Therefore, to improve the anaemic status and living circumstances of patients living with HIV, immediate action on the linked factors is needed, such as monitoring for maintenance of CD4 counts >200 cells/μL and avoiding progression of HIV to the advanced WHO clinical stages, suppressed viral load, preventing opportunistic infections and parasitic infestation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Glioblastoma (GBM) represents an aggressive brain tumor, characterized by intra- and inter-tumoral heterogeneity and therapy resistance, leading to unfavourable prognosis. An increasing number of studies pays attention on the regulation of ferroptosis, an iron-dependent cell death, as a strategy to reverse drug resistance in cancer. However, the debate on whether this strategy may have important implications for the treatment of GBM is still ongoing. In the present study, we used ferric ammonium citrate and erastin to evaluate ferroptosis induction effects on two human GBM cell lines, U-251 MG, with proneural characteristics, and T98-G, with a mesenchymal profile. The response to ferroptosis induction was markedly different between cell lines, indeed T98-G cells showed an enhanced antioxidant defence, with increased glutathione levels, as compared to U-251 MG cells. Moreover, using bioinformatic approaches and analysing publicly available datasets from patients' biopsies, we found that GBM with a mesenchymal phenotype showed an up-regulation of several genes involved in antioxidant mechanisms as compared to proneural subtype. Thus, our results suggest that GBM subtypes differently respond to ferroptosis induction, emphasizing the significance of further molecular studies on GBM to better discriminate between various tumor subtypes and progressively move towards personalized therapy., (© 2024. The Author(s).)

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its guanosine diphosphate (GDP)- and guanosine triphosphate (GTP)-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report that D3S-001, a next-generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as epithelial growth factor and hepatocyte growth factor, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust antitumor activity preclinically and translated into promising clinical efficacy in an ongoing phase 1 trial (NCT05410145). Significance: The kinetic study presented in this work unveils, for the first time, that a GDP-bound conformation-selective KRAS G12C inhibitor can potentially deplete cellular active KRAS in the presence of growth factors and offers new insights into the critical features that drive preclinical and clinical efficacy for this class of drugs., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues., Objectives: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs)., Methods: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection., Results: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%., Conclusions: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure., (© 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: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs., Methods: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure., Results: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028)., Conclusions: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women., (© 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: A dolutegravir (DTG)-based antiretroviral regimen has been rolled out for pregnant women in low- and middle-income countries since 2020. However, available safety data are limited to a few clinical trials and observational studies. Hence, we present real-world pregnancy and birth outcome safety data from a large sample multicenter cohort study in Ethiopia., Methods: A retrospective cohort study was conducted in fourteen hospitals across Ethiopia from 2017 to 2022. HIV-infected pregnant women were followed from the date of prevention of mother-to-child transmission (PMTCT) care enrolment until the infant was 6-8 weeks old. The primary safety outcome was a composite of adverse pregnancy events comprising spontaneous abortion, intrauterine fetal death (IUFD) before onset of labor, preterm birth, and maternal death. Additionally, a composite adverse birth outcome was assessed, comprising intrapartum fetal demise, low birth weight, and neonatal death. Finally, a composite of adverse pregnancy or birth outcome was also investigated. The exposure of interest was the antiretroviral treatment (ART) regimen used during pregnancy for PMTCT of HIV., Results: During the study period, 2643 women were enrolled in routine PMTCT care. However, 2490 (92.2%) participants were eligible for the study. A total of 136/1724 (7.9%, 95% CI: 6.7-9.3%) women experienced adverse pregnancy outcomes. Fewer women in the DTG-based group (5.4%, 95% CI: 3.7-7.5%) had adverse pregnancy outcomes than in the Efavirenz (EFV)-based group (8.3%, 95% CI: 6.6-10.3%), P = 0.004. After controlling for baseline differences, the DTG group had a 43% lower risk of adverse pregnancy outcomes (adjusted odd ratio (AOR), 0.57; 95% CI, 0.32-0.96%) and a 53% lower risk of preterm birth (AOR, 0.47; 95% CI, 0.22-0.98%) compared to the EFV group. A total of 103/1616 (6.4%, 95% CI: 5.2-7.7%) women had adverse birth outcomes. Although the difference was not statistically significant, fewer women in the DTG group (30/548; 5.5%, 95% CI: 3.7-7.7%) than in the EFV group (57/830; 6.9%, 95% CI: 5.2-8.8%) had adverse birth outcomes., Conclusions: In this study, we observed that DTG-based regimens were associated with better pregnancy and birth outcome safety profiles, reaffirming the WHO recommendation. However, a prospective study is recommended to assess uncaptured maternal and perinatal adverse outcomes, such as congenital abnormalities, and infant growth and neurocognitive development., (© 2024. The Author(s).)