CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

157

Early Bactericidal Activity of the Alpibectir-Ethionamide (AlpE) Combination Against Tuberculosis Jeantelle Du Preez 1 , Caryn Upton 1 , Laurynas Mockeliunas 2 , Michel Pieren 3 , Ulrika Simonsson 2 , Andreas H. Diacon 1 , Glenn E. Dale 3 , Pierre Delique 4 , Lisa Husband 4 , Simon Tiberi 5 , Sophie Penman 5 , Thabo Mabuka 1 , Mandi Nieuwenhuys 1 , Anteneh Yalew 1 , Veronique de Jager 1 1 TASK Applied Science, Cape Town, South Africa, 2 Uppsala University, Uppsala, Sweden, 3 BioVersys AG, Basel, Switzerland, 4 BioVersys SAS, Lille, France, 5 GlaxoSmithKline, London, UK Background: Dose-dependent tolerability reduces the utility of ethionamide for tuberculosis (TB) treatment at standard doses (750 to 1000 mg). Alpibectir (formerly BVL-GSK098) stimulates an alternative pathway of bacterial ethionamide bioactivation leading to retained activity at lower exposures in vivo. We report results on the first cohort evaluating the early bactericidal activity (EBA), safety and tolerability of the alpibectir-ethionamide (AlpE) combination (NCT05473195). Methods: Adults with newly diagnosed, rifampicin- and isoniazid-susceptible pulmonary TB were randomised 5:1 to receive 7 days of AlpE 9 mg/250 mg or isoniazid 300 mg as microbiological control. EBA was assessed by the change in time to culture positivity (TTP-EBA0–7) using a mixed-effects model. Serum concentrations of ethionamide and its active sulfoxide metabolite were explored as covaries in a pharmacokinetic/pharmacodynamic (PK/PD) model. Treatment-emergent adverse events (TEAEs) were assessed daily. Results: 15 participants were randomised to AlpE and 3 to isoniazid. Most participants were male (78%) with a mean age and weight of 33.6 years and 52.9 kg, respectively. One participant withdrew for reasons unrelated to treatment. Median TTP-EBA0–7 (2.5th–97.5th percentiles) was 45.28 (28.78 – 78.12) and 48.41 (42.02 – 54.89) hours for AlpE and isoniazid, respectively. Isoniazid activity was in range of previous results. The median maximum serum concentrations (C) of ethionamide (1230 ng/mL) and ethionamide-sulfoxide (2050 ng/mL), were reached approximately 1 hour after AlpE administration. The mean half-life for ethionamide and ethionamide-sulfoxide was 1.47 hours. Median area under concentration-time curve (AUC) of ethionamide and ethionamide-sulfoxide was 3662 and 5119 h*ng/mL, respectively. Higher ethionamide-sulfoxide exposure significantly increased EBA where each 100 h*ng/mL unit of increase resulted in a 3.68% increase in time to positivity (TTP) slope. 19 (73%) of the 26 mild (76.9%) and moderate (23.1%) TEAEs occurred in AlpE arm, among them self-limiting nausea, flatulence, and diarrhoea in 5 participants. Conclusion: AlpE was well tolerated, safe and showed bactericidal activity similar to isoniazid in participants with tuberculosis. AlpE can be added to the growing list of novel antituberculosis agents for drug-susceptible and drug-resistant TB. The study is ongoing with escalating doses of alpibectir and ethionamide to optimize the combination.

158

NAFLD and Advanced Fibrosis Are Common in Adults With HIV and Associated With Unique Histology Jordan E Lake 1 , Daniela S. Allende 2 , Oscar W. Cummings 3 , Jennifer Price 4 , Susanna Naggie 5 , Eduardo Vilar-Gomez 3 , Samer Gawrieh 3 , Alice L. Sternberg 6 , Sonya Heath 7 , Richard Sterling 8 , Rohit Loomba 9 , Mark Sulkowski 6 , Laura Wilson 10 , Naga Chalasani 3 , David Kleiner 11 1 University of Texas at Houston, Houston, TX, USA, 2 Cleveland Clinic, Cleveland, OH, USA, 3 Indiana University, Indianapolis, IN, USA, 4 University of California San Francisco, San Francisco, CA, USA, 5 Duke University, Durham, NC, USA, 6 The Johns Hopkins University, Baltimore, MD, USA, 7 University of Alabama at Birmingham, Birmingham, AL, USA, 8 Virginia Commonwealth University, Richmond, VA, USA, 9 University of California San Diego, La Jolla, CA, USA, 10 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 11 National Cancer Institute, Bethesda, MD, USA Background: Non-alcoholic fatty liver disease (NAFLD) may be more common among people with HIV (PWH), but unique risk factors for NAFLD in PWH (NAFLD-PWH) are poorly understood. We examined the prevalence of and risk factors for NAFLD and advanced fibrosis (AF) in a cohort of PWH without other known causes of liver disease, as well as histological features of NAFLD in persons with and without HIV. Methods: In an ongoing prospective study, PWH ≥18 years of age on suppressive antiretroviral therapy (ART) were screened for NAFLD (controlled attenuation parameter ≥263 dB/m) and AF (liver stiffness measurement ≥11 kPa) using vibration controlled transient elastography. For histology, 107 biopsies each from NAFLD-PWH (cases) and NAFLD in people without HIV (controls) were matched on age/sex/race/ethnicity/BMI/ALT. Biopsies were centrally read using the NASH CRN scoring system. Logistic regression evaluated associations with NAFLD and AF. Results: PWH (n=654) had mean age 53 years, 73% male sex at birth, 51% were non-Hispanic Black and 20% Hispanic. NAFLD and AF prevalence were 53% and 6%, respectively. Older age, male sex, greater BMI or waist circumference and higher ALT and triglyceride concentrations associated with greater NAFLD odds, and non- Hispanic Black race with lower odds. Greater BMI or waist circumference, higher AST and alkaline phosphatase concentrations and lower platelet counts associated with greater odds of AF, and non-Hispanic Black race with lower odds (all p<0.05). NAFLD-PWH had less steatosis (63% grade 1/2 vs. 47%, p=0.01), less inflammation (70% grade 1/2 vs. 60%, p=0.03) and less hepatocyte ballooning (none: 61% vs. 45%, many 15% vs 27%, p=0.03) and portal inflammation (8% >mild vs. 21%) than controls. As a result, NAS was lower in NAFLD- PWH (3.2 ± 1.6 vs 4.0 ± 1.6, p<0.001), with a trend towards less steatohepatitis (61% vs. 71%, p=0.09). Regression analyses observed less steatosis, portal inflammation and ballooning but more fibrosis in NAFLD-PWH (all p<0.05). Conclusion: In summary, in our cohort of PWH undergoing systematic screening, NAFLD prevalence was high, with traditional metabolic risk factors but not HIV-/ART-specific characteristics dominating risk for NAFLD and AF. Traditional histologic drivers of fibrosis were less pronounced in NAFLD-PWH and yet fibrosis stage was higher vs. matched controls without HIV, suggesting HIV-specific factors beyond hepatic necroinflammation may contribute to fibrosis in NAFLD-PWH. Semaglutide Reduces Metabolic-Associated Steatotic Liver Disease in People With HIV: The SLIM LIVER Jordan E Lake 1 , Douglas W. Kitch 2 , Amy Kantor 2 , Raja Muthupillai 3 , Karin Klingman 4 , Christina Vernon 5 , Carl J. Fichtenbaum 6 , Sonya Heath 7 , Hugo Perazzo 8 , Kathleen Corey 9 , Todd T. Brown 10 , Alan Landay 11 , Fred R. Sattler 12 , Kristine M. Erlandson 13 1 University of Texas at Houston, Houston, TX, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Forespect, PLLC, Houston, TX, USA, 4 National Institutes of Health, Rockville, MD, USA, 5 DLH Corporation, Silver Spring, MD, USA, 6 University of Cincinnati, Cincinnati, OH, USA, 7 University of Alabama at Birmingham, Birmingham, AL, USA, 8 Oswaldo Cruz Foundation - Fiocruz, Rio de Janeiro, Brazil, 9 Massachusetts General Hospital, Boston, MA, USA, 10 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 11 Rush University, Chicago, IL, USA, 12 University of Southern California, Los Angeles, CA, USA, 13 University of Colorado Anschutz Medical Campus, Aurora, CO, USA Background: Metabolic-Associated Steatotic Liver Disease (MASLD) is common among people with HIV (PWH) and likely synergistic with HIV-1 to accelerate hepatic injury and organ dysfunction. The glucagon-like peptide-1 receptor agonist semaglutide is associated with cardiometabolic improvements in the general population through its effects on weight reduction and systemic inflammation. We designed a phase IIb, single-arm, pilot study of the effects of semaglutide on magnetic resonance imaging-proton density fat fraction (MRI- PDFF)-quantified intrahepatic triglyceride (IHTG) content in PWH and MASLD.

Oral Abstracts

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CROI 2024