CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

2913) copies (cps)/1000cells and positively correlated with serum HDV-RNA (Rho=0.63, P=0.05). Regarding HBV intrahepatic reservoir, median (IQR) cccDNA was 3 (0.1-24) cps/1000cells and pgRNA was 8 (1-147) cps/1000cells. Nevertheless, we observed an abundant production of total HBs transcripts (median[IQR] total HBs RNAs: 6,028[409-19,137] cps/1000 cells), positively correlated with serum HBs (Rho=0.54; P=0.04). By analyzing the source of HBs transcripts, we found that >90% of them derived from integrated HBV-DNA, with a poor contribution of cccDNA transcriptional activity, supporting that HDV persistence is mainly sustained by integrated HBV DNA-derived HBs in HBeAg[-] HDV chronic infection. Finally, no difference in intrahepatic HDV-RNA levels was observed according to HBV reservoir size (median[IQR]: 787[1-5,495] and 880[1-3,338] cps/1000cells in pts with cccDNA5 cps/1000cells, p=0.9), while HBV markers were significantly lower in pts with a more restricted HBV reservoir (median [IQR]: 1[1-10] vs 147[9-406] cps/1000cells for pgRNA and 0.3[0.2-1] vs 73[7-243] cps/1000cells for cccDNA-derived HBs transcripts in cccDNA5 cps/1000cells, p<0.01 for both). Overall data suggest the existence of independent HBV and HDV replicative pathways. Conclusion: HDV replication pathway acts independently from the size of intrahepatic HBV reservoir and is fueled by an abundant production of HBs transcripts, mainly derived from integrated HBV-DNA. These issues are crucial for defining mechanisms underlying HDV persistence, that could hamper the success of therapeutic strategies. A 4-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline for Pulmonary TB: Interim Results Rodney Dawson 1 , Andreas H. Diacon 2 , Simbarashe Takuva 3 , Yongge Liu 4 , Bo Zheng 4 , Vatsala Karwe 4 , Tomohiro Sasaki 5 , Jeffrey Hafkin 4 1 University of Cape Town, Cape Town, South Africa, 2 TASK Applied Science, Cape Town, South Africa, 3 Otsuka Novel Products GmbH, Munchen, Germany, 4 Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD, USA, 5 Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan Background: There remains an urgent need for short-duration, potent, and safe anti-tuberculosis (TB) agents effective against drug-susceptible and drug resistant strains of Mycobacterium tuberculosis. Quabodepistat (QBS; formerly OPC-167832) is a novel anti-TB agent that targets decaprenylphosphoryl-β-D ribose 2 ′ -oxidase (DprE1). In a prior study, QBS in combination with delamanid (DLM) and bedaquiline (BDQ) for 14 days was well tolerated and exhibited similar early bactericidal activity to the standard of care regimen, RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide) in patients with drug susceptible pulmonary TB (DS-TB). Methods: This interim analysis of the phase 2b/c, randomized trial (NCT05221502) evaluates the safety, efficacy, and pharmacokinetics of QBS in combination with DLM and BDQ for 4 months in participants with DS-TB compared to 6-month RHEZ treatment. Participants were randomized (1:2:2:1; stratified by chest x-ray bilateral cavitation and HIV status) to once-daily QBS 10 mg, 30 mg, or 90 mg in combination with DLM and BDQ, or RHEZ. The follow-up period (to 52 weeks post-randomization) is ongoing. The primary endpoint was proportion of participants achieving sputum culture conversion (SCC) by the end of the treatment period. Here, we report interim results after 117/122 (96%) randomized participants completed study treatment. Results: At enrollment, most participants were male (65%), of Black African race (68%) with a median age of 31 years (range 18–65), a median BMI of 19 kg/m 2 , with bilateral cavitation (19%), and HIV-negative (100%) status. In the modified intention-to-treat population (n=121), SCC at end of treatment was achieved by 96% (96/100) in the pooled QBS arms and 91% (19/21) in the RHEZ arm (Table 1). Similar SCC rates were observed in the per-protocol analysis (n=108). The percentages of participants experiencing at least one Division of AIDS ≥Grade 3 adverse event (AE) were 15%, 12%, 11%, and 5% in the QBS 10-mg, 30-mg, 90-mg, and RHEZ arms, respectively. There was one treatment discontinuation due to death (QBS 30-mg arm) from severe/worsening TB. No serious AEs were attributed to trial medications. No clinically significant QTc prolongation events, QTc prolongation ≥500 ms, or liver enzyme (ALT/AST) elevations ≥5 times the upper limit of normal were reported. Conclusion: In this interim analysis, high rates of SCC were achieved with the QBS-based three-drug treatment regimen. The regimen was generally well tolerated and warrants further investigation.

required to optimise drug ratios and confirm safety through GLP toxicology assessments to support first-in-human evaluation.

Oral Abstracts

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Intrahepatic HDV Activity Is Fueled by Integrated HBV DNA-Derived HBs Independently From cccDNA Size Stefano D'Anna 1 , Lorenzo Piermatteo 1 , Elisabetta Teti 2 , Andrea Di Lorenzo 2 , Giuseppina Brancaccio 3 , Umberto Cillo 3 , Alessandro Vitale 3 , Leonardo Baiocchi 2 , Antonella Olivero 4 , Giovanni Battista Gaeta 5 , L. Sarmati 2 , Mario Rizzetto 4 , Gian Paolo Caviglia 4 , Valentina Svicher 1 , Romina Salpini 1 1 University of Rome Tor Vergata, Rome, Italy, 2 Hospital of Rome Tor Vergata, Rome, Italy, 3 Azienda Ospedaliera di Padova, Padua, Italy, 4 University of Torino, Torino, Italy, 5 Seconda Università degli Studi di Napoli, Napoli, Italy Background: HDV exploits HBV surface proteins (HBs) for its morphogenesis and de novo entry into hepatocytes. Here, we investigate HBV and HDV replicative activity and their still undefined interplay in liver biopsies from patients (pts) with chronic co-infection. Methods: Liver tissue was analysed from 25 pts (71% NUC-treated; 96% HBeAg[-]). Intrahepatic levels of covalently closed circular DNA (cccDNA), pregenomic HBV-RNA (pgRNA) and HDV-RNA were quantified by droplet digital PCR (ddPCR), also used to quantify total-, cccDNA derived- and integrated HBV-DNA derived- HBs transcripts as in Grudda, 2022. Results: Pts were characterized by high serum levels of HDV-RNA and HBs (median [IQR]: 6.3[3.8-7.7] logIU/mL and 14,460[5,207-21,118] IU/mL) and low HBV viremia (detectable in 48% of pts, median[IQR]: 50[34-214] IU/ml). Median (IQR) ALT was 72 (52-102) U/L. Intrahepatic HDV-RNA was median (IQR) 787(1-

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CROI 2024