Genetic polymorphisms in the sodium taurocholate cotransporting peptide (NTCP encoded by ) have been described, but their role in untreated and treated patients with chronic hepatitis delta (CHD) remains unknown. Virological response (VR) to the NTCP inhibitor bulevirtide (BLV) was achieved at week 48 by >70% of patients with CHD, but nearly 15% experienced virological non-response (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in patients with CHD. BLV-untreated and -treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing. Of the six NTCP polymorphisms studied in 209 untreated patients with CHD, carriers of the rs17556915 TT/CC (n = 142) compared to CT (n = 67) genotype presented with higher median HDV RNA levels (5.39 4.75 log IU/ml, = 0.004). Of 209 patients receiving BLV monotherapy at 2 mg/day, 76 were evaluated at week 24 and 40 up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (n = 43) compared to CT (n = 33) carriers (5.38 4.72 log IU/ml, = 0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 . 17/33, = 0.565), the former group presented VNR more often than PR (9/11 9/23, = 0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in BLV-untreated and -treated patients with CHD and may contribute to identifying patients with different early virological responses to BLV. Although several sodium taurocholate cotransporting polypeptide () genetic polymorphisms have been described, no data are available on their potential role in modifying HDV RNA load or treatment response to bulevirtide (BLV) in patients with chronic hepatitis delta (CHD). In this study, we demonstrated that patients with CHD, either treated or untreated, carrying NTCP rs17556915 TT/CC, presented higher baseline HDV RNA levels compared to those with the CT genotype. Higher HDV RNA levels in TT/CC carriers compared to CT carriers were also confirmed in patients with CHD treated with BLV monotherapy up to 96 weeks. Furthermore, carriers of TT/CC, compared to CT genotype, more frequently showed viral non-response (VNR) than partial response (PR) at week 24 of BLV treatment, and 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. This is the first study demonstrating a potential role of NTCP genetic polymorphisms in influencing HDV viral load and early virological response to BLV monotherapy. Since no direct HDV resistance to BLV has been described so far, if confirmed in larger studies, the genetic polymorphisms in may help identify patients with different patterns of early virological response to BLV.

中文翻译：

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牛磺胆酸钠共转运多肽 (NTCP) 多态性可能影响 HDV RNA 载量和对布列韦肽的早期反应


牛磺胆酸钠共转运肽（由 编码的 NTCP）的基因多态性已被描述，但其在未经治疗和已治疗的慢性丁型肝炎 (CHD) 患者中的作用仍不清楚。超过 70% 的 CHD 患者在第 48 周时对 NTCP 抑制剂 bulevirtide (BLV) 出现病毒学应答 (VR)，但近 15% 的患者出现病毒学无应答 (VNR) 或部分应答 (PR)。本研究旨在评估 NTCP 基因多态性是否影响先心病患者的基线 HDV RNA 载量和对 BLV 的反应。未接受 BLV 治疗和接受过 BLV 治疗的患者均被纳入一项回顾性横断面和纵向研究。在接受 BLV 治疗的患者中收集基线和长达 96 周的临床和病毒学特征。通过Sanger测序鉴定NTCP基因多态性。在 209 名未经治疗的 CHD 患者中研究的 6 个 NTCP 多态性中，与 CT (n = 67) 基因型相比，rs17556915 TT/CC 的携带者 (n = 142) 表现出较高的中位 HDV RNA 水平 (5.39 4.75 log IU/ml，= 0.004）。在接受 2 毫克/天 BLV 单药治疗的 209 名患者中，有 76 名患者在第 24 周和第 40 周直至第 96 周进行了评估。与 CT (n = 33) 相比，TT/CC (n = 43) 证实了较高的平均基线 HDV RNA 水平载体（5.38 4.72 log IU/ml，= 0.010）。尽管 TT/CC 和 CT 携带者之间的 24 周 VR 相当 (25/43 . 17/33, = 0.565)，但前一组在第 24 周时比 PR 更频繁地出现 VNR (9/11 9/23, = 0.02) 7/9 TT/CC 基因型携带者在 BLV 治疗第 48 周时仍保持 VNR。 NTCP rs17556915 C>T 遗传多态性可能会影响未经 BLV 治疗和接受 BLV 治疗的 CHD 患者的基线 HDV RNA 载量，并可能有助于识别对 BLV 具有不同早期病毒学反应的患者。 尽管已经描述了几种牛磺胆酸钠共转运多肽 () 遗传多态性，但尚无数据表明它们在改变慢性丁型肝炎 (CHD) 患者中 HDV RNA 载量或对布列韦肽 (BLV) 治疗反应中的潜在作用。在这项研究中，我们证明，与携带 CT 基因型的患者相比，携带 NTCP rs17556915 TT/CC 的先心病患者，无论是治疗还是未治疗，都表现出更高的基线 HDV RNA 水平。在接受 BLV 单药治疗长达 96 周的 CHD 患者中，TT/CC 携带者的 HDV RNA 水平也高于 CT 携带者。此外，与 CT 基因型相比，TT/CC 基因型携带者在 BLV 治疗第 24 周时更频繁地表现出病毒无应答 (VNR)，而不是部分应答 (PR)，并且 7/9 TT/CC 基因型携带者在第 48 周时仍保持 VNR BLV 治疗。这是第一项证明 NTCP 基因多态性在影响 HDV 病毒载量和对 BLV 单药治疗的早期病毒学反应中的潜在作用的研究。由于迄今为止尚未描述 HDV 对 BLV 的直接耐药性，如果在更大规模的研究中得到证实，基因多态性可能有助于识别对 BLV 具有不同早期病毒学反应模式的患者。