NATAP：TDF 对 HDV 的功效

StephenW

NATAP：TDF 对 HDV 的功效

总而言之，由于感染了 delta 肝炎的 HIV 患者群体所代表的独特机会，我们研究了替诺福韦的长期效果，该药物对 HIV 和 HBV 均具有双重抗病毒作用，并在 10 年前作为抗逆转录病毒药物上市销售.在所有接受替诺福韦治疗的患者中，血清 HDV-RNA 稳步下降，其中超过一半的患者在 5 年内无法检测到。通过瞬时弹性成像测量，这种病毒学结果导致肝纤维化显着改善，9 名患者中有 5 名肝硬化消退。据我们所知，这项研究首次提供了有力的证据，支持口服抗病毒药物对慢性丁型肝炎的临床益处。在目前缺乏耐受性更好的药物的情况下，我们建议应将替诺福韦视为 HDV 感染的治疗选择，承认其益处主要在长期暴露后得到认可，可能并非对所有患者都有效。

在我们的研究中，我们报告了接受替诺福韦治疗并中位随访近 5 年的相对较大系列慢性丁型肝炎患者的病毒标志物和组织学估计结果。所有患者均实现了完全的 HBV 抑制，同时 HDV 复制显着减少（HDV-RNA 清除率超过一半）以及肝纤维化改善（10 人中有 5 人肝硬化消退）。据我们所知，这是第一项毫无疑问地证明口服抗病毒药物对慢性丁型肝炎具有临床益处的研究。基于这些数据，我们建议应考虑将替诺福韦作为 HDV 感染的治疗选择，并意识到其益处主要在长期内得到认可，可能并非对所有患者都有效。

我们的研究结果表明，替诺福韦对 delta 肝炎的益处很可能是该药物对 HBV 的有效抗病毒活性之后的间接作用的结果。 HDV-RNA 的减少和/或抑制在数月内发生，并且在所有患者中都发生了完全的 HBV-DNA 抑制。然而，血清 HBsAg 的浓度并未遵循相同的趋势，并且在整个研究期间保持相对稳定。其他人也报道了在接受替诺福韦治疗的患者中 HBsAg 的类似不受影响的动力学 [34-39]，这反对替诺福韦在整个减少 HBV 包膜蛋白产生的过程中对三角洲肝炎的益处。然而，我们没有检查我们的患者在长期替诺福韦治疗下是否出现不同 HBsAg 组分释放的失衡。假设，长期替诺福韦治疗后大 HBsAg 同种型的产生减少可能会损害新肝细胞的 HDV 感染性，并以这种方式最终导致 HDV-RNA 抑制 [40]。

值得注意的是，肝纤维化的改善与血清 HDV-RNA 的完全抑制显着相关。尽管我们几乎所有的 delta 肝炎患者长期服用替诺福韦后血清 HDV-RNA 下降，但未完全抑制 HDV-RNA 的患者肝纤维化并没有改善，这表明 delta 患者的肝损伤主要是由 HDV 复制驱动的而不是HBV感染。

在我们的系列中，我们无法确定任何实现 HDV-RNA 抑制的预测因子。尽管在所有患者中引入替诺福韦后 HBV-DNA 很快变为阴性，但清除 HDV 的 10 名个体达到 HDV-RNA 阴性的中位时间为 54 个月。这一观察结果表明，替诺福韦对 delta 肝炎的任何益处只有在延长时间后才会显现。
长期替诺福韦治疗对 HIV 感染患者的丁型肝炎的疗效
AIDS 2014 Vincent Sorianoa,b, Eugenia Vispoa, Rocı ́o Sierra-Enguitaa,Carmen de Mendozac, Jose ́ V. Ferna ́ndez-Monteroa,Pablo Labargaa 和 Pablo Barreiroa,b

StephenW

NATAP: TDF Efficacy on HDV

In summary, thanks to the unique opportunity represented by a population of HIV patients with delta hepatitis, we investigated the long-term effect of tenofovir, which exhibits dual antiviral effect against both HIV and HBV, and was marketed as an antiretroviral agent 10 years ago. Serum HDV-RNA steadily declined in all patients receiving tenofovir and became undetectable in more than a half of them by 5 years. This virological outcome resulted in significant improvements in hepatic fibrosis as measured by transient elastography, with regression of cirrhosis in five out of nine patients. In our knowledge, this study is the first to provide robust evidence in favour of a clinical benefit of oral antivirals on chronic hepatitis delta. In the absence of current, more well tolerated medications, we propose that tenofovir should be considered as a therapeutic option for HDV infection, acknowledging its benefit would mainly be recognized after prolonged exposure and perhaps not in all patients.

In our study, we report outcomes for viral markers and histological estimates in a relatively large series of chronic hepatitis delta patients treated with tenofovir and followed for a median of nearly 5 years. Complete HBV suppression was achieved in all patients along with significant reductions in HDV replication (with clearance of HDV-RNA in more than a half) along with improvements in liver fibrosis (with regression of cirrhosis in five out of 10). In our knowledge, this is the first study that demonstrates unquestionably a clinical benefit of oral antivirals on chronic hepatitis delta. On the basis of these data, we propose that tenofovir should be considered as a therapeutic option for HDV infection, being aware that its benefit would mainly be recognized in the long term and perhaps not in all patients.

Our results suggest that the benefit of tenofovir on delta hepatitis is most likely the result of an indirect effect that follows the potent antiviral activity of the drug on HBV. Reduction and/or suppression of HDV-RNA occurred over months and followed complete HBV-DNA suppression in all patients. However, concentrations of serum HBsAg did not follow the same trend and remained relatively stable during the whole length of the study. Similar unaffected kinetics for HBsAg in patients treated with tenofovir have been reported by others [34–39], which argues against a benefit of tenofovir on delta hepatitis throughout reducing the production of the HBV envelope protein. However, we did not check whether a dysbalance in the release of distinct HBsAg fractions under prolonged tenofovir therapy had occurred in our patients. Hypothetically, a reduction in the production of the large HBsAg isoform on long-term tenofovir treatment could impair HDV infectivity of new hepatocytes and in this way ultimately result in HDV-RNA suppression [40].

It is noteworthy that the improvement in liver fibrosis was significantly linked to the achievement of complete suppression of serum HDV-RNA. Although almost all our patients with delta hepatitis experienced declines in serum HDV-RNA on long-term tenofovir, liver fibrosis did not improve in those who did not completely suppress HDV-RNA, suggesting that hepatic damage in delta patients is mainly driven by HDV replication rather than by HBV infection.

We could not identify any predictor of the achievement of HDV-RNA suppression in our series. Whereas HBV-DNA became negative soon after introducing tenofovir in all patients, the median time to reach negative HDV-RNA in the 10 individuals who cleared HDV was 54 months. This observation suggests that any benefit of tenofovir on delta hepatitis would be manifest only after extended periods.
Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients
AIDS 2014 Vincent Sorianoa,b, Eugenia Vispoa, Rocı ́o Sierra-Enguitaa,Carmen de Mendozac, Jose ́ V. Ferna ́ndez-Monteroa,Pablo Labargaa and Pablo Barreiroa,b