替诺福韦艾拉酚胺
FDA 已经批准替诺福韦艾拉酚胺(替诺福韦的一种新型前体药物)用于治疗成人慢性 HBV 感染伴代偿性肝病。与第一代前体药物相比(富马酸替诺福韦二吡呋酯),替诺福韦艾拉酚胺产生的活性代谢物替诺福韦的细胞内水平较高,血浆水平较低;因此需要的剂量更低。已经证明替诺福韦艾拉酚胺 (Tenofovir alafenamide) 与富马酸替诺福韦二吡呋酯的有效性相似,但其对骨和肾有改善。[126]Chan HLY, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterology & Hepatology. 2016;3:185-195.[127]Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterology & Hepatology. 2016;3:196-206.欧盟委员会 (European Commission, EC) 在 2017 年 1 月已经批准了该药,[128]Gilead. European Commission grants marketing authorization for Gilead’s Vemlidy® (tenofovir alafenamide, TAF) for the treatment of chronic hepatitis B virus infection. January 2017. http://www.gilead.com/ (last accessed 25 July 2017).http://www.gilead.com/news/press-releases/2017/1/european-commission-grants-marketing-authorization-for-gileads-vemlidy-tenofovir-alafenamide-taf-for-the-treatment-of-chronic-hepatitis-b-virus-infectionEASL 指南推荐该药。[31]European Association For The Study Of The Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-398.http://www.journal-of-hepatology.eu/article/S0168-8278(17)30185-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/28427875?tool=bestpractice.comAASLD 准备将替诺福韦艾拉酚胺加入现行指南。
伐托他滨
是L-核苷类似物(左旋核苷类似物),通过抑制RNA依赖性DNA的合成发挥作用。在HBeAg阳性患者中它有强效抑制HBV DNA效果。在一项研究中,经过4周伐托他滨治疗后,99.9%的患者出现病毒载量的下降并且安全性较好。[129]Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:285-294.http://www.ncbi.nlm.nih.gov/pubmed/17218162?tool=bestpractice.com动物模型试验数据提示伐托他滨联合替比夫定能够协同抑制HBV的复制,联合治疗的研究目前正在进行。[129]Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:285-294.http://www.ncbi.nlm.nih.gov/pubmed/17218162?tool=bestpractice.com
基因治疗
应用反义分子、核酶和小片段干扰核糖核酸分子进行的基因治疗已经出现。这种治疗方案目的是下调和抑制肝细胞内HBV RNA合成。这种治疗方案在体外和动物模型中证实有效,但尚未展开人体试验。[130]McCaffrey AP, Nakai H, Pandey K, et al. Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol. 2003;21:639-644.http://www.ncbi.nlm.nih.gov/pubmed/12740585?tool=bestpractice.com一个潜在的问题是采用何种方式将这些小分子药物运送至肝细胞内并且送至HBV复制的位点。[129]Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:285-294.http://www.ncbi.nlm.nih.gov/pubmed/17218162?tool=bestpractice.com其他的关注点还有安全性:非特异性免疫应答的激活,有关基因治疗的争论,免疫激活后可能出现乙型肝炎暴发。目前已有I期临床试验展开。