替诺福韦地索普西富马酸盐对阿德福韦耐药恩替卡韦耐药慢

StephenW

Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial
Young-Suk Lim1,low asterisk,'Correspondence information about the author Young-Suk Lim†,Email the author Young-Suk Lim
, Geum-Youn Gwak2,†
, Jonggi Choi1
, Yung Sang Lee1
, Kwan Soo Byun3
, Yoon Jun Kim4
, Byung Chul Yoo5
, So Young Kwon5
, Han Chu Lee1,low asterisk,'Correspondence information about the author Han Chu LeeEmail the author Han Chu Lee
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DOI: https://doi.org/10.1016/j.jhep.2019.02.021 |


    •240 weeks of TDF monotherapy provided an increasing virologic response rate in patients with multidrug-resistant HBV.
    •Virologic breakthrough was rare and not associated with emergence of additional resistance mutations.
    •The HBeAg seroconversion rate was very low and no patient achieved HBsAg seroclearance up to week 240.
    •Prolonged continuous treatment may be needed to maintain viral suppression in these patients.
    •Progressive and significant decreases in renal function and bone mineral density after week 144 raise safety concerns.

Background & Aims

Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks.
Methods

One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks.
Results

At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (−3.21 ml/min/1.73 m2 by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm2) at the femur (−2.48%, p <0.001).
Conclusions

Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density.

(ClinicalTrials.gov No, NCT01639066 and NCT01639092).
Lay summary

In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.
Keywords:
Adefovir dipivoxil, Entecavir, Hepatitis B virus, Lamivudine, Resistance, HBV

StephenW

替诺福韦地索普西富马酸盐对阿德福韦耐药恩替卡韦耐药慢性乙型肝炎的单药治疗：5年临床试验
Young-Suk Lim1，低星号，'关于作者Young-Suk Lim†的通讯信息，通过电子邮件发送作者Young-Suk Lim
，Geum-Youn Gwak2，†
，Jonggi Choi1
，Yung Sang Lee1
，Kwan Soo Byun3
，Yoon Jun Kim4
，Byung Chul Yoo5
，So Young Kwon5
，韩楚李，低星号，关于作者韩楚李的通讯信息，作者韩楚李
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DOI：https：//doi.org/10.1016/j.jhep.2019.02.021 |


    •240周的TDF单药治疗为多药耐药的HBV患者提供了越来越高的病毒学应答率。
    •病毒学突破罕见，与其他耐药突变的出现无关。
    •HBeAg血清学转换率非常低，直到240周时没有患者达到HBsAg血清清除率。
    •可能需要延长持续治疗以维持这些患者的病毒抑制。
    •144周后肾功能和骨密度逐渐显着下降，引起安全性问题。

背景与目的

替诺福韦地索普西富马酸盐（TDF）单药治疗对抗乙型肝炎病毒和/或阿德福韦（ADV）的乙型肝炎病毒（HBV）患者的TDF加恩替卡韦（ETV）联合治疗效果不佳。尽管如此，接受长达144周的TDF单药治疗的患者的病毒学应答率并不理想。我们的目的是评估长达240周的TDF单药治疗的有效性和安全性。
方法

一项试验纳入了无ADV耐药的ETV耐药患者（n = 90），另一项试验包括ADV耐药患者（n = 102）。大多数患者（91.2％）也有拉米夫定耐药。患者按1：1随机分组接受TDF单药治疗或TDF + ETV联合治疗48周，然后进行TDF单药治疗直至240周。我们比较了研究与240周时汇总人群的安全性。
结果

在第240周，血清HBV DNA <15IU / ml的患者在完整分析组中ETV和ADV耐药组之间没有显着差异（84.4％对73.5％; p = 0.07），这是显着不同的通过治疗分析（92.7％对79.8％; p = 0.02）。在整个240周期间，7名患者发生了与药物依从性差的病毒学紊乱。没有人发展出额外的HBV耐药突变。在基线时的170名HBV e抗原（HBeAg）阳性患者中，12名（7.1％）在第240周达到HBeAg血清转换。没有达到HBV表面抗原血清清除率。在估计的肾小球滤过率（在CKD-EPI方程为-3.21ml / min / 1.73m2，p <0.001）和股骨上的骨矿物质密度（g / cm2）（-2.48）的第240周观察到从基线显着降低。 ％，p <0.001）。
结论

长达240周的TDF单药治疗在HBV耐ETV和/或ADV的严重预治疗患者中提供了增加的病毒学应答率。然而，它与较差的血清学反应和肾功能和骨矿物质密度降低有关。

（ClinicalTrials.gov否，NCT01639066和NCT01639092）。
放置摘要

在慢性感染对包括拉米夫定，恩替卡韦和/或阿德福韦在内的多种药物的乙型肝炎病毒的患者中，与TDF加恩替卡韦的联合治疗相比，替诺福韦地索普西酯富马酸盐（TDF）单一疗法显示出非劣效性。尽管如此，短期TDF单药治疗与次优病毒学应答相关，其长期安全性尚不确定。该研究显示240周的TDF单药治疗在大多数患者中提供了病毒学应答，但它与血清学反应差，肾功能和骨密度降低有关。
关键词：
阿德福韦酯，恩替卡韦，乙型肝炎病毒，拉米夫定，耐药，HBV