替比夫定对肾功能的潜在利益不超过它的高速率抗病毒耐药

StephenW

Potential Benefit of Telbivudine on Renal Function Does Not Outweigh Its High Rate of Antiviral Drug Resistance and Other Adverse Effects

    Suna Yapali
    ,
    Anna S. Lok

Five nucleos(t)ide analogs (NUCs) are approved for the treatment of hepatitis B. NUC therapy had been shown to reverse fibrosis and cirrhosis, and to reduce the risk of hepatic decompensation and hepatocellular carcinoma.1, 2 Although NUCs are effective in suppressing hepatitis B virus (HBV) replication, they do not eradicate the virus; therefore, most patients require long-term treatment. Long-term efficacy, safety, drug resistance, and costs are the major considerations in determining which NUC should be considered as first-line treatment.

NUCs are generally safe and well-tolerated, but side effects have been reported including nephrotoxicity, neuropathy, myopathy, lactic acidosis, and decrease in bone mineral density.1, 3, 4, 5, 6 Of these, nephrotoxicity associated with adefovir or tenofovir has received the most attention. Nephrotoxicity manifesting as decrease in glomerular filtration rate (GFR) is more common in patients who are >50 years old, have baseline renal insufficiency, hypertension and/or diabetes mellitus.7 Proximal renal tubular injury—resembling Fanconi syndrome with hypophosphatemia, hypouricemia, aminoaciduria, and glycosuria—had also been reported.8 In most instances, nephrotoxicity is reversible after dose reduction or discontinuation of treatment. The postulated mechanisms of nephrotoxicity associated with adefovir and tenofovir treatment include increased intracellular influx through organic anion transporters and/or a defect in its luminal excretion through multidrug-resistance–associated proteins, or mitochondrial toxicity in the proximal tubular cells of the kidney.9 Lamivudine and entecavir have not been reported to be associated with nephrotoxicity. All NUCs approved for HBV are eliminated by the kidneys and dose adjustments are needed in patients with impaired renal function. Renal impairment is common in patients with decompensated cirrhosis and in liver transplant recipients. Therefore, renal safety is an important factor in deciding which NUC is most appropriate for patients with hepatitis B, particularly those who have other risk factors for renal impairment.

In this issue of the Gastroenterology, Gane et al10 reported the results of a comprehensive analysis of renal function in the telbivudine clinical trial database. This database included 1367 patients with compensated chronic hepatitis B randomized to receive telbivudine or lamivudine for 2 years in the GLOBE study, 655 patients in the GLOBE study and in a similar study in China (Study 015) who received telbivudine in the feeder study and in the extension study (A2303) for a total duration up to 4 years, 70 patients who continued to receive telbivudine in another extension study (CN04E1) for a total duration of 4–6 years, 66 patients who discontinued telbivudine treatment at the end of the GLOBE study or Study 015 owing to efficacy, 398 patients who received lamivudine in the GLOBE study and telbivudine for 2 years in the extension study (A2303), and 228 patients with decompensated cirrhosis randomized to receive telbivudine or lamivudine for 2 years in Study A2301.6, 11, 12, 13, 14

Renal function was assessed by 3 different calculations for estimated GFR (eGFR), Cockroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration. The authors showed that renal function assessed by serum creatinine and the 3 formulas for eGFR improved in patients who received telbivudine during the GLOBE trial, whereas those who received lamivudine had a decline in renal function. The changes in eGFR at the end of 2 years of treatment were +8.5% versus –0.5% for the entire cohort of patients who received telbivudine versus lamivudine, respectively; +11.4% versus –2.4% for patients age >50 years; +17.2% versus +4.3% for those with eGFR ≤90 mL/min/1.73 m2 at baseline; and +7.2% versus +2.3% for patients with cirrhosis. Multivariate analysis of baseline factors in the GLOBE study that predicted a shift in eGFR from baseline of 60–90 to ≥90 mL/min/1.73 m2 at year 2 were telbivudine treatment (odds ratio [OR], 2.51), younger age (OR, 0.94), and non-Caucasian race (OR, 0.34). Improvement in eGFR was maintained during long-term telbivudine treatment. At year 4, mean increase of eGFR was +14.9 mL/min/1.73 m2 and 74% (165/223) of the telbivudine-treated patients with baseline eGFR of 60–89 mL/min/1.73 m2 had eGFR of ≥90 mL/min/1.73 m2.

Among the patients who received lamivudine in the GLOBE/015 studies with no evidence of genotypic resistance at the end of the feeder studies, eGFR improved by 8.9% after 2 years of lamivudine and by 9.5% after 2 years of telbivudine treatment in the extension studies.

In patients with decompensated cirrhosis, eGFR at year 2 improved by 2.0 mL/min/1.73 m2 in the patients who received telbivudine but declined by 4.6 mL/min/1.73 m2 in those who received lamivudine.

The study by Gane et al10 showed that improvement in eGFR was observed in chronic hepatitis B patients treated with telbivudine. The improvement in eGFR was maintained during continuous treatment of telbivudine for up to 6 years and was observed in various subpopulations. Although the mechanism responsible for the improvement in renal function is unclear, the results are convincing.

What are the implications of these results? Is the improvement in renal function specific for telbivudine? Does the benefit on renal function outweigh the risk of antiviral resistance and other adverse effects of telbivudine? Should telbivudine be recommended as a first-line antiviral agent for hepatitis B?

Gane et al10 showed that improvement in eGFR was observed in the telbivudine group but not in the lamivudine group in the GLOBE study; however, in the subgroup of patients in GLOBE/015 studies who did not have genotypic resistance after 2 years of lamivudine, an improvement in eGFR was observed and the percentage of change in eGFR was similar to that observed after 2 years of telbivudine treatment in the extension studies. Thus, although the authors found that improvement in eGFR during telbivudine treatment was not related to virologic response, it is possible that a higher rate of virologic breakthrough in the lamivudine group in the GLOBE study might have contributed to the minor decline in eGFR in the entire lamivudine group.

Improvement in renal function has not been systematically examined in patients receiving other HBV NUCs. Registration trials and clinical studies have focused on the incidence of renal impairment (Table 1).1, 3, 5, 14, 15, 16, 17, 18, 19, 20, 21, 22 Renal impairment was reported in studies of other HBV NUCs, but not in studies of telbivudine. Reports of some telbivudine trials provided data on improvement in eGFR but did not specify whether any patient had deterioration in renal function.6, 11, 12, 13, 14 Renal impairment is more commonly associated with adefovir than with other HBV NUCs and more common in patients with decompensated cirrhosis than in those with compensated liver disease.5, 15, 16, 17, 18, 22 Despite their similarities in molecular structure, nephrotoxicity is less common with tenofovir treatment than with adefovir treatment, occurring in 1% of patients with HBV monoinfection and compensated liver disease after ≤5 years of tenofovir treatment.1 A retrospective, match-control study comparing 230 patients with chronic hepatitis B who had received 2 years of telbivudine or entecavir treatment showed that, compared with baseline, serum creatinine and eGFR improved significantly in both groups after 1 year of treatment but no significant difference was observed in either group at year 2.23 Similarly, a shift toward a better eGFR category was seen in both groups at year 1 but not at year 2.
Table 1. Renal Safety of Approved Nucleos(t)ide Analogs for Chronic Hepatitis B and Dose Adjustments According to Renal Function

a Data obtained from product monographs.

b Data obtained from references 1,3,5,6,13-22. Renal impairment was defined as an increase in serum creatinine by ≥0.5 mg/dL and confirmed by 2 consecutive laboratory results in references 3, 5, 15-22; serum creatinine increase from baseline by ≥0.5 mg/dL and serum creatinine clearance <50 mL/min in references 1 and 3; definition of renal impairment was not provided in references 6, 13, and 14, time dependent changes in eGFR by Modification of Diet in Renal Disease (MDRD) in reference 13, and by MDRD and Chronic Kidney Disease Epidemiology Collaboration in reference 14.

c For lamivudine-refractory patients; 1 mg/d if GFR ≥50 mL/min, 0.5 mg/d or 1 mg every 48 hours if GFR 30-49 mL/min, 0.3 mg/d or 1 mg every 72 hours if GFR 10-29 mL/min, 0.1 mg/d or 1 mg every 7 days if on dialysis.

The key question is whether improvement in renal function outweighs the risk of antiviral drug resistance and other adverse effects of telbivudine to justify its use as a first-line antiviral agent for hepatitis B. Despite its potent antiviral activity, telbivudine has a low barrier to antiviral drug resistance and shares similar resistance mutations as lamivudine. A phase III clinical trial of telbivudine found that viral resistance was observed in 25.1% and 39.5% of hepatitis B e antigen (HBeAg)-positive patients and in 10.8% and 25.9% of HBeAg-negative patients after 2 years of telbivudine and lamivudine, respectively.6 Of the patients who did not have genotypic resistance at year 2 and who continued to receive telbivudine in the extension study, the cumulative rate of antiviral resistance at 4 years was 10.6% in HBeAg-positive and 10.0% in HBeAg-negative patients.13 By contrast, phase III trials of entecavir and tenofovir in nucleoside-naïve patients showed genotypic resistance rates at 5 years of 1.2% and 0%, respectively.1, 24 In an attempt to decrease the rate of antiviral resistance, the roadmap approach was tested in a prospective study of 100 HBeAg-positive patients. Patients with detectable HBV DNA at week 24 were to receive add-on tenofovir and 45% did so.25 The high percentage of patients in whom tenofovir had to be added as a rescue therapy by week 24 negates its benefit of being a lower cost HBV NUC. Telbivudine has been associated with myopathy and peripheral neuropathy and these adverse events were more frequent and severe when telbivudine was used in combination with pegylated interferon, leading to early termination of that trial. In patients who received 4 years of telbivudine monotherapy, muscle symptoms (including myalgia, muscular weakness, musculoskeletal pain, myopathy, myositis, and musculoskeletal discomfort), peripheral neuropathy, and grade 3–4 increase in serum creatine kinase levels were observed in 6.1%, 1.2%, and 15.9% of patients, respectively.13

In summary, although Gane et al10 provided tantalizing data suggesting that telbivudine may be renal protective, it is not clear whether this protective effect is specific to telbivudine. This potential benefit does not outweigh the high rate of antiviral drug resistance and neuromuscular adverse effects. Therefore, these results, albeit being highly relevant from the clinical and safety profile perspectives, do not support the use of telbivudine as a first-line NUC in hepatitis B treatment and should not prompt revision to existing guidelines.

StephenW

替比夫定对肾功能的潜在利益不超过它的高速率抗病毒耐药性等不良影响

    苏娜Yapali
    ，
    安娜· S.乐

五核苷（酸）类似物（ NUCs ）被批准用于乙型肝炎NUC疗法的治疗已被证明能逆转纤维化和肝硬化，以及降低肝功能失代偿和肝细胞癌carcinoma.1 ， 2的风险虽然NUCs能有效地抑制B型肝炎病毒（HBV ）复制，他们不根除病毒，因此，大多数患者需要长期治疗。长期疗效，安全性，耐药性，成本的国统会应被视为一线治疗决定的主要考虑因素。

NUCs通常是安全且耐受性良好，但副作用已有报道，包括肾毒性，神经病变，肌病，乳酸性酸中毒，以及减少骨质density.1 ，3，4 ，5，6其中，阿德福韦或替诺福韦相关的肾毒性已经收到了最多的关注。肾毒性表现为减少，肾小球滤过率（GFR ）是较常见的病人谁是> 50岁，有基线肾功能不全，高血压和/或糖尿病mellitus.7近端肾小管损伤，类似范可尼综合征伴低血磷，低尿酸血症，氨基酸尿和糖尿-亦已reported.8在大多数情况下，肾毒性是剂量减少的治疗或停药后是可逆的。肾毒性的阿德福韦和替诺福韦治疗相关的假定机制包括通过有机阴离子转运增加细胞内的流入和/或在其管腔排泄的缺陷，通过多药耐药相关蛋白，或线粒体毒性的kidney.9拉米夫定的近端肾小管上皮细胞和恩替卡韦没有被报道与肾毒性相关。批准用于乙肝所有NUCs被需要的患者肾功能受损的肾脏和剂量调整淘汰。肾功能不全的患者常见的失代偿期肝硬化和肝移植受者。因此，肾脏安全性是决定其国统会是最适合乙肝患者，特别是那些谁还有其他的危险因素肾功能损害的重要因素。

在这个问题上的消化，甘恩等[10]报道，在替比夫定的临床试验数据库的肾功能进行综合分析的结果。这个数据库包括1367例代偿性慢性乙型肝炎随机的GLOBE研究， 655例患者中GLOBE研究，并在中国类似的研究（研究015 ）谁收到替比夫定在馈线学习和接受替比夫定或拉米夫定2年扩展研究（ A2303 ），总工期长达4年， 70例患者谁继续接受替比夫定在另一个延伸研究（ CN04E1 ）为4-6年的总时长，谁停止替比夫定治疗时的底66例GLOBE研究或研究015由于疗效，谁在延伸研究（ A2303 ）接受拉米夫定GLOBE研究和替比夫定为2年， 228例失代偿期肝硬化患者398随机接受替比夫定或拉米夫定2年的研究A2301 。 6 ， 11 ， 12 ， 13 ， 14

肾功能是由3个不同的计算估计肾小球滤过率（ eGFR）为， Cockroft - 高尔特，饮食修正肾脏疾病，以及慢性肾脏病流行病学协作评估。研究者发现肾功能血清肌酐和3个公式的eGFR在谁的GLOBE试验期间接受替比夫定的患者改善了评估，而那些谁收到拉米夫定有肾功能下降。在表皮生长因子受体在2年治疗结束时的变化是+8.5 ％和-0.5 ％，对谁分别接受替比夫定与拉米夫定治疗，患者整个队列; 11.4 ％对病人-2.4 ％年龄> 50岁; 17.2 ％对那些与表皮生长因子受体≤ 90 mL/min/1.73平方米基线4.3 ％，而+7.2 ％对肝硬化患者的2.3％ 。在GLOBE研究的基线因素预测eGFR的一个转变，从60-90基线≥ 90 mL/min/1.73平方米在一年多因素分析2例替比夫定治疗（胜算比[OR] ， 2.51 ） ，年龄较轻（或，0.94 ）和非高加索人种（OR 0.34 ） 。改进的eGFR在长期替比夫定治疗维持。在4年内，平均eGFR的增加是替比夫定治疗的患者中14.9 mL/min/1.73平方米和74 ％ （165/ 223）为60-89 mL/min/1.73平方米基线eGFR的有≥ 90毫升的eGFR / min/1.73平方米。

其中谁在馈线学业结束后接受拉米夫定在GLOBE/015研究，没有证据基因型耐药的患者，表皮生长因子受体提高了8.9 ％， 2年后拉米夫定和9.5％后，在扩展研究2年替比夫定治疗。

在失代偿性肝硬化，表皮生长因子受体在今年2 2.0 mL/min/1.73平方米，谁收到替比夫定，而是由4.6 mL/min/1.73平方米在那些谁收到拉米夫定拒绝了患者的改善。

由甘恩等[10]的研究表明，改善表皮生长因子受体，观察替比夫定治疗慢性乙型肝炎患者。表皮生长因子受体在改善过程中不断替比夫定治疗的长达6年维持，观察在不同的亚群。虽然负责肾功能改善的机制尚不清楚，其结果是令人信服的。

什么是这些结果的意义？是肾功能的改善特定替比夫定？是否对肾功能的益处大于抗病毒耐药和替比夫定的其他不良影响的风险？应该替比夫定被推荐为一线抗病毒药剂B型肝炎？

甘恩等[10]表明，改进的eGFR观察替比夫定组中，但不拉米夫定组中GLOBE研究中，然而，在患者中GLOBE/015研究谁后2年内拉米夫定并无基因型耐药性，一个子组改善表皮生长因子受体，观察和改变表皮生长因子受体的比例相似，在以后的扩展研究2年替比夫定治疗观察。因此，虽然笔者发现在替比夫定治疗表皮生长因子受体的改善是不相关的病毒学应答，它可能是一种更高的速率在GLOBE研究拉米夫定组病毒学突破可能给未成年人下降EGFR在整个贡献拉米夫定组。

改善肾功能还没有得到系统的研究中接受其他乙肝NUCs患者。注册试验和临床研究都集中在肾功能不全的发生率（表1） 。1， 3 ， 5 ， 14 ， 15 ， 16 ， 17 ， 18 ， 19 ， 20 ， 21 ， 22肾损害报道的其他研究乙肝NUCs ，但不是在替比夫定的研究。替比夫定的一些试验报告中提供的数据对改善表皮生长因子受体，但没有指定任何病人是否有肾function.6恶化， 11 ， 12 ， 13 ， 14肾损害较常与阿德福韦关联比与其他乙肝NUCs和更常见失代偿性肝硬化比那些代偿性disease.5 ， 15 ， 16 ， 17 ， 18 ， 22尽管他们在分子结构上的相似性，肾毒性是替诺福韦治疗不太常见的比用阿德福韦治疗，患者的乙肝病毒1 ％发生单一感染后≤ 5年替诺福韦treatment.1的代偿性肝病的回顾性，匹配控制比较230例曾接受2年替比夫定或恩替卡韦治疗谁慢性乙型肝炎的研究表明，与基线血清肌酐和EGFR相比提高显著两组治疗1年，但没有显著差异，观察在任何一组在今年2.23后同样，一个转向一个更好的eGFR类别于今年1可见两组，但不是在2年。
表1中。批准的核苷（酸）类似物治疗慢性乙型肝炎和剂量调整的肾脏安全性根据肾功能
拉米夫定 阿德福韦 恩替卡韦 替比夫定 替诺福韦

A DATA从产品专着获得的。

B DATA从文献获得1,3,5,6,13-22 。肾功能受损被定义为增加血清肌酐≥ 0.5毫克/分升，并连续2个实验室的结果在参考文献证实3 ， 5 ， 15-22 ，血清肌酐升高，从基线由≥ 0.5毫克/分升，血清肌酐清除率< 50未提供在引用6 ， 13肾功能损害的定义，和14 ，与时间有关的表皮生长因子受体在国会通过肾脏疾病（ MDRD ）的修改在参考13的变化，并通过MDRD和慢性肾脏;毫升/分钟的参考文献1和3在参考14病流行病学协作。

c对于拉米夫定耐药的患者， 1毫克/天，如果肾小球滤过率≥ 50毫升/分钟， 0.5毫克/天或1毫克每48小时，如果肾小球滤过率30-49毫升/分钟， 0.3毫克/天或1毫克每72小时，如果肾小球滤过率10 -29毫升/分钟， 0.1毫克/天或1毫克每7天，如果在透析治疗。

关键的问题是，是否在改善肾功能胜过抗病毒耐药性和替比夫定，以证明其作为一线抗病毒药剂B型肝炎尽管其强大的抗病毒活性使用其他不良影响的风险，替比夫定具有低门槛的抗病毒耐药性和股类似的耐药突变的拉米夫定。替比夫定的III期临床试验发现，抗病毒，观察乙肝e抗原（HBeAg ）阳性患者的25.1 ％和39.5 ％和10.8 ％，而HBeAg阴性患者的25.9 ％， 2年后替比夫定和拉米夫定的， respectively.6谁没有基因型耐药在今年2和谁继续接受替比夫定在延伸研究的患者中，抗病毒耐药的4年的累积发生率为10.6％， HBeAg阳性和HBeAg阴性患者10.0％ 0.13相比之下，恩替卡韦和替诺福韦在核苷初治患者的III期临床试验结果显示基因型耐药率5年为1.2％和0 ％ ， respectively.1 ， 24在试图降低抗病毒药物的耐药率，路线图的方法在100例HBeAg阳性患者的前瞻性研究进行了测试。患者可检测到HBV DNA在24周分别接受附加替诺福韦和45 ％做过的患者so.25高百分比的人替诺福韦必须由第24周被添加为抢救治疗否定了作为一个成本较低的HBV其利益国统会。替比夫定一直伴随着肌病和周围神经病变而这些不良反应是更加频繁和严重时，替比夫定用于与聚乙二醇干扰素结合，导致提前终止该试验。谁收到4年替比夫定单药治疗的病人，肌肉症状（包括肌痛，肌肉无力，肌肉骨骼疼痛，肌病，肌炎，肌肉骨骼不适） ，周围神经病变，以及3-4级增加血清肌酸激酶水平在6.1 ％观察，1.2％，和患者的15.9 ％ ， respectively.13

综上所述，虽然甘恩等[10]提供了诱人的数据表明，替比夫定可能是肾功能的保护，目前尚不清楚这种保护作用是否是特定的替比夫定。这种潜在的益处不超过抗病毒抗药性的高速率和神经肌肉的不良影响。因此，这些结果虽然是从临床和安全性的观点具有很强的针对性，不支持在乙肝治疗中使用替比夫定作为一线NUC也不应该及时修订现有准则