AASLD2012:长期替诺福韦治疗安全和有效,小骨量丢失

StephenW

长期替诺福韦治疗安全和有效,小骨量丢失
AASLD 2012: Tenofovir Safe and Effective for Long-term Hepatitis B Treatment with Little Bone Loss


    Published on Tuesday, 13 November 2012 00:00
    Written by Liz Highleyman



Tenofovir (Viread) continues to be safe and highly effective for treating chronic hepatitis B through 8 years of follow-up, researchers reported at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012) this week in Boston. Another study showed minimal bone loss among tenofovir-treated patients using the FRAX method.

Several nucleoside/nucleotide analogs are active against hepatitis B virus (HBV), but with long-term use HBV develops resistance to older drugs like lamivudine (Epivir-HBV), thereby compromising sustained effectiveness.

Tenofovir disoproxil fumarate -- which has potent activity against both HBV and HIV -- has a higher barrier to resistance. Gilead Study 102 and 103 showed that it maintains HBV DNA suppression, is well-tolerated, and shows no evidence of resistance through 6 years for previously untreated chronic hepatitis B patients.

Scott Fung from Toronto General Hospital and colleagues conducted a Phase 3b study of tenofovir for treatment-experienced hepatitis B patients. Participants were receiving lamivudine at study entry but had HBV viral load of 1000 IU/mL or more and documented lamivudine resistance (e.g., M204I/V or L180M mutations); some had also used adefovir (Hepsera) for no more than 48 weeks.

The analysis included 280 participants, about half of whom were hepatitis B "e" antigen (HBeAg) positive. Approximately two-thirds were enrolled in Europe and one-third in North America. They had been infected with HBV for 10 years on average and had been taking lamivudine for about 4 years.

About three-quarters of participants were men, about 60% were white, about 35% were Asian, and the average age was about 47 years. HBV genotype A was most common (22%), followed by B (14%), C (19%), and D (45%). At baseline the mean HBV DNA level was about 6.5 log copies/mL.

About 60% of participants had elevated alanine aminotransferase (ALT) at study entry. People with pre-existing kidney function impairment (creatinine clearance < 50 mL/min) were excluded, as were individuals with HIV or hepatitis C coinfection. At baseline about 30% of patients had evidence of low bone density (osteopenia or osteoporosis) on spine DEXA scans and about 20% had bone loss in hip scans.

Participants were randomly assigned to take tenofovir alone or coformulated tenofovir/emtricitabine (Truvada, approved for HIV treatment). Safety and efficacy were evaluated over 96 weeks.

Assessments included kidney biomarkers (serum creatinine, creatinine clearance, serum phosphorus) because tenofovir can cause kidney toxicity in susceptible individuals, and DEXA bone density scans because the drug has been linked to bone loss in people with HIV.

Results

    About 90% of participants in both study arms completed 96 weeks of treatment.
    An intent-to-treat analysis at 96 weeks showed good -- and statistically equivalent -- efficacy in the tenofovir monotherapy and tenofovir/emtricitabine arms:

o   Undetectable HBV DNA (< 400 copies/mL or < 69 IU/mL): 89% vs 86%, respectively;

o   ALT normalization: 62% vs 63%, respectively;

o   HBeAg loss: 15% vs 13%, respectively;

o   HBeAg seroconversion: 11% vs 10%, respectively;

o   Hepatitis B surface antigen (HBsAg) loss: 0 and 1 patients, respectively.

    No tenofovir resistance was detected in 18 tested participants through 96 weeks.
    Both treatments were generally well-tolerated.
    Only 1 patient experienced a serious adverse event.
    3 people (1%) discontinued treatment due to adverse events.
    No participants had a confirmed serum creatinine increase of > 0.5 mg/dL from baseline, 1% had reduced serum phosphorus < 2 mg/dL, and 3% had creatinine clearance < 50 mL/min (most of whom had below normal kidney function at baseline).
    No clinically relevant bone loss was observed according to spine and hip bone mineral density T-scores and Z-scores, which compare bone density to population norms.
    5 people experienced trauma-associated bone fractures, but no non-traumatic fractures -- those due to fragility in the absence of injury -- were reported.

Based on these findings the researchers concluded, "A high rate of HBV DNA suppression with no detectable [tenofovir] resistance was achieved with [tenofovir] in patients with documented lamivudine resistance through 96 weeks."

"Similar efficacy between the [monotherapy] and combination therapy arms supports the use of [tenofovir] monotherapy in this population," they continued. "[Tenofovir] was safe and well tolerated, with a low rate of renal events and no evidence of clinically relevant bone loss."

Since the 2 treatments were equally safe and effective, Fung said that tenofovir alone should be considered adequate.
Bone Loss

In a related study, Upkar Gill from the Institute of Cell and Molecular Science in London and colleagues looked specifically at bone mineral density changes among chronic hepatitis B patients taking tenofovir.

The study was designed to show whether the World Health Organization's FRAX score is consistent with DEXA scans and bone-related biomarkers (e.g., serum alkaline phosphatase and calcium levels) for determining bone loss in this population, as the WHO method is less expensive and can be widely used in resource-limited settings.

FRAX is a web-based tool that combines several variables to calculate 10-year fracture risk, including sex, age, body mass index, individual and family history of fractures, smoking, and use of alcohol or steroids. The FRAX score may help determine which individuals could benefit from DEXA scans, ongoing monitoring, and lifestyle modification to reduce their risk.

The analysis included 122 hepatitis B patients who had used tenofovir for at least 48 weeks, and 48 individuals not exposed to the drug. About 70% were men, two-thirds were Asian, and the rest were about evenly split between black and white participants. The median age was 45 years in the tenofovir group and 36 in the control group. The tenofovir group had similar proportions of people with mild, moderate, and severe liver fibrosis, but in the control group nearly two-thirds had mild fibrosis. About 10% of participants were smokers and about 16% said they drank alcohol.

Results

    Tenofovir recipients had a significantly lower average hip T-score than unexposed patients.
    T-scores for the lumbar spine and femoral neck (hip joint), however, did not differ significantly.
    Small changes in bone density were seen soon after starting tenofovir, but levels soon reached a plateau with no further bone loss progression.
    There was no correlation between duration of tenofovir use and bone loss at any site.
    There was no overall correlation between bone biochemistry and changes in bone mineral density.
    Tenofovir recipients had a tendency towards increased serum alkaline phosphatase, but the difference did not reach statistical significance.
    In a univariate analysis, older age, body mass index, smoking, and tenofovir use were all significant risk factors for bone loss.
    In a multivariate analysis controlling for other factors, however, the effect of tenofovir was no longer significant.
    Overall, 75% of tenofovir-exposed patients were determined to have a low risk of fractures according to pre-DEXA FRAX scores, and none required treatment for bone loss.
    FRAX score predicted major hip fractures as well as DEXA scans and did not miss any high-risk patients:

o   Sensitivity: 100%;

o   Specificity: 84%;

o   Negative predictive value: 100%;

o   Positive predictive value: 40%.

"We demonstrate the utility of FRAX as an alternative tool to assess fracture risk over time," the researchers concluded. "We recommend the use of FRAX to consolidate treatment decisions in chronic hepatitis B," reducing the need for costly DEXA scans, they added.

Using this method, Gill explained, people with low risk for bone fractures can be reassured, medium-risk patients can be monitored, and high-risk individuals can receive interventions.

11/13/12

References

S Fung, P Kwan, M Fabri, et al. Efficacy and Safety of Tenofovir DF (TDF) in Chronic Hepatitis B Virus Infected Patients with Documented Lamivudine Resistance (LAM-R). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 20.

U Gill, A Zissimopoulos, S Al-shamma, et al. FRAX score in the assessment of Bone Mineral Density changes in Tenofovir treated Chronic Hepatitis B patients: comparison with bone biochemistry and DEXA scanning. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 22.

StephenW

替诺福韦（VIREAD的）仍然是安全和有效的治疗慢性乙型肝炎通过8年的随访中，研究人员在第63届会议的美国协会肝病（AASLD 2012）本周在波士顿的研究报告。另一项研究显示最小的骨质流失在使用FRAX方法替诺福韦治疗的患者中。

几种核苷/核苷酸类似物对乙型肝炎病毒（HBV），HBV，但长期使用产生耐药性的药物如拉米夫定（拉米HBV），从而影响了持续的有效性。

富马酸替诺福韦酯 - 有较强的活性，对HBV和HIV  - 具有较高的耐药屏障。 Gilead公司研究102和103表明其维持HBV DNA抑制，耐受性好，6年以前未经治疗的慢性乙肝患者的抵抗力，并无证据显示。

斯科特·冯从多伦多总医院和他的同事进行了第3B期研究替诺福韦治疗经验的乙肝患者。参加者接受拉米夫定在进入研究，但HBV病毒载量为1000 IU / mL以上并记录拉米夫定耐药性（例如，M204I / V或L180M突变），一些人还用阿德福韦（阿德福韦酯），不超过48个星期。

该分析包括280名，其中约半数是B型肝炎的“e”抗原（HBeAg）阳性。大约有三分之二被纳入欧洲和北美三分之一的。他们已经感染乙肝病毒的10岁，平均服用拉米夫定约4年。

大约四分之三的参与者为男性，约60％是白人，约35％为亚洲人，平均年龄为47岁。 HBV基因型A是最常见的（22％），其次是B（14％），C（19％），D（45％）。在基线HBV DNA水平平均约为6.5日志拷贝/毫升。

约60％的参与者进入研究时，谷丙转氨酶（ALT）升高。人与预先存在的肾功能损害（肌酐清除率<50毫升/分钟）被排除在外，因为是个人与艾滋病毒或丙型肝炎合并感染。在基线时，约30％的患者有低骨密度（骨量减少或骨质疏松症）的脊柱骨密度扫描，约20％的骨量丢失的髋关节扫描的证据。

参与者被随机分配服用替诺福韦单独或共配制替诺福韦/恩曲他滨（TRUVADA，批准用于HIV治疗）。超过96周的安全性和有效性进行了评估。

评估包括肾脏的生物标志物（血清肌酐，肌酐清除率，血清无机磷），因为替诺福韦可引起肾毒性易感人群，DEXA骨密度扫描，因为该药物已被证实与艾滋病毒感染者的骨量丢失的。

结果

    约90％的参与者在两个研究组完成了96周的治疗。
    意向性治疗分析，在96周表现出良好的 - 等效 - 替诺福韦单药治疗的疗效和替诺福韦/恩曲他滨武器：

Ø检测不到HBV DNA（<400拷贝/ ml或<69 IU /毫升）：89％和86％，分别;

ØALT复常率分别为62％和63％，;

ØHBeAg消失，分别为15％和13％;

ØHBeAg血清转换率分别为11％和10％，;

ØB型肝炎表面抗原（HBsAg）损失：0和1例患者分别。

    无的替诺福韦电阻检测在18至96周的测试参与者。
    两种治疗一般耐受性良好。
    仅有1例患者出现严重不良事件。
    3人（1％）因不良事件停止治疗。
    没有参与了基线血清肌酐升高> 0.5 mg / dL的1％降低血清磷2毫克/分升，3％的肌酐清除率<50毫升/分钟（其中大部分低于肾功能正常基准）。
    根据脊椎和髋部骨密度T值和Z值，比较骨质密度人口的规范，没有临床相关的骨质流失。
    5人经历了创伤相关的骨折，但没有非外伤性骨折 - 那些没有受伤的脆弱性 - 。

基于这些发现，研究人员得出结论，“没有检测到替诺福韦]电阻率较高的HBV DNA抑制实现与替诺福韦的患者经过96周的拉米夫定耐药性文件。”

“类似的疗效之间的单药治疗和综合治疗武器支持使用[替诺福韦单药治疗，”他们继续在这个人口。 “替诺福韦是安全的，耐受性良好，低利率的肾脏事件，也没有证据与临床有关的骨质流失。”

由于同样安全和有效的治疗，凤说，替诺福韦应该仅仅被认为是足够的。
骨质流失

在一项相关研究，Upkar吉尔研究所细胞与分子科学学院在伦敦和他的同事看了特别是在慢性乙型肝炎患者服用替诺福韦之间的骨密度变化。

这项研究被设计到显示的世界健康组织的FRAX得分是否符合DEXA扫描和骨骼相关的生物标志物（例如，血清碱性磷酸酶和钙的水平）确定骨损失在这个人口，因为在WHO的方法是更便宜的可在资源有限的环境中得到广泛的应用。

FRAX是一个基于网络的工具，它结合几个变量来计算10年骨折风险，包括性别，年龄，身体质量指数，个人和家族骨折史，吸烟，使用酒精或类固醇。 FRAX得分，可以帮助确定哪些人可以受益于DEXA扫描，持续监测和生活方式的改变，以减少他们的风险。

分析包括122例乙肝患者曾用替诺福韦至少48周，48个人没有接触到药物。约70％为男性，三分之二是亚裔，其余约各占一半黑人和白人之间的参与者。年龄中位数为45岁，在替诺福韦组和对照组36。替诺福韦组也有类似比例的人患有轻度，中度和重度肝纤维化，但在对照组中，近三分之二有轻度纤维化。约10％的参与者都是吸烟者，约16％的受访者表示，他们喝酒。

结果

    替诺福韦受助人有一个显着较低的平均得分比臀T-未曝光的患者。
    然而，T-腰椎和髋关节股骨颈（）的分数，并没有差异显著。
    后不久就开始替诺福韦看到的骨质密度小的变化，但水平很快到达了高原，没有进一步的骨质流失进展。
    替诺福韦使用的持续时间和骨量丢失任何网站之间不存在相关性。
    有没有一个整体的骨生化及骨密度的变化之间的相关性。
    替诺福韦受助人血清碱性磷酸酶增加的倾向，但这种差异并未达到统计上的显着性。
    在单因素分析，年龄，体重指数，吸烟，和替诺福韦的使用都显着骨质流失的危险因素。
    然而，在控制了其他因素的多变量分析中，替诺福韦的效果不再显着。
    总体而言，75％的替诺福韦暴露患者进行了测定，根据预DEXA FRAX分数低风险的骨折，并没有需要治疗的骨质流失。
    FRAX评分预测髋部骨折以及DEXA扫描，并没有错过任何高风险的患者：

Ø灵敏度：100％;

Ø特异性：84％;

Ø阴性预测值：100％;

Ø阳性预测值40％。

“我们展示的效用FRAX作为一种替代工具，以评估骨折的风险随着时间的推移，研究人员得出结论。”他们补充说，“我们推荐使用的的FRAX巩固在慢性乙肝治疗的决定，减少了昂贵的DEXA扫描。

吉尔解释说，使用这种方法，可以放心骨折的低风险，中等风险的患者可监控，高风险的个人可以接受的干预措施。

12年11月13日

参考文献

小号丰关，P，M飞达等。替诺福韦DF（TDF）在慢性乙型肝炎病毒感染者与记录拉米夫定耐药（LAM-R）的疗效和安全性。第63届年度会议的美国协会肝病（AASLD 2012）的研究。波士顿，2012年11月9-13日。摘要20。

ü吉尔，A Zissimopoulos，的Al-shamma，等。的FRAX得分在评估替诺福韦治疗慢性乙型肝炎患者的骨密度变化：比较与骨生化和DEXA扫描。第63届年度会议的美国协会肝病（AASLD 2012）的研究。波士顿，2012年11月9-13日。摘要22。