Prospective Randomized Study for the Comparison of Adding Adefovir Dipivoxil and Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 219
- 试验地点
- 2
- 主要终点
- PCR negativity (<60 IU/ml) of HBV DNA
研究概览
简要总结
Antiviral resistance mutations limit the efficacy of therapy for chronic hepatitis B. At year 2, resistance to adefovir may occur as high as 25% in patients with history of lamivudine resistance. Resistance to entecavir is reported to be 10% in lamivudine refractory patients during the same period. However, combination of lamivudine and adefovir decreased the adefovir resistance rate as low as 0% in the recent studies. By overcoming the antiviral resistance, the efficacy of therapy will be maximized. This study is intended to compare the efficacy of two strategies, combination of lamivudine and adefovir vs. entecavir monotherapy in patients with lamivudine resistance.
详细描述
Recently, published data showed combination of lamivudine and adefovir lead to PCR negativity (<1000 copies/mL) up to 80% in the treatment of lamivudine-resistant chronic hepatitis B at year 2 [Rapti et al. Hepatology 2007 Feb;45(2):307-13.]. Other studies also showed 76% and 69% PCR negativity in mostly HBeAg negative subjects [Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:556A-557A, Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:693A-694A].
In the study for the treatment of lamivudine-resistant chronic hepatitis B patients which included HBeAg positive subjects more predominantly, entecavir monotherapy showed 34% of PCR negativity (<300 copies/mL) at year 2 [Tenney DJ, et al. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11].
Although it is assumed that combination of lamivudine and adefovir would be more effective than entecavir monotherapy for lamivudine resistant patients, we cannot verify the assumption, because there is no data directly comparing these two strategies until now.
The aim of this study is to determine the most effective therapy for the patients with lamivudine resistant chronic hepatitis B. We will compare the PCR negativity (<60 IU/ml) of HBV DNA at year 2 in patients receiving 'the combination of lamivudine and adefovir' and 'entecavir monotherapy'.
Since we are planning to include lamivudine-resistant chronic hepatitis B patients regardless of HBeAg status, we assumed the PCR negativity (<300 copies/mL or <60 IU/mL) in adefovir-lamivudine combination and entecavir monotherapy group as 55% and 34%, respectively, considering HBeAg status and lower detection limit of PCR.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chronic hepatitis B patients (positive HBsAg > 6 months)
- •Age > 16 year old
- •Serum alanine aminotransferase (ALT) >1.5 x ULN
- •History of treatment with lamivudine more than 6 months
- •Proven lamivudine resistant mutation
- •HBV DNA level> 20000 IU/mL
- •Compensated liver disease (Child-Pugh-Turcotte score over 7; prothrombin time prolonged more than 3 sec above ULN or INR over 1.5; serum albumin >3 g/dL; total bilirubin <2.5 mg/dL; No history of variceal bleeding, ascites, or hepatic encephalopathy)
- •Patients willing to give informed consent
排除标准
- •Out of inclusion criteria
- •Any one of following
- •Serum phosphorus level under 2.4 mg/dL
- •Serum creatinine level over 1.5 mg/dL or creatinine clearance <50 mL/min
- •Absolute neutrophil count lower than 1000 cell/mL
- •Hb level under 10 g/dL (male), under 9 g/dL (female)
- •Serum AFP >100 ng/mL
- •History of treatment with interferon-a, thymosin-alfa 1, or nucleos(t)ide analogue other than lamivudine in 6 months of screening
- •Recipient of organ transplantation
- •Positive antibody test to HIV, HCV or HDV
- •Pregnant or breast feeding women
- •Patients with hepatocellular carcinoma or uncontrolled malignant disease
- •Habitual alcohol drinker (>140 g/week for men, >70 g/week for women)
研究组 & 干预措施
A
combination therapy
干预措施: combination of lamivudine+adefovir vs entecavir (Drug)
B
entecavir
干预措施: combination of lamivudine+adefovir vs entecavir (Drug)
结局指标
主要结局
PCR negativity (<60 IU/ml) of HBV DNA
时间窗: At the end of year 2 (since starting rescue therapy for lamivudine resistance)
次要结局
- 1. PCR negativity (<60 IU/ml) of HBV DNA at year 1 (interim analysis) 2. Degrees of HBV DNA reduction 3. ALT normalization 4. HBeAg seroconversion 5. Development of resistant mutation 6. Virologic breakthrough 7. Biochemical breakthrough(At the end of year 2 except interim analysis)
研究者
Hyung Joon Yim
associate professor
Korea University