标题: Expert Insight Into: Nucleos(t)ide Analog Therapy in Patients with Decompensated [打印本页] 作者: StephenW 时间: 2011-11-18 11:37 标题: Expert Insight Into: Nucleos(t)ide Analog Therapy in Patients with Decompensated
Based on the Article:
Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72.
(Course HBV6.13)
Published on October 06, 2011 Article Review
Expert Faculty: Helen S. Te, MD
Medical Writer: Shawn E. Kuhmann, PhD
Clinical Insights
This phase II study demonstrates that in CHB patients with decompensated liver disease, tenofovir and emtricitabine/tenofovir had similar tolerability and renal safety when compared with entecavir.
Both entecavir and tenofovir appear to be safe and effective in this difficult-to-treat population, but more studies will be required to confirm these results, with particular attention paid to renal parameters and lactic acidosis.
PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.
In chronic hepatitis B (CHB) patients with compensated liver disease, sustained suppression of hepatitis B virus (HBV) DNA, in order to prevent worsening liver disease, is the goal of antiviral therapy. These treatments include five oral nucleos(t)ide analogs as well as interferon alfa (standard and pegylated). Entecavir and tenofovir are the preferred first-line nucleos(t)ide analogs because of their efficacy and barriers to resistance. Oral nucleos(t)ide analogs are also recommended for CHB treatment in patients with decompensated liver disease, based on studies with lamivudine and adefovir showing improved clinical outcomes in decompensated CHB patients.
A study of entecavir in 144 compensated and 55 decompensated patients showed that entecavir was similarly effective in both populations and that Child-Turcotte-Pugh scores were improved, generally within 6 months, in decompensated patients. Another study compared entecavir to adefovir in decompensated CHB and found that entecavir had superior virologic efficacy, but that 1-year survival rates were similar. Entecavir has reduced efficacy in patients with lamivudine-resistant HBV, and entecavir resistance may develop in these patients. Renal impairment has been reported with tenofovir use, mostly in human immunodeficiency virus patients, and renal dysfunction is common in decompensated liver disease. Because of the limited safety and efficacy data with entecavir and tenofovir in this patient population, a phase II trial was performed to assess the safety and tolerability of tenofovir, emtricitabine/tenofovir, and entecavir in patients with decompensated CHB.
The global study randomized 112 patients to receive tenofovir (300 mg; n = 45), emtricitabine/tenofovir (200 mg/300 mg; n = 45), or entecavir (0.5 mg for patients with <6 months lamivudine exposure and no lamivudine resistance mutations, otherwise 1.0 mg; n = 22). At the investigator's discretion, patients were allowed to switch to open-label emtricitabine/tenofovir if they did not have an HBV DNA decrease ≥2 log10 at week 8, had virologic breakthrough, or had HBV DNA >400 copies/mL at week 24. There were no significant differences in baseline demographics between the groups. The study results through 48 weeks were presented.
The primary endpoints of the study were tolerability and safety based on renal parameters. Tolerability failure—permanent discontinuation due to adverse events—occurred in 7 patients: 3 receiving tenofovir (6.7%), 2 receiving emtricitabine/tenofovir (4.4%), and 2 receiving entecavir (9.1%), all while receiving blinded study drug.
Table 1. Summary of tolerability failures in a study of tenofovir, emtricitabine/tenofovir, and entecavir therapies in CHB patients with decompensated liver disease
Patient Study drug Considered related to study drug Outcome
1 Emtricitabine/tenofovir No Died within 30 days of last dose of study drug: liver failure secondary to cirrhosis and sepsis.
2 Tenofovir No Died within 30 days of last dose of study drug: endstage liver disease.
3 Entecavir No Died within 30 days of last dose of study drug: disease deterioration/exacerbation of hepatitis B.
4 Entecavir No Died within 30 days of last dose of study drug: septic shock.
5 Tenofovir No Discontinued study with renal failure following liver transplantation. Study drug had not been resumed following transplantation.
6 Emtricitabine/tenofovir Yes Grade 2 allergic reaction following first dose of study drug that resolved after second and final dose.
7 Tenofovir No Interrupted study drug with hepatic encephalopathy and hepatorenal syndrome. Did not resume study drug and died 2 days following final dose.
Confirmed renal parameters meeting the safety threshold—increase in serum creatinine ≥0.5 mg/dL above baseline or serum phosphorus levels <2.0 mg/dL—were observed in 8 patients: 4 receiving tenofovir (8.9%), 3 receiving emtricitabine/tenofovir (6.7%), and 1 receiving entecavir (4.5%). One of the confirmed increases in serum creatinine in the tenofovir group occurred after the patient switched to open-label emtricitabine/tenofovir. The difference between the combined tenofovir-containing treatment groups and the entecavir group was not significant for either tolerability or renal parameters (P = .622 and P = 1.00, respectively).
During blinded treatment, adverse events occurred in 82.2% of the patients in the tenofovir group, 93.3% of patients in the emtricitabine/tenofovir group, and 77.3% of patients in the entecavir group; grade 3 or 4 laboratory abnormalities occurred in 46.7%, 51.1%, and 45.5% of patients, respectively. Adverse events and laboratory abnormalities were consistent with advanced liver disease. The percentage of patients with adverse events related to study drug were low and similar among the groups (17.8%, 15.6%, and 9.1% for tenofovir, emtricitabine/tenofovir, and entecavir, respectively). Six deaths occurred, but none were considered related to study drug. No cases of lactic acidosis were reported.
HBV DNA levels were <400 copies/mL in 70.5%, 87.8%, and 72.7% of patients in the tenofovir, emtricitabine/tenofovir, and entecavir groups, respectively at 48 weeks of treatment; ALT was normalized in 46.2%, 64.0%, and 41.2% of patients. In the tenofovir and emtricitabine/tenofovir groups, hepatitis B e antigen (HBeAg) loss occurred in 21.4% and 26.7% of patients, and HBeAg seroconversion occurred in 21.4% and 13.3% of patients, respectively. HBeAg loss or seroconversion was not observed in the entecavir group. Decreases in Child-Turcotte-Pugh score of ≥2 points occurred in 25.9%, 48.0%, and 41.7% of patients in the tenofovir, emtricitabine/tenofovir, and entecavir groups, respectively. One patient in the emtricitabine/tenofovir group had an increase of ≥2 points in the Child-Turcotte-Pugh score. The median change from baseline in model for endstage liver disease (MELD) scores was -2.0 in all groups. Six liver transplants were performed: 2 in the tenofovir group, 4 in the emtricitabine/tenofovir group. No transplant patients experienced HBV recurrence. Two of the three patients in the entecavir group who entered the study with lamivudine resistance mutations switched to open-label emtricitabine/tenofovir due to an incomplete response at week 24; all three patients had a complete response at week 48. No resistance to tenofovir or entecavir was observed in the study.
The study's authors concluded that the tenofovir-containing regimens were well tolerated and showed no significant difference in renal safety parameters compared with entecavir in patients with decompensated CHB. Although the study was not designed to compare efficacy between the treatment groups, all three treatments demonstrated efficacy with regards to virologic, biochemical, and clinical outcomes.
Reference
Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72.
全球研究随机112例患者接受替诺福韦(300毫克; N = 45),恩曲他滨/替诺福韦(200 mg/300毫克; N = 45),或恩替卡韦(<6个月的拉米夫定暴露患者和0.5毫克,没有拉米夫定耐药突变,另有1.0毫克; N = 22)。在研究人员的自由裁量权,病人被允许到开关开放标签恩曲他滨/替诺福韦,如果他们没有在8周一个乙肝病毒的DNA下降≥2 log10的病毒学突破,或有乙肝病毒的DNA> 400拷贝/ 24周毫升。在组与组之间的基线人口统计学没有显著差异。通过48周的研究结果。