干扰素可能对C型肝炎再度治疗有害


  【24drs.com】根据最近的统合分析,当C型肝炎和慢性肝病患者发生复发或对最初的治疗无反应时,使用干扰素单独治疗不是个好主意。事实上,使用这种方法反而会增加死亡和副作用风险。
  
  这篇回顾发表于1月的考科蓝系统性文献回顾资料库,是由加州大学David Geffen医学院消化疾病与胃肠科医学教授Ronald Koretz医师等人进行。
  
  作者们写道,慢性C型肝炎的治疗结果一般是以持续病毒反应为代表(也就是说,治疗6个月后,血液中测不出病毒RNA。),不过,这个检测指标(以及之前采用的生化和组织学指标)尚未被验证过。
  
  作者们表示,缺乏验证并不令人惊讶,因为很少进行评估临床结果(死亡或出现肝硬化)的随机临床试验,病患通常要在感染数年后才会死亡或发生肝硬化。
  
  作者们指出,进行初步治疗但未产生持续病毒反应的病患,变成再度治疗的可能对象,但是,对于某些无法耐受ribavirin或蛋白酶抑制剂标准治疗的病患,医师们通常考量使用干扰素再度治疗,这是合理的选项。
  
  为了更加厘清干扰素治疗的实际临床效果,研究者回顾了7篇比较安慰剂或未治疗与干扰素单一治疗之临床试验资料。
  
  其中两篇试验(「Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C]」和「Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3]」)被认为是低偏见风险;这两篇试验共包括1,676名病患,两篇都是评估严重纤维化病患进行长期低剂量pegylated干扰素治疗的临床结果。
  
  其它5篇试验共包括了300名病患,被认为高偏见风险。
  
  Koretz医师等人报告指出,当他们纳入发表的所有结果时,发现各种原因死亡率没有显著差异(78/843 [9.3%] vs 62/867 [7.2%];风险比[RR]),1.30;95%信心区间[CI],0.95 - 1.79;3篇试验)。他们也未发现肝脏相关死亡率有显著差异(41/532 [7.7%] vs 40/552 [7.2%];RR,1.07;95% CI,0.70 - 1.63;2 篇试验)。
  
  当研究者仅纳入低偏见风险的2篇试验时,他们指出,接受干扰素的病患,其所有原因死亡率显著较高(78/828 [9.4%] vs 57/848 [6.7%];RR,1.41;95% CI,1.02 - 1.96)。
  
  不过,他们指出,接受干扰素的病患较少食道静脉曲张破裂出血(4/843 [0.5%] vs 18/867 [2.1%];RR,0.24;95% CI,0.09 - 0.67;3篇试验),但是,研究者认为,干扰素的高贵成本无法证明它适用于此适应症。
  
  使用干扰素的病患比较不会发生腹水、肝性脑病变或肝细胞癌或需要肝脏移植。
  
  作者们写道,只有1篇试验包括了生活质量资料,该试验中,接受干扰素的病患疼痛分数显著恶化;接受干扰素的病患也比较可能发生副作用,大多是血液系统并发症、感染、类流感症状和皮疹。
  
  不过,干扰素治疗确实和病毒显著反应较佳有关(20/557 [3.6%] vs 1/579 [0.2%];RR,15.38;95% CI,2.93 - 80.71;4篇试验)。此外,衡量发炎程度以及纤维化程度的METAVIR活性分数也改善(36/55 [65%] vs 20/46 [43.5%];RR, 1.49;95% CI,1.02 - 2.18;2篇试验),研究者表示,纤维化的组织学评估没有显著差异。
  
  作者们强调,他们回顾的临床资料仅限于使用pegylated干扰素再度治疗之严重纤维化病患的组织学证据。
  
  作者们指出,这种情况下,使用干扰素再度治疗并不会提供显著的临床效益,而且,当只有考量低偏见风险的试验时,再度治疗数年甚至会增加所有原因死亡率,这类治疗也会产生副作用。
  
  总结来说,两种最常用的指标:持续病毒反应和发炎标记,都未经验证,即使这些指标有所改善,但是临床结果并未改善(或甚至更糟)。持续病毒反应率低的这群病患,无法验证持续病毒反应,对于接受治疗的其它组慢性C型肝炎病患,应验证使用持续病毒反应的假设效度。
  
  资料来源:http://www.24drs.com/professional/list/content.asp?x_idno=6982&x_classno=0&x_chkdelpoint=Y
  

Interferon May Be Harmful in Retreatment of Hepatitis C

By Steven Fox
Medscape Medical News

When patients with hepatitis C and chronic liver disease suffer relapses or fail to respond to initial treatment, monotherapy with interferon may not be a good idea, according to results from a recent meta-analysis. In fact, employing that approach may raise the risks for death and adverse effects.

The review is published in the January issue of the Cochrane Database of Systematic Reviews and was conducted by Ronald Koretz, MD, professor of medicine, digestive diseases and gastroenterology, David Geffen School of Medicine, University of California, Los Angeles, and colleagues.

"The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated," the authors write.

The lack of validation is not surprising, the authors say, because very few randomized clinical trials evaluating clinical outcomes (mortality or manifestations of cirrhosis) have been conducted, as patients usually do not die or develop cirrhosis until years after they have been infected.

Patients who undergo initial therapy but do not produce sustained viral responses become potential candidates for retreatment, the authors note, but for some patients in whom standard treatment with ribavirin or protease inhibitors cannot be tolerated, clinicians often consider retreatment with interferon to be a reasonable option.

All-Cause Mortality Worse

To find out more about the actual clinical effects of retreatment with interferon, the investigators reviewed data from 7 clinical trials in which monotherapy retreatment with interferon was compared with placebo or no treatment.

Two of the trials (the Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C] and Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3] trials) were considered to be at low risk for bias. Together, those trials included 1676 patients. Both assessed the clinical outcomes of patients with severe fibrosis who underwent long-term low-dose retreatment with pegylated interferon therapy.

The other 5 trials included a total of 300 patients and were considered to be at high risk for bias.

Dr. Koretz and colleagues report that when they included all trials with published outcomes in their review they saw no significant difference in all-cause mortality (78/843 [9.3%] vs 62/867 [7.2%]; risk ratio [RR], 1.30; 95% confidence interval [CI], 0.95 - 1.79; 3 trials). They also did not find a significant difference in hepatic-related mortality (41/532 [7.7%] vs 40/552 [7.2%]; RR, 1.07; 95% CI, 0.70 - 1.63; 2 trials).

However, when the reviewers included only the 2 trials considered at low risk for bias, they noted that all-cause mortality was significantly higher among patients who received interferon (78/828 [9.4%] vs 57/848 [6.7%]; RR, 1.41; 95% CI, 1.02 - 1.96).

They do note, however, that there was less variceal bleeding in patients who received interferon (4/843 [0.5%] vs 18/867 [2.1%]; RR, 0.24; 95% CI, 0.09 - 0.67; 3 trials). Still, the researchers comment that the prohibitive cost of interferon would not justify it for this indication alone.

Patients administered interferon were no more likely to develop ascites, encephalopathy, or hepatocellular carcinoma or to need liver transplants.

Only one of the trials included quality-of-life data, and in that trial pain scores were significantly worse in patients receiving interferon, the reviewers write. Patients receiving interferon were also more likely to suffer adverse effects, most commonly hematologic complications, infections, influenza-like symptoms, and rashes.

SVR a Surrogate Marker?

Interferon therapy did appear, however, to be associated with significantly better viral responses (20/557 [3.6%] vs 1/579 [0.2%]; RR, 15.38; 95% CI, 2.93 - 80.71; 4 trials). In addition, METAVIR activity scores, gauging degree of inflammation as well as the extent of fibrosis, also improved (36/55 [65%] vs 20/46 [43.5%]; RR, 1.49; 95% CI, 1.02 - 2.18; 2 trials). However, the reviewers say they saw no significant differences in histologic assessments of fibrosis.

The authors stress that the clinical data they reviewed were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon.

"In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events," the authors note.

In conclusion, they write, "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated."

The authors have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. 2013:1:CD003617.

    
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