Hepatitis B Treatment with Entecavir Lowers Risk of Liver Cancer
Details
Category: HBV Treatment
Published on Thursday, 01 August 2013 00:00
Written by Liz Highleyman
Long-term treatment with entecavir (Baraclude) significantly reduces the chances of developing hepatocellular carcinoma compared with no treatment, and appears to lower the risk more than an older drug, especially for the most at-risk patients, according to a report in the July 2013 issue of Hepatology.
Over years or decades, chronic hepatitis B virus (HBV) infection can cause advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer. Treatment with nucleoside/nucleotide analogs lowers HBV viral load, which slows liver disease progression, but therapy must be continued long-term and older drugs such as lamivudine (Epivir-HBV) are prone to resistance.
Tetsuya Hosaka and colleagues from Toranomon Hospital in Tokyo compared the incidence of HCC among 472 Japanese chronic hepatitis B patients recruited between 2004 and 2010 who were treated with 0.5 mg entecavir, and 1143 untreated control patients in a retrospective cohort.
About two-thirds of participants were men and the average age was 42 years. The most common HBV genotype was C (70%) and 19% had pre-existing liver cirrhosis; hepatitis C and HIV coinfection were excluded. After propensity score matching to eliminate baseline differences in disease status and other factors, there were 316 participants remaining in each group.
The researchers also compared findings in this study against prior research using 3 previously reported HCC risk scales. Risk scores were calculated taking into account patient age, sex, cirrhosis status, alanine aminotransferase (ALT) level, hepatitis B "e" antigen (HBeAg) level, baseline HBV DNA viral load, and albumin and bilirubin levels.
Results
Only 4 of the 472 entecavir recipients (0.8%) developed drug resistance mutations during follow-up.
Over a total 13,986 person-years of follow-up, 12 people treated with entecavir and 144 untreated control patients developed HCC, yielding incidence rates of 7.69 and 11.63, respectively, per 1000 person-years.
The cumulative incidence of HCC over 5 years was 3.7% in the entecavir group versus 13.7% in the untreated group, a statistically significant difference.
In a multivariate analysis adjusting for known HCC risk factors, participants treated with entecavir were significantly less likely to develop HCC than those in the untreated control group (hazard ratio 0.37, or 63% risk reduction).
Looking at risk scores, the greatest HCC risk reduction occurred among high-risk patients, such as older people and those with cirrhosis.
In a subgroup analysis of patients with cirrhosis, entecavir treatment in this study reduced HCC incidence significantly more than the effect observed in a previous study in which 182 cirrhotic patients received lamivudine without "rescue therapy" in case of treatment failure.
"Long-term entecavir treatment may reduce the incidence of HCC in HBV-infected patients," the study authors concluded. "The treatment effect was greater in patients at higher risk of HCC."
"We found that the entecavir treatment effect to reduce the risk of HCC was more prominent among cirrhosis and high-risk patients despite the lack of interactions between entecavir treatment and pre-existing cirrhosis or risk factors," they elaborated in their discussion. "The lower treatment effect among lower-risk patients was somewhat not surprising. HCC development among low-risk patients is generally rare, and therefore, the treatment effect may not have occurred in large enough numbers during the treatment period allotted in our study to be able to detect a difference."
"Conducting a long-term study to examine the effect of antiviral therapy with HCC as the endpoint would be time-consuming and challenging," they continued. "Such a study would require a large sample size and would, therefore, be costly. In addition, the increases in choices of therapy over time would make it difficult to conduct a long-term study using a single therapy. Owing to ethical issues, it would be difficult to recruit or follow a naive, untreated cohort over an extended period of time."
Entecavir is among the most effective currently available hepatitis B therapies. Another potent modern drug, tenofovir (Viread), has also been shown to reduce the risk of liver cancer, as reported at this year's EASL International Liver Congress. That study, in contrast, found that among non-cirrhotic patients the effect of tenofovir became noticeable after about 2 years of treatment and significant at 6 years, but the protective effect was less pronounced among people with cirrhosis, perhaps because their number was small.
Editorial
In an editorial accompanying the latest report, Morris Sherman from the University of Toronto also commented on the difficult of proving that hepatitis B treatment reduces the incidence of HCC.
"Entecavir and tenofovir are both highly effective, very well tolerated, and there is very little to no resistance. The fall in viral load on treatment is dramatic. The effect on inflammation as measured by ALT or on biopsy is equally impressive. Yet the effect of these agents on long-term outcomes such as the development of cirrhosis and HCC remains in question."
He notes that a Cochrane-type systematic review and meta-analysis including 27 trials with more than 7000 patients (presented at the 2012 AASLD Liver Meeting) "came to the conclusion that the evidence showed only a minor reduction in HCC incidence in cirrhosis patients and no effect in non-cirrhosis patients."
"[W]e can summarize the evidence from this current study and from others as follows," Sherman wrote. "Suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC. Suppression of viral replication in non-cirrhosis also reduces the risk of HCC, but since the risk of HCC is not as high as in cirrhosis patients, the magnitude of the risk reduction is less. It is not yet clear whether treatment of non-cirrhosis, if instituted early enough, can eliminate the risk of HCC altogether."
Considering the difficulty, time, expense, and ethical issues involved in doing further long-term randomized clinical trials with HCC as an endpoint, he suggested "we may never get that answer," but "that should not stop us from providing treatment for those with active disease."
8/1/13
References
T Hosaka, F Suzuki, M Kobayashi, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 58(1):98-107. July 2013.
M Sherman. Does Hepatitis B Treatment Reduce the Incidence of Hepatocellular Carcinoma? (Editorial). Hepatology 58(1):18-20. July 2013.
"最后这几段好像说非肝硬化患者服用恩替,对降低肝癌发生率影响不大" - 不错. 你要阅读说明为什么 -
"but since the risk of HCC is not as high as in cirrhosis patients, the magnitude of the risk reduction is less."
但因为非肝硬化肝癌的风险没有肝硬化肝癌的风险的高, 风险降低的幅度比较少.
Article first published online: 7 JAN 2013
Conclusions
Successful treatment of CHB can decrease the risk
of HCC. The protective effect of IFN-a is likely to be
limited to patients with cirrhosis who are sustained
responders, a relatively small proportion of patients.
The effect of IFN-a in patients without cirrhosis is
unclear. Treatment with nucleoside analogs appears
more effective in lowering the risk of HCC development,
probably through more potent and persistent
suppression of viral replication, though the effect may
be blunted with the occurrence of resistance. Whether
the current two first-line agents (entacavir and tenofovir),
which have greater potency and lower resistance
rates than lamivudine and adefovir, can further reduce
the risk of development of HCC have yet to be proven
结论
成功治疗慢性乙型肝炎可减少风险
肝癌。 α-干扰素的保护作用可能是
肝硬化患者持续有限
应答的患者比例相对较小。
干扰素的患者无肝硬化的影响
不清楚。核苷类似物治疗出现
更有效地降低肝癌发展的风险,
可能是通过更有力和持久
抑制病毒复制,但效果
与耐药性的发生钝化。是否
目前两个一线药物(entacavir和替诺福韦)
有更大的效力和更低的电阻
率比拉米夫定和阿德福韦,可以进一步降低
发展为肝细胞癌的风险尚未得到证实 作者: 疯一点好 时间: 2013-8-7 16:41