*CURRENT DESCRIPTORS: *I01. Patient-centered, Natural History and Effectiveness Research
*TITLE: *Hepatocellular Carcinoma Risk In Chronic Hepatitis B Patients Achieving Viral Suppression With Antiviral Therapy.
*AUTHORS (FIRST NAME, LAST NAME): *_Simon Ghaly_^1 , Raghubinder S. Gill^2 , Mathew J. Keegan^2 , Peter W. Angus^3 , Jacob George^4 , Amanda J. Nicoll^5 , Matthew Law^6 , Marie Sinclair^7 , Lucy Y. Lim^3 , Hasanka Ratnayake^5 , Anna Dunn^5 , Simone I. Strasser^2 , Amany Zekry^1
*Institutional Author(s): *
*INSTITUTIONS (ALL): *1. Gastroenterology and Hepatology, St. George Hospital, Sydney, NSW, Australia.
2. AW Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
3. Gastroenterology and Liver Transplant Unit, The Austin Hospital , Melbourne, VIC, Australia.
4. Storr Liver Unit, Millennium Institute, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.
5. Gastroenterology and Hepatology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
6. The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
7. Gastroenterology and Hepatology, Monash Medical Center, Melbourne, VIC, Australia.
*ABSTRACT BODY: *Effective viral suppression with antiviral therapy has been shown to reduce the development of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected patients. Scarce data exist however, on the group of patients who still develop HCC despite achieving HBV viral suppression with therapy. We aimed therefore, to characterise the risks and predictors for the development of HCC in this patient cohort.
Methods: This was a multicentre, retrospective analysis of HCC development in chronic hepatitis B over an 11-year period. HBV infected patients who achieved viral suppression (defined by HBV DNA <200IU/ml persistently) on antiviral therapy for at least 6 month and yet developed HCC were identified from hospital records. These were compared to a group of HBV infected patients achieving viral suppression with antiviral therapy and who did not develop HCC during follow-up. These were matched for duration of antiviral therapy and follow up from the time of therapy initiation.
Results: 537 patients with hepatitis B-related HCC were identified. Of these, 101 patients with viral suppression on antiviral therapy were identified and compared to a matched group of 99 HBV-patients with virological suppression, but without HCC development. Among these 200 patients, mean age at HCC diagnosis was 54.9±10.4 year old, the majority were of Asian background (66%), and were predominately male (80%). The median follow-up was 35.5 (range 6-144) months. Of the HCC group 30% were non cirrhotic. Among the HCC and the control group, 77% and 55% respectively had received initial lamivudine therapy. By univariate analysis, those who developed HCC were more likely to be male (OR 2.21 p=0.031), age >60 (OR 2.32, p= 0.034), HBeAg negative (OR 1.9, p=0.037) and have been exposed to lamivudine (OR 2.713 p=0.001). Baseline viral load, time taken to achieve viral suppression, and the development of lamivudine resistance (as defined by the need to switch to other therapy due to failure to achieve undetectable viral load during follow up), did not reach statistical significance. On multivariate analysis age>60, male gender and lamivudine exposure (OR 3.12, 95%CI: 1.61-6.05) remained independent predictors of HCC development.
Conclusions. In our cohort, despite achieving viral suppression with anti viral therapy, there was still an increased risk of HCC primarily related to older age, and exposure to lamivudine therapy. The association with lamivudine exposure raises the possibility of drug-induced mutations associated with an increased risk of HCC development - this possibility is currently under investigation. 作者: StephenW 时间: 2012-11-20 16:13
方法:这是一项多中心,回顾性分析在慢性B型肝炎的肝癌发展超过11年的时间。 HBV感染患者的抗病毒治疗至少6个月达到病毒抑制(持续HBV DNA <200IU/ml)和尚未开发的HCC患者从医院的记录标识。这些进行了比较,一组HBV感染的患者达到抑制病毒的抗病毒治疗,谁没有在后续开发HCC。这些相匹配的抗病毒治疗的持续时间和后续治疗开始的时间。
Discussion The results of our systematic review show that the medium-term risk of HCC is significantly lower in chronic hepatitis B patients receiving effective oral antiviral therapy. In three studies including untreated controls, HCC developed in 2.8% of treated and in 6.4% of untreated chronic hepatitis B patients (p=0.003). Although only one of these three studies was randomised [22], the untreated controls had many similar characteristics with the treated patients in the second study [26] and were selected to match the treated patients in the third study [32]. It should be noted that treatment significantly reduced the HCC incidence in the only randomised trial [22]. Given the benefits of antiviral therapy, it is unethical not to offer treatment to chronic hepatitis B patients who meet treatment criteria. These data therefore represent the best evidence supporting the efficacy of nucleos(t)ide analogue therapy in reducing the incidence of HCC in chronic hepatitis B patients.
Achievement of virological remission after the initial treatment course was found to be extremely important for the reduction of HCC incidence. In studies including nucleos(t)ide naive patients, HCC developed significantly less frequently in patients remaining in virological remission than in those with virological breakthrough or no response (2.3% vs 7.5%, p<0.001). This finding is in agreement with the well known association between levels of HBV replication and HCC risk [8]. It is not surprising that viral suppression decreased but did not eliminate the risk of HCC in chronic HBV patients because HBV DNA may have already integrated into the host genome before the onset of treatment and may have already resulted in genomic alterations and/or chromosomal instability [39], [40]. Furthermore, in patients who have been infected for a long time or who have already progressed to cirrhosis, malignant transformation of hepatocytes may be present before the onset of treatment. Finally, some of the tumours may have been present at the start of treatment and were not detected by routine clinical evaluations. The latter hypothesis is in agreement with the finding that approximately one fourth (23%) of HCC cases in nucleos(t)ide naive patients were diagnosed within the first year of treatment.
The rate of HCC was significantly higher in lamivudine resistance than in nucleos(t)ide naive patients (7.1% vs 3.8%, p=0.001) despite a shorter duration of follow-up. This is partly related to the more frequent presence of cirrhosis among patients with lamivudine resistance, but even among cirrhotics, the incidence of HCC was significantly higher in patients with lamivudine resistance than in those who were nucleos(t)ide naive (18% vs 11%, p=0.015). Achievement of virological response did not seem to significantly reduce the HCC risk in patients with lamivudine resistance, as HCC was detected in 9% of such patients with and in 6% of those without detectable viremia during rescue therapy (p=0.466). These data suggest that the maintenance of viral suppression over a long period of time is needed to reduce the risk of HCC. It has also been suggested that mutations associated with lamivudine resistance, in particular, changes at position 181 of the reverse transcriptase domain of the HBV polymerase have direct oncogenic potential [41], [42].
It is well known that the HCC risk is highest among untreated chronic HBV patients with cirrhosis and that severe fibrosis and cirrhosis predispose to the development of HCC [1], [2], [4]. Our data show that the risk of HCC remains high in cirrhotic patients receiving nucleos(t)ide analogue therapy. HCC developed in 11% of cirrhotic and in only 0.5% of non-cirrhotic chronic hepatitis B patients who were naive to nucleos(t)ide agents (p<0.001) and in 18% of cirrhotic and 0% of non-cirrhotic patients with lamivudine resistance (p<0.001). The effect of the severity of cirrhosis (compensated vs decompensated) on HCC risk could not be evaluated because of the small number of patients.
Other factors found to be associated with the risk of HCC were older age, regular HCC surveillance and inclusion of HBeAg negative cases. Older age is a well known risk factor for HCC [1], [2], [4], but the higher HCC rate in the studies with mean/median age 50years vs <50years might be, at least partly, related to the higher proportion of cirrhotic patients in the studies with older patients. Indeed, cirrhosis was present in a higher percent of patients in studies with mean/median age 50years (543/1085 or 50% vs 511/2202 or 23%, p<0.001) (Table 1). The association between HCC risk and HCC surveillance may be related to a higher proportion of patients with cirrhosis in studies with HCC surveillance. The proportion of nucleos(t)ide naive patients with cirrhosis was significantly higher in studies which reported regular HCC surveillance [19], [21], [22], [25], [26], [27], [32], [35], [36] than those which did not [18], [20], [23], [24], [28], [29], [34] (566/1200 or 47% vs 488/2087 or 23%, p<0.001). The association between HCC risk and HBeAg-negative status may be related to the older age and more frequent presence of cirrhosis in HBeAg-negative patients. The proportion of patients with cirrhosis was significantly higher in studies with almost exclusively HBeAg negative [19], [20], [21], [26], [28], [29], [35] than studies with predominantly HBeAg-positive patients [18], [32], [34] (536/1245 or 43% vs 97/1200 or 8%, p<0.001) (Table 1).
In conclusion, medium-term nucleos(t)ide analogue therapy significantly reduces but it does not completely eliminate the risk of HCC, particularly in patients with pre-existing cirrhosis. Patients with cirrhosis undergoing antiviral treatment should continue to undergo HCC surveillance. Maintenance of virological remission is important for the reduction of HCC risk. Our findings suggest that HCC risk is increased in patients who experience virologic breakthrough even if HBV replication is subsequently suppressed by rescue therapy. This observation provides further evidence that lamivudine is not an optimal first-line treatment for chronic hepatitis B, as it is associated with very high rates of drug resistance during long-term treatment. Our study is limited by the poor quality of many of the included studies, the heterogeneous patient populations, the variations in treatment regimens and patient monitoring, the differences in definitions of response, and the wide range in sensitivity of HBV DNA assays used to assess virological response and the different duration of follow-up. In addition, because incidence of HCC was not a primary outcome in these studies, details regarding screening of HCC at baseline and HCC surveillance during therapy, diagnostic criteria of HCC and timing of HCC diagnosis were not specified in most studies. Nevertheless, the large number of patients and the results of subgroup analyses reinforce the validity of our conclusions. The vast majority of the current data on HCC risk in chronic hepatitis B patients treated with nucleos(t)ide analogues come from studies on lamivudine. It is anticipated that the newer nucleos(t)ide analogues, such as entecavir and tenofovir, will further reduce the HCC incidence given their greater potency and better resistance profiles.