Prevention of new hepatocellular carcinoma with concomitant antiviral therapy in chronic hepatitis B patients whose initial tumor was successfully ablated

Abstract

One of the major goals of antiviral treatment for chronic hepatitis B (CHB) is prevention of hepatocellular carcinoma (HCC). Prospective and retrospective studies have demonstrated reduced HCC incidence in CHB patients with Lamivudine (LAM) therapy.1-3 In prospective study of 3,653 HBV carriers,4 the most important risk factor for HCC was HBV DNA levels. The incidence of HCC correlated with HBV DNA levels at entry and throughout the study period. We investigated whether antiviral therapy prevents new HCC in CHB patients who have already developed HCC. It is the standard of care to ablate tumor locally unless tumor is large or has metastasized. Local treatments include surgery, transarterial chemoembolization (TACE), percutaneous ethanol injection (PCEI), cryoablation or radiofrequency tumor ablation (RFA). In the majority of patients, however, even after successful interventional therapy, new, recurrent or metastatic tumor would occur and patients die of advanced HCC resulting from uncontrolled HBV infection. In recent years, several reports from Japan have shown improved survival with lamivudine (LAM) therapy in patients following local treatment of HCC.5-8 We report the effect of antiviral therapy on long-term survival (some patients approaching >10 years) of CHB patients whose initial HCC is locally ablated. This study was approved by the Institutional Review Board of Thomas Jefferson University. Diagnosis of HCC was made by magnetic resonance imaging (MRI), alphafetoprotein (AFP) or histology. The 1.5 Tesla contrast enhanced MR imaging was used to assess HCC. The MRI criteria for HCC9, 10 included a mass demonstrating low to intermediate T1 signal on precontrast images, homogeneous, heterogeneous, or ring enhancement during the hepatic arterial phase and/or moderate hyperintensity on intermediate T2-weighted fat suppressed spin-echo images with washout relative to surrounding liver parenchyma on delayed post contrast images. Nodules that were hyperintense on T1-weighted pulse sequences but did not demonstrate arterial phase enhancement or T2 hyperintensity were considered dysplastic. Fifteen CHB patients with a single HCC (≤4 cm, the size defined as locally curable) received local ablation and were judged to have a complete response to one of the following modalities; resection, cryoablation, TACE, RFA and PCEI. MRI was obtained 1 month after ablation and at 3 month intervals subsequently. All were HBs-Ag positive, anti-HCV negative and Asian Americans. None received antiviral therapy before HCC diagnosis. Six patients, diagnosed between 1991 and 1997 who received no antiviral therapy were considered the historical controls. Nine patients diagnosed between 2000 and 2004 received antiviral therapy immediately at diagnosis, initially with LAM later with tenofovir (TDF) which was available off-label in 2001, and with adefovir (ADV) in 2002. Decision to add ADV or TDF was based on LAM resistance defined by the virologic breakthrough. We examined patients' clinical course and compared the survival between the treated and untreated. Table 1 compares two groups. Median age, size of HCC and AFP levels between the two are similar. Six untreated patients show a median survival of 12.5 months and nine treated a median survival of 60 months. Survival difference between the two is significant (p = 0.006 by Mann-Whitney). Table 2 shows details of the untreated. Not shown in the table are the median bilirubin 1.1 mg/dL (0.9–2.0) and ALT 48 U/L (37–81). HBV DNA levels were measured at different times and by outside laboratories using different cut-off levels. Since Thomas Jefferson University Hospital is a tertiary center, patients usually had HBV DNA done before their first visit. Because this group was not on anti-HBV therapy, HBV DNA levels were not assayed at regular intervals during the follow up. All underwent local tumor ablation and were considered to have successful elimination. All six developed new tumor(s) at one or multiple sites. Five died within 17 months. One developed new HCC at 20 months and died of multiple HCC at 36 months. Table 3 shows nine treated patients. Not shown in the table are median bilirubin 0.8 mg/dL (0.4–1.1) and ALT 59 U/L (28–158). All received LAM, later with ADV or TDF in some. HBV DNA became undetectable in all nine patients at median 8 months (range 3–13 months). For those who brought the HBV DNA from outside, subsequent HBV DNA during therapy were assayed at Jefferson Hospital by a solution hybridization assay (Abbott Laboratories, North Chicago, IL) between 2000 and 2002 with a lower limit of detection (LLOD) of 1.6 pg/mL, from 2003 onward by RT-PCR (Quest Diagnostics, Horsham, PA) with a LLOD of 500 copies/mL and recently <160 copies/mL. Three patients developed LAM resistance at months 22, 24, and 27 and placed on combination therapy. In two, TDF was added to LAM before LAM resistance. Two patients lost HBV DNA following LAM treatment and have remained virus free for 4 and 5 years, respectively, on LAM. All patients on antiviral therapy have maintained undetectable HBV DNA and are being followed at 3–4 monthly intervals while on therapy. Seven patients have not developed new HCC or recurrence. One (Pt. 14) patient developed a recurrent tumor at treated site at 6 month and underwent TACE. He died of other disease at 53 months without evidence of HCC. Another patient (Pt.15) underwent TACE but developed new lesions and died at 14 months. With antiviral therapy, it seems possible to prevent new tumor in patients whose initial tumor is successfully ablated. Ablative therapies have evolved with the development of more powerful devices which can deposit more energy into tumors and create a potentially greater zone of necrosis. While patients treated later may have benefited from the improvement of available devices, it is important to consider that all had achieved complete necrosis of the index tumor based on imaging studies. Status of liver disease by Child-Pugh class could be considered somewhat advanced for the untreated group (4A, 1B and 1C) than for the treated group (8A and 1B). However, we do not know whether poor liver function alone would increase the development of new HCC. HBV associated HCC often occurs in noncirrhotic liver. We believe that prevention of new tumor and improved survival observed in these patients are attributed to successful suppression of HBV replication. Similar observations have been made in Japan but our study covers the longest observation period. By this time of report, two longest survivors are alive beyond 10 years and five are alive and well between 6 and 9 years. In summary our results suggest that anti-HBV therapy for CHB patients even after developing HCC may prevent new tumor and improve survival. This novel treatment strategy offers an alternative to liver transplantation in patients with HBV related HCC. Yours sincerely, Hie-Won Hann, Diane Bergin, Robert Coben, Anthony J. DiMarino