china has the greatest economic and social burdens of hepatitis b and hepatocellular carcinoma ( hcc ) in the world . an estimated 1/3 of global individuals infected with the hepatitis b virus ( hbv ) reside in china , with 130 million carriers , 30 million chronically infected and 300 thousand hbv - related deaths each year . a high serum hbv deoxyribonucleic acid ( dna ) level has been found to be a key risk factor for hcc development in hbv carriers . therefore , the effective antiviral therapy suppressing hbv virus load could reduce hcc risk and also the risk of hcc recurrence after hepatic resection for hbv - related hcc . however , in patients with hcc complicating chronic hepatitis b , the evidence is still insufficient whether antiviral treatment is protective against new hcc development ( level iii ) . for patients undergoing surgical treatment for hbv - related hcc , a number of important questions remain undefined , including for when antiviral therapy should be initiated and what are the endpoints of therapy . in this report , we described the unusual case of a patient who suffered post - operative hbv reactivation closely followed by hcc recurrence due to the withdrawal of nucleoside analogs after sustained viral clearance . a 66-year - old male patient was admitted to first affiliated hospital , zhejiang university school of medicine , china in january 2006 . the patient who had a 15-year history of hbv infection and treated with lamivudine ( lam ) ( 100 mg once daily , take orally , glaxosmithkline , uk ) , was found lam - resistant mutation in the ymdd motif of the polymerase gene ( rtm204i ) in 2006 ; thus an additional adefovir ( adv ) ( 10 mg once daily , take orally , glaxosmithkline , uk ) was given . five months later , the patient was admitted to our hospital for a high alpha - fetoprotein ( afp ) level ( 642.2 ng / ml ) . hcc was highly suspected by the computed tomography ( ct ) [ figure 1 ] . therefore , a local tumor resection was performed and the pathology confirmed the mass nature of hcc with high - moderate differentiation [ figure 2 ] . serum afp level decreased sharply after the operation and viral load was stable with persistent undetectable hbv dna . during the following long - term follow - up , the patient was in a satisfactory status [ table 1 ] . computed tomography ( ct ) the liver ct scan showed a 2.6 cm  2.4 cm mass in the segment iii in 2006 ( a ) and two occupancies ( 3.0 cm  2.2 cm and 1.5 cm  1.3 cm ) located in the right lobe of cirrhotic liver in 2010 ( b ) histopathological findings of the primary and recurrent hepatocellular carcinoma ( hcc ) . in 2006 , the patient was found a focal lesion in the segment iii of liver with cirrhosis . histopathological examination of liver tumor showed hcc with high - moderate differentiation ( a , h and e , original magnification 400 ) . immunohistochemical study showed alpha - fetoprotein ( afp ) ( + ) ( b , h and e , original magnification 100 ) , cd34 (  ) and cytokeratin ( ck ) (  ) . in 2010 , the patient was found two occupancies located in the right lobe of cirrhotic liver . both tumors were confirmed by pathology as poorly differentiated hcc ( c , h and e , original magnification 400 ) and the immunohistochemisty showed cd34 ( + ) ( d , h and e , original magnification 400 ) , afp (  ) and ck (  ) patient hepatic status and viral loads during eight years follow up in march 2009 , the patient was found hepatitis b envelope antigen ( hbeag ) seroconversion . one month later , the patient suffered fatigue , nausea , jaundice , abdominal distension and then hepatic encephalopathy . umol / l ) ( normal range : 3.4 - 17.1 umol / l ) , aminoleucine transferase ( alt ) ( 808 u / l ) and international normalized ratio ( inr ) ( 2.2 ) ( normal range : 2.0 - 2.5 ) . viral markers showed hbv reactivation ( hbsag 421.91 ng / ml ( normal range : 0 - 0.18 ng / ml ) , hbeag 11.7 ng / ml , antibody to hepatitis b core antigen 120.63 ng / ml and hbv dna 4.68  10 copies / ml ( normal range : < 10 copies / ml ) . the patient was diagnosed as hbv - related acute - on - chronic liver failure ( aclf ) and treated with combined nucleoside analogs ( lam [ 100 mg once daily , take orally , glaxosmithkline , uk ] and adv [ 10 mg once daily , take orally , glaxosmithkline , uk ] ) and foscarnet sodium injection ( 3 g once daily , chia - tai tianqing pharmaceutical co. , ltd . , china ) besides other conservative therapies . two weeks later , the patient was noted an obviously improved liver function ( alt / ast 68/81 iu / l , tb 71 umol / l , inr 1.3 ) and a decreased viral load ( hbv dna 6.31  10 copies / ml ) . a gradually resolution of hepatic encephalopathy and ascites was also achieved . after a 2-month conservative treatment , the patient gained a sustained clinical remission of aclf with normal liver function and undetectable hbv dna . in september 2010 , the patient was found two occupancies located in the right lobe of cirrhotic liver [ figure 1 ] with normal serum afp level . both tumors were confirmed by pathology as poorly differentiated hcc and the immunohistochemistry showed different results from the initial one 's [ figure 2 ] . in addition , real - time polymerase chain reaction revealed positive results of covalently closed circular dna ( cccdna ) and hbv - x gene levels in the recurrent hcc and primary one , although serum hbv dna levels were undetectable [ figure 3 ] . ct scan performed post - operatively showed no evidence of disease recurrence up to now . polymerase chain reaction ( pcr ) results of the primary and recurrent hepatocellular carcinoma ( hcc ) . real - time pcr showed positive expression of covalently closed circular deoxyribonucleic acid ( a ) and hepatitis b virus - x genes ( b ) in the primary and recurrent hcc ; although , the serum viral load was undetectable the prevention and treatment of hepatitis b and hcc is a long - term program and challenging task . although several programs such as universal hbv vaccination in infants , hbv guidelines and hcc screening have been initiated by the chinese government , it is a long way to win the war against hbv infection in china . this case presented nature history of chronic hbv infection and typical progression from hbv infection to cirrhosis and finally hcc . in the management of this patient , several questions had been addressed : what is the optimal duration of antiviral therapy in patients with hbv - related hcc ? what is the relationship between hbv reactivation and hcc recurrence after surgery ? how important is the serum afp level as the predictor of recurrence ? the development of nucleoside analogs has made great strides in the treatment of hbv infections . it is well - known now that treatment with lam not only delays the disease progression , but also reduces the incidence of hcc . the addition of adv to ongoing lam therapy could achieve the excellent virological response and biochemical response in lam - resistant patients ; however , it can not suppress hepatocarcinogenesis . this case proved again that hcc surveillance is important for patients with lam - resistant mutation . for patients with hbv infection , serum hbv dna levels is not only the key risk factor for development of hcc , but also a strong predictor of post - operative hcc recurrence . consequently , lam based antiviral therapy was applied to patients after hepatic resection for hbv - related hcc recently and it was found improving liver function , decreasing the risk of liver failure and hcc recurrence . in this case , nucleoside analogs treatment showed potent effect in stabilizing inflammatory activity and inhibiting hbv dna replication even during the perioperative period , when the patient had marked decreased immunologic function . interferon was not applied in this case and other cirrhotic patients with hbv - related hcc in our center because it may lead to hepatitis flare . the well control of viral load before and after operation led to a satisfactory tumor - free survival . until date , current guidelines have not differentiated the management of patients with hbv - related hcc differently from those without hcc . the optimal antiviral treatment protocol for patients with hcc complicating chronic hepatitis b , especially in those who underwent curative resection is still unknown . a recent meta - analysis reviewed 9 cohort studies including 551 patients showed that antiviral therapy could significantly reduce the risk of tumor recurrence after curative treatment of hbv - related hcc . there is an increasing consensus in support of antiviral therapy after curative treatment of hcc . however , an important question that addressed by this case is to be defined , how long is the antiviral treatment duration . until date study from kuzuya et al . showed a mean treatment period of 22.7  14.2 months during a 38.0  21.6 months follow - up among 16 patients who received lam therapy after treatment for hcc . however , they did not show the reason why discontinued of antiviral therapy and the consequence . they did not analyze the relationship between the withdrawal of treatment and tumor recurrence either . hbeag seroconversion is a critical milestone in the clinical course of chronic hepatitis b and an allowance for the withdrawal of antiviral treatment with sustained low viral load . a suggestion from asian - pacific guidelines showed that the nucleoside analogs treatment can be discontinued if hbeag seroconversion with undetectable hbv dna on 2 separate occasions at least 6 months apart in hbeag - positive patients . however , this case demonstrated that even 13 months of consolidation therapy was not enough for patients who underwent surgical resection for hbv - related hcc . high levels of hbv cccdna which serves as an indicator of hbv replication in the tumor tissues were found ; although , the serum viral load was well - controlled . as we all know , hbv is associated with liver carcinogenesis through integration of the hbv genome into the host chromosome and expression of trans - activating factors . because hbv - induced inflammatory damage and gene mutations have been proved to be associated to hcc , the thresholds of viremia to initiate therapy and long - term antiviral therapy applied in patients with hbv - related hcc should be lower than those without hcc . after hcc surgery , indefinite duration antiviral treatment is essential to tight control the viral load and to suppress the hepatocarcinogenesis , regardless of hbeag seroconversion . intensive researches are imperative to deeply understand the management of patients with hbv - related hcc ; although , people start to realize the management of hbv is as important as treating hcc in the past decade . so far limited data have focused on the hbv reactivation - induced aclf after curative resection for hcc . according to the data from singapore , the incidences of post - operative aclf were 8.5% and most of aclf developed in the early post - operative period due to the declined immune function . different form the reported cases , this case suffered aclf in the long - term post - operative follow - up and due to the hbv reactivation caused by the withdrawal of antiviral treatment . sharply accumulation of endotoxins in circulation leaded to the severe impairment of organs including brain , liver , kidney and gastrointestinal tract . to rapidly reduce the viral load and improve patient condition , foscarnet is a viral dna polymerase inhibitor and has been found valid in quickly reducing hbv dna levels in chronic hbv infected patients . foscarnet sodium injection is of great important for aclf patients with vomit or variceal bleeding or hepatic coma or other conditions with invalid gut absorption . moreover , it is cheap and can be widely accepted by most of patients in mainland china . further large - sample and well - designed studies are needed to evaluate the efficacy of foscarnet on patients with hbv reactivation induced aclf . the association between hbv reactivation and hcc recurrence after hcc surgery is remain unclear . in general , there are two types of hcc recurrence after curative resection . early hcc recurrence were found associated with tumor factors and surgical strategy and may due to intra - hepatic metastasis . while late hcc recurrence were related to high viral loads and hepatic inflammatory activity . our results showed different pathologies between the recurrent hcc and the initial one , which indicated that the late hcc recurrence possibly due to de novo hepatocarcinogenesis of non - cancerous liver tissues rather than intra - hepatic metastasis . this case was also consisted with the previous studies that post - operative viral load were highly associated with late recurrence of hcc . moreover , the time interval from the occurrence of hbv reactivation - induced aclf to hcc recurrence was so short and we found high levels of cccdna and hbv - x gene in the tumor tissues . up to now , in the absence of a dominant oncogene encoded by the hbv genome , only indirect roles of hbv on hepatocarcinogenesis have been proposed , including hbv dna integration into the host genome , induction of genetic instability by viral integration or by the regulatory protein hbx . our findings suggested that reactivation of hbv replication seemed to play a direct role in the late recurrence of hcc after surgical resection . afp has long been used as a standard serum tumor marker for the screening and diagnosis of hcc since the 1970s . it is also widely used for the evaluation of treatment response and detection of recurrence after curative resection in afp - producing hcc . however , some patients with high afp level at initial hcc diagnosis presented normal afp levels at hcc recurrence , which was consistent with our findings . the monitor of serum afp level is not deemed sufficient for surveillance of tumor recurrence in such patients . besides the measurement of afp levels and other so called tumor markers , the imaging tests should be performed regularly and frequently to monitor the tumor recurrence directly . in conclusion , our findings suggest that hbv reactivation after hcc surgery may induce hepatitis flare and hepatocarcinogenesis , thus indefinite duration antiviral therapy and tight viral control should be performed in patients with chronic hepatitis b and hbv - related hcc . the development of nucleoside analogs has made great strides in the treatment of hbv infections . it is well - known now that treatment with lam not only delays the disease progression , but also reduces the incidence of hcc . the addition of adv to ongoing lam therapy could achieve the excellent virological response and biochemical response in lam - resistant patients ; however , it can not suppress hepatocarcinogenesis . this case proved again that hcc surveillance is important for patients with lam - resistant mutation . for patients with hbv infection , serum hbv dna levels is not only the key risk factor for development of hcc , but also a strong predictor of post - operative hcc recurrence . consequently , lam based antiviral therapy was applied to patients after hepatic resection for hbv - related hcc recently and it was found improving liver function , decreasing the risk of liver failure and hcc recurrence . in this case , nucleoside analogs treatment showed potent effect in stabilizing inflammatory activity and inhibiting hbv dna replication even during the perioperative period , when the patient had marked decreased immunologic function . interferon was not applied in this case and other cirrhotic patients with hbv - related hcc in our center because it may lead to hepatitis flare . the well control of viral load before and after operation led to a satisfactory tumor - free survival . until date , current guidelines have not differentiated the management of patients with hbv - related hcc differently from those without hcc . the optimal antiviral treatment protocol for patients with hcc complicating chronic hepatitis b , especially in those who underwent curative resection is still unknown . a recent meta - analysis reviewed 9 cohort studies including 551 patients showed that antiviral therapy could significantly reduce the risk of tumor recurrence after curative treatment of hbv - related hcc . there is an increasing consensus in support of antiviral therapy after curative treatment of hcc . however , an important question that addressed by this case is to be defined , how long is the antiviral treatment duration . until date , study from kuzuya et al . showed a mean treatment period of 22.7  14.2 months during a 38.0  21.6 months follow - up among 16 patients who received lam therapy after treatment for hcc . however , they did not show the reason why discontinued of antiviral therapy and the consequence . they did not analyze the relationship between the withdrawal of treatment and tumor recurrence either . hbeag seroconversion is a critical milestone in the clinical course of chronic hepatitis b and an allowance for the withdrawal of antiviral treatment with sustained low viral load . a suggestion from asian - pacific guidelines showed that the nucleoside analogs treatment can be discontinued if hbeag seroconversion with undetectable hbv dna on 2 separate occasions at least 6 months apart in hbeag - positive patients . however , this case demonstrated that even 13 months of consolidation therapy was not enough for patients who underwent surgical resection for hbv - related hcc . high levels of hbv cccdna which serves as an indicator of hbv replication in the tumor tissues were found ; although , the serum viral load was well - controlled . as we all know , hbv is associated with liver carcinogenesis through integration of the hbv genome into the host chromosome and expression of trans - activating factors . because hbv - induced inflammatory damage and gene mutations have been proved to be associated to hcc , the thresholds of viremia to initiate therapy and long - term antiviral therapy applied in patients with hbv - related hcc should be lower than those without hcc . after hcc surgery , indefinite duration antiviral treatment is essential to tight control the viral load and to suppress the hepatocarcinogenesis , regardless of hbeag seroconversion . intensive researches are imperative to deeply understand the management of patients with hbv - related hcc ; although , people start to realize the management of hbv is as important as treating hcc in the past decade . so far limited data have focused on the hbv reactivation - induced aclf after curative resection for hcc . according to the data from singapore , the incidences of post - operative aclf were 8.5% and most of aclf developed in the early post - operative period due to the declined immune function . different form the reported cases , this case suffered aclf in the long - term post - operative follow - up and due to the hbv reactivation caused by the withdrawal of antiviral treatment . sharply accumulation of endotoxins in circulation leaded to the severe impairment of organs including brain , liver , kidney and gastrointestinal tract . to rapidly reduce the viral load and improve patient condition , foscarnet is a viral dna polymerase inhibitor and has been found valid in quickly reducing hbv dna levels in chronic hbv infected patients . foscarnet sodium injection is of great important for aclf patients with vomit or variceal bleeding or hepatic coma or other conditions with invalid gut absorption . moreover , it is cheap and can be widely accepted by most of patients in mainland china . further large - sample and well - designed studies are needed to evaluate the efficacy of foscarnet on patients with hbv reactivation induced aclf . the association between hbv reactivation and hcc recurrence after hcc surgery is remain unclear . in general , there are two types of hcc recurrence after curative resection . early hcc recurrence were found associated with tumor factors and surgical strategy and may due to intra - hepatic metastasis . while late hcc recurrence were related to high viral loads and hepatic inflammatory activity . our results showed different pathologies between the recurrent hcc and the initial one , which indicated that the late hcc recurrence possibly due to de novo hepatocarcinogenesis of non - cancerous liver tissues rather than intra - hepatic metastasis . this case was also consisted with the previous studies that post - operative viral load were highly associated with late recurrence of hcc . moreover , the time interval from the occurrence of hbv reactivation - induced aclf to hcc recurrence was so short and we found high levels of cccdna and hbv - x gene in the tumor tissues . up to now , in the absence of a dominant oncogene encoded by the hbv genome , only indirect roles of hbv on hepatocarcinogenesis have been proposed , including hbv dna integration into the host genome , induction of genetic instability by viral integration or by the regulatory protein hbx . our findings suggested that reactivation of hbv replication seemed to play a direct role in the late recurrence of hcc after surgical resection . afp has long been used as a standard serum tumor marker for the screening and diagnosis of hcc since the 1970s . it is also widely used for the evaluation of treatment response and detection of recurrence after curative resection in afp - producing hcc . however , some patients with high afp level at initial hcc diagnosis presented normal afp levels at hcc recurrence , which was consistent with our findings . the monitor of serum afp level is not deemed sufficient for surveillance of tumor recurrence in such patients . besides the measurement of afp levels and other so called tumor markers , the imaging tests should be performed regularly and frequently to monitor the tumor recurrence directly . in conclusion , our findings suggest that hbv reactivation after hcc surgery may induce hepatitis flare and hepatocarcinogenesis , thus indefinite duration antiviral therapy and tight viral control should be performed in patients with chronic hepatitis b and hbv - related hcc .
this report describes a 66-year - old male who had a long history of hepatitis b virus ( hbv ) infection . 
 he was found hepatocellular carcinoma ( hcc ) 5 months after lamivudine resistance mutation and then received a successful hepatectomy . 
 three years later , hepatitis b envelope antigen seroconversion was achieved and nucleoside analogs were discontinued . after the withdrawn of antiviral treatment , hbv reactivated and acute - on - chronic liver failure ( aclf ) occurred 
 . 
 anti - hbv treatment improved the patient clinical condition . 
 three months after the remission of aclf , the patient was diagnosed as hcc recurrence and received another hepatectomy . 
 this case illustrates indefinite duration antiviral therapy and tight viral control should be performed in patients with hbv - related hcc .