P- Reviewer: He ST, Kaya M, Narciso-Schiavon JL, Quarleri J S- Editor: Ma N L- Editor: A E- Editor: Liu XM
Published online Nov 21, 2014. doi: 10.3748/wjg.v20.i43.16053
Revised: April 22, 2014
Accepted: July 24, 2014
Published online: November 21, 2014
In the past few decades, chronic hepatitis B (CHB) has evolved from a disease that was untreatable and progressive, to one that can be easily controlled with antiviral therapy. However, patients with severe liver disease still remain difficult to treat despite the availability of highly potent nucleos(t)ide analogs. These include those with underlying cirrhosis, severe flares of CHB, hepatocellular carcinoma (HCC), and for those undergoing liver transplantation. For those with established cirrhosis, antiviral therapy should be considered for all, as unpredictable flares can still occur, which can be fatal for those with advanced chronic liver disease. However, even with effective viral suppression, the development of HCC can still occur. For patients with severe flares of CHB, although the use of antiviral can improve long term outcomes, a significant proportion may still die without liver transplantation. The short term prognosis of these patients is dependent on both the severity of flare and underlying pre-existing liver disease. In patients with decompensated cirrhosis, liver failure secondary to severe flares, or those with HCC, liver transplantation may be curative. After liver transplantation, long term antiviral therapy is required to prevent graft loss from recurrent hepatitis B infection. The use of hepatitis B immune globulin (HBIG) in combination with an oral antiviral agent has been the mainstay of post-transplant antiviral regimen for over a decade. With newer and more potent antiviral agents such as tenofovir and entecavir, use of these agents along with HBIG have demonstrated to be effective in preventing significant recurrence in the long term.
Core tip: This review discusses the treatment of chronic hepatitis B in patients with underlying severe liver disease, including cirrhosis, acute on chronic liver failure, hepatocellular carcinoma, and those undergoing liver transplantation. Despite the availability of highly potent antiviral drugs, these patients are often difficult to manage. The use of currently available antiviral agents is discussed along with its efficacy in these patients with severe hepatitis B liver disease.
- Citation: Fung J, Lai CL, Yuen MF. Management of chronic hepatitis B in severe liver disease. World J Gastroenterol 2014; 20(43): 16053-16061
- URL: https://www.wjgnet.com/1007-9327/full/v20/i43/16053.htm
- DOI: https://dx.doi.org/10.3748/wjg.v20.i43.16053
With an estimated 400 million people worldwide infected with the hepatitis B virus (HBV), chronic hepatitis B (CHB) continues to be a major global health problem. Up to 40% of patients infected with CHB may develop liver complications, including cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC). In a recent study of 6689 CHB patients, HBV was the cause of death in over 40%, and the rate was similar between non-Asians and Asia-Pacific Islander origin. Not until the recent decade, CHB was largely a progressive and untreatable disease. The major milestone in CHB management was the approval of the first nucleoside/nucleotide analogue (NA), lamivudine (LAM) in 1998. However, LAM was associated with high rates of resistance. Since then, four other NAs have been approved for the treatment of CHB, namely adefovir (ADV), entecavir (ETV), telbivudine, and tenofovir (TDF). All NAs are effective in achieving the short term goals of HBV DNA suppression and normalization of liver parenchymal enzymes[4-11]. The key difference between the NAs pertain to their varying barriers to resistance. Through the effects of viral suppression, long-term treatment with NAs can reduce and prevent the development of cirrhosis and reduce the development of HCC[13-17]. However, a significant proportion of HBV carriers remain untreated for various reasons. As CHB is largely asymptomatic, HBV carriage is unlikely to be apparent unless it is screened. Once diagnosed, treatment may not be instituted because of ineligibility according to current treatment guidelines, cost, compliance to follow-up, and patient’s own decision. It is therefore not surprising that a significant proportion of HBV carriers can present for the first time with advanced liver disease.
In patients with advanced fibrosis and established cirrhosis, long term therapy with NAs can lead to regression of fibrosis and even cirrhotic changes[18-22]. However, in advanced stages of cirrhosis, when the liver is already contracted with gross lobular architectural distortions and portal hypertension, the changes are likely to be irreversible. Although antiviral therapy should ideally have been started prior to the onset of progressive liver fibrosis, there are major reasons for treating patients with established cirrhosis. The goals of treatment for this population are to prevent further liver injury and progressive liver damage leading to decompensation, to improve liver function, and to decrease the risk of HCC development and ultimately, to reduce mortality.
Ideally, all CHB patients with cirrhosis and detectable viral load should be considered for treatment. However, there are differences in the criteria for starting antiviral therapy for HBV cirrhosis between the major regional treatment guidelines. The European Association for the Study of the Liver guidelines recommend that treatment should be started using a drug with low resistance profile irrespective of the level of alanine aminotransferase (ALT) as this may be normal in advanced liver disease. The American Association for the Study of Liver Diseases (AASLD) guidelines suggest that treatment for compensated patients should only be started when ALT > × 2 upper limit of normal, or if the HBV DNA level is elevated (> 2000 IU/mL) with elevated ALT. For patients with decompensated cirrhosis, treatment should be promptly initiated with a NA that can rapidly suppress viral load with a low risk of drug resistance. The Asia Pacific Association for the Study of the Liver (APASL) guidelines recommend treatment for those with HBV DNA levels ≥ 2000 IU/mL with compensated cirrhosis. However, spontaneous flares of hepatitis can occur at any time, and in patients with cirrhosis (even if compensated), these episodes may lead to decompensation, increasing chance of death or the need for liver transplantation (LT). Therefore, all HBV cirrhotic patients who remain hepatitis B surface antigen (HBsAg) positive should be considered for antiviral therapy.
The duration of therapy for patients with cirrhosis should be long-term. For compensated cirrhosis, the AASLD guidelines recommend that treatment can be stopped in hepatitis B e antigen (HBeAg)-positive patients if they undergo HBeAg seroconversion together with at least 6 mo of consolidation therapy, or in the event of HBsAg seroconversion for HBeAg-negative patients. However, the risk of virological rebound in patients with treatment-induced HBeAg seroconversion after cessation of antiviral therapy has been shown to be significantly high. As virological rebound and subsequent flare after discontinuing treatment may result in decompensation in cirrhotic patients, it would be prudent to consider long-term maintenance antiviral therapy. For decompensated patients, life-long treatment is recommended.
The long term benefits of oral antiviral therapy in cirrhotic CHB patients was established in a multicenter randomized placebo-controlled trial of 651 patients using LAM, showing significant reduction in overall disease progression, lower rate of Child-Pugh score increase, and a reduction in the development of HCC. Subsequent non-placebo trials have demonstrated the efficacy of newer NAs in decompensated liver disease. A randomized study comparing ETV and ADV demonstrated superior viral suppression with ETV, with similar improvements in Child-Pugh scores. A randomized study comparing TDF (n = 45), TDF + emtricitabine (n = 45), and ETV (n = 22) showed similar efficacy in HBV DNA suppression, and improvement in Child-Pugh and MELD scores. In fact, an earlier study using LAM showed a biphasic survival pattern, with a high mortality rate within the first 6 mo due to liver failure in patients with decompensated cirrhosis. Factors associated with early mortality included bilirubin, creatinine, and HBV DNA levels. For those surviving beyond 6 mo, the long term survival was excellent (88% at 3 years). The importance of HBV DNA suppression in decompensated cirrhotic patients was highlighted in a randomized placebo-controlled trial using TDF in 27 patients. Those patients treated with TDF had significant reduction in HBV DNA levels with improvements in Child-Pugh and MELD scores, and reduction in mortality. A greater than 2 log reduction in HBV DNA levels at week 2 was found to be an independent predictor of survival.
It is likely that the short term survival is independent of the type of antiviral therapy, and non-head to head comparison studies have shown similar 1-year survival rates of 84%-93% between the five currently approved NAs in decompensated CHB cirrhosis[29,31,32]. As previously mentioned, virtually all patients with cirrhosis who are commenced on antiviral therapy will require life-long treatment. Therefore, NAs with a high barrier to resistance should be used to minimize the risk of virological breakthrough and subsequent flares, as this can often lead to disastrous consequences in patients with established cirrhosis[33-38]. A recent meta-analysis comparing ETV and LAM showed similar reduction in mortality, with better virological response and lower rate of resistance observed in those treated with ETV.
In patients with severe liver disease, there should be heightened vigilance to ensure that any adverse effects from medication use are minimized. There have been cases of severe lactic acidosis occurring with the use of ETV in patients with impaired liver function. These patients all had higher MELD scores of > 18 with impaired creatinine clearance. Therefore, patients with renal impairment should have their antiviral dose adjusted accordingly. In the randomized trials of ETV in decompensated cirrhosis, no lactic acidosis was reported[27,28].
Acute flare of CHB can occur in both treatment-naïve patients and those already on antiviral therapy. In the former setting, loss of immunotolerance in HBeAg-positive patients may result in acute flares. For those who are HBeAg-negative, ongoing viral replication can still occur, leading also to recurrent flares. For treated patients, acute flares can occur with cessation of therapy or non-compliance, and also with the development of drug resistant mutations. In severe cases, acute flares can lead to acute on chronic liver failure (AOCLF). The APASL consensus has defined AOCLF as an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 wk by ascites and/or encephalopathy in patients with existing chronic liver disease. The development of AOCLF depends on 2 key factors, the severity of the acute insult and the degree of underlying chronic liver disease. Liver failure can occur with a moderate flare with underlying cirrhosis, or with a severe flare in non-cirrhotic patients.
As discussed previously, the biphasic pattern of survival means that a significant proportion will succumb within the first few mo of presentation even with the commencement of antiviral therapy. The use of molecular adsorbent recirculating system (MARS) can decrease plasma concentration of bilirubin, creatinine, and ammonia in AOCLF. Initial small randomized trials of patients with AOCLF suggested that using albumin dialysis may improve survival[42-44]. However, in a recent multicenter trial of 189 AOCLF patients randomized to receive MARS (n = 95) vs standard (n = 94) therapy, there was no difference in the 28 d transplant-free survival (60% vs 59.2% respectively, P = 0.88) and in the 90-d transplant-free survival (44.7% vs 43.7% respectively, P = 0.97). Thus although MARS therapy is safe in this group of patients, there does not appear to be any survival benefit.
Therefore, for those patients not responding to antiviral therapy, LT remains the only curative option. For those with evidence of liver decompensation, early referral to a LT center is recommended. There is currently no consensus on whom and when to transplant, and the most widely adopted criteria is the King’s criteria for acute liver failure. However, many of these patients have underlying chronic liver disease and may not fulfil the criteria for acute liver failure. In addition, patients with AOCLF often evolved into a chronic state, without fulfilling the King’s criteria, but remain decompensated without transplantation. There are studies showing that MELD score on presentation could be used to predict mortality from AOCLF. For patients with MELD score greater than 30, the short-term mortality can be as high as 92% even when NAs are given[46,47]. These patients should be urgently considered for LT. For those with intermediate MELD score e.g., 20-30, the short-term mortality is around 44%-50%. Monitoring other prognostic parameters is therefore required and LT may also be required. These parameters include prothrombin time, INR, creatinine, sodium, the presence of hepatic encephalopathy, the presence of cirrhosis, hepatorenal syndrome, HBeAg status, and albumin[48-51]. In the absence of the definite criteria for AOCLF, clinical judgment is often made on factors such as the presence of hepatic encephalopathy, degree of liver dysfunction including the level of jaundice and coagulopathy, the presence of multiorgan involvement, and the use of imaging to determine the presence of underlying cirrhosis, portal hypertension and dynamic changes in liver size with serial scanning.
The outcome after LT for AOCLF is excellent, and is similar to those achieved by LT for other liver conditions. In a study of 50 patients with acute flare of CHB and 99 cirrhotic patients with acute decompensation, the 5-year survival rate was 93.2% and 90.5% respectively.
It is well known that HBV replication is an important contributing factor for the development of HCC. Antiviral therapy remains the cornerstone in reducing the incidence in HCC. Studies using LAM demonstrate a reduction in HCC development in both cirrhotic and non-cirrhotic patients, although the benefit is diminished by the development of drug resistance[3,13,55]. Failure to remain in virological remission is a risk factor for HCC. A case control study showed a lower cumulative 5-year HCC incidence in patients treated with ETV compared to the control group (3.7% vs 13.7% respectively, P < 0.001), with a lower risk of HCC in the ETV group (HR = 0.37, 95%CI: 0.15-0.91, P = 0.30). An analysis of 2671 CHB patients, antiviral therapy was associated with a lower risk of HCC compared with non-treated patients (adjusted HR = 0.39, 95%CI: 0.27-0.56, P < 0.001). Several meta-analyses/systematic reviews have also shown the benefits of antiviral therapy in reducing the rate of HCC development[58-61]. A recent systematic review and meta-analysis however was less clear on the benefits of antiviral therapy in preventing HCC and mortality. Unfortunately, antiviral therapy will not completely remove the risk of HCC, especially for those with established cirrhosis where the liver is already prone to carcinogenesis even without viral replication. Therefore, close follow-up and stringent surveillance for the development of HCC is essential for all cirrhotic patients.
Once HCC develops, treatment for HBV will depend on the stage of disease and the treatment undertaken. Ideally, all patients should be on antiviral therapy as the majority will have underlying cirrhosis. Even for non-cirrhotic patients, the fact that HCC has developed shows that the virus itself has an important role in hepatocarcinogenesis. For non-surgical patients, a high viral load prior to chemotherapy results in higher rates of severe hepatitis during chemotherapy. The APASL guidelines recommend that antiviral treatment should be commenced in all HCC patients with HBV DNA > 2000 IU/mL before and/or after curative therapy, and treatment should be started preemptively for all patients undergoing transarterial chemo-embolization (TACE). Longer survival has been shown in patients receiving TACE with the additional of antiviral therapy. For those with advance stage HCC where survival is limited, resistance becomes less of an issue, and a more cost-effective approach may be recommended.
For the overwhelming majority of patients with HCC, surgical removal of the tumor by resection or LT is the only curative option; the latter will be discussed in a subsequent section. Antiviral therapy is important for patients undergoing resection as the hepatic reserves will be limited and compromised in the post-operative period. Therefore, flares of hepatitis may lead to decompensation for untreated patients. Surgery and anesthesia may also impart a state of immunosuppression in the early post-operative period, thereby increasing the risk of HBV reactivation. A high pre-operative viral load has been associated with worse overall and recurrence-free survivals after curative resection. There is also the potential increased risk of recurrent HCC due to the process of necrosis and regeneration of remaining hepatocytes, which may induce DNA mutations and instability. Up-regulation of adhesion molecules on cells lining sinusoids may increase the risk of distant metastasis.
Viral load and hepatic inflammatory activity have been associated with late recurrences after HCC resection. A cohort of 72 resected patients with HBV-related HCC showed that the absence of antiviral treatment was a risk in tumor recurrence. An HBV DNA of > 2000 IU/mL at the time of resection was a significant risk factor (RR = 22.3, 95%CI: 3.3-150.5, P = 0.001). In a nationwide cohort study from Taiwan of 4051 untreated vs 518 NA-treated CHB patients with resected HCC, even though there was a higher rate of cirrhosis in the latter (38.7% vs 48.6% respectively, P < 0.001), the risk of HCC recurrence was lower in the NA-treated patients (43.6% vs 20.5% respectively, P < 0.001). NA use was independently associated with a significantly lower HCC recurrence risk (HR = 0.67, 95%CI: 0.55-0.81, P < 0.001).
Therefore, antiviral therapy plays an important role in preventing the development of HCC, but also in the recurrence of HCC after curative resection. A meta-analysis also demonstrated the beneficial effects of antiviral therapy with regards to HCC recurrence (OR = 0.59, 95%CI: 0.35-0.97, P = 0.04), and liver-related mortality (OR = 0.13, 95%CI: 0.02-0.69, P = 0.02). Another recent meta-analyses including 20 studies demonstrated that the presence of high viral load significantly increased overall HCC recurrence risk after curative therapy, whereas antiviral therapy had potential beneficial effects in preventing recurrence.
Indications for LT in CHB include severe flares, chronic decompensation, and the development of HCC. The goals of therapy for these patients have been discussed in detail for patients with acute flares, decompensated cirrhosis, and also for patients with HCC. There is also evidence to suggest that antiviral therapy before LT may prevent HBV recurrence after LT by reducing the level of viremia to extremely low levels[76-78]. After LT, the primary goal of antiviral therapy is to prevent HBV recurrence and to prevent graft loss. Prior to the availability of effective HBV prophylaxis in the 1980s, LT for CHB was a relative contraindication. High rates of graft re-infection leading to severe flares and loss of graft occurred in the absence of antiviral therapy. The use of hepatitis B immune globulin (HBIG) after LT was the first major milestone in the prevention of post-transplant HBV recurrence. HBIG monotherapy reduced HBV recurrence by a rate of approximately 70%. As it is a type of passive immunization, the effects are immediate and transient, resulting in the need for frequent antibody titer monitoring and parental injection. The second milestone was the approval of LAM for the treatment of CHB. Although LAM monotherapy is effective in preventing 60%-95% of HBV recurrence, a major disadvantage is the high rate of drug resistance. By combining HBIG with LAM, over 95% of HBV recurrence can be prevented. This combination has been the mainstay of therapy for most LT centers worldwide for the past few decades. The cost of HBIG therapy can be reduced through the use of lower doses which have shown to be equally efficacious.
With the availability of highly potent NAs with low drug resistance rates, recent studies have shown that an HBIG-free regimen can be adopted. An early small-scaled study demonstrated that HBIG can be safely withdrawn with the addition of ADV together with LAM without an increase risk in virological relapse. A recent study also demonstrated no HBV recurrence at 96 wk for patients treated with emtricitabine + TDF + HBIG, with cessation of HBIG after 6 mo post LT. A completely HBIG-free regimen in a cohort of CHB patients using ETV monotherapy, has been reported, showing no episodes of HBV flares or graft loss secondary to recurrent HBV infection. The combination of LAM + ADV without HBIG has also been shown to be effective. A recent large long-term cohort study of 362 CHB post-LT patients receiving only NAs without HBIG showed that at year 8 after LT, 98% had undetectable HBV DNA. Moreover, the survival was excellent at 83% at 8 years, with no mortality related to HBV recurrence. This clearly shows that an HBIG-free regimen is safe and effective, and increasing studies have also demonstrated the efficacy of this therapeutic approach[87-93].
However, HBIG remains part of the antiviral prophylaxis in many transplant centers. It has to be said that the use of HBIG is likely to result in a higher rate of HBsAg negativity due to the fact that the passive anti-HBs antibodies will bind with HBsAg, leading to a further reduction in detection rate when compared with HBIG-free protocols. However, this does not signify eradication of HBV as cessation of prophylaxis is likely to result in reactivation. Therefore, life-long antiviral therapy is currently the standard of care after LT for CHB.
In patients with CHB, complications of liver disease can occur in around 40% of patients, including cirrhosis and HCC. The use of interferon-based therapy is largely contra-indicated for those with severe liver disease; therefore treatment is restricted to the use of NAs. After curative resection, adjuvant interferon therapy also fails to demonstrate any reduction in recurrence of HCC after curative resection. Although there are slight variations between the different major regional treatment guidelines, general recommendations can be made with the use of the current available NAs in the treatment of patients with cirrhosis, AOCLF, HCC, and after LT. The use of drugs with high antiviral potency and high barrier to resistance is recommended (ETV or TDF), to minimize the development of resistance, virological breakthrough and biochemical flare. Earlier drugs with low antiviral potency or low barrier to resistance, such as LAM or ADV, should not be used. The duration of treatment is life-long for the overwhelming majority, with cessation of therapy perhaps only possible for those with HBsAg seroconversion. Ongoing surveillance for HCC is an essential component of management for cirrhotic patients. In patients with HCC, antiviral therapy is recommended to preserve liver function in the non-tumor liver, especially for those undergoing liver resection and loco-regional ablative therapy. For those with AOCLF and those with decompensated cirrhosis, early consideration for transplantation is recommended if available. Although antiviral therapy is effective for AOCLF, a significant proportion will still succumb. Life-long prophylaxis is currently the standard of care for patients after transplant. With the newer NAs, a regimen without the use of HBIG has been shown to be effective with excellent long-term outcome.
|1.||Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. 2003;362:2089-2094. [PubMed]|
|2.||Szpakowski JL, Tucker LY. Causes of death in patients with hepatitis B: a natural history cohort study in the United States. Hepatology. 2013;58:21-30. [PubMed] [DOI]|
|3.||Yuen MF, Seto WK, Chow DH, Tsui K, Wong DK, Ngai VW, Wong BC, Fung J, Yuen JC, Lai CL. Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther. 2007;12:1295-1303. [PubMed]|
|4.||Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263. [PubMed]|
|5.||Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339:61-68. [PubMed]|
|6.||Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816. [PubMed] [DOI]|
|7.||Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800-807. [PubMed]|
|8.||Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011-1020. [PubMed]|
|9.||Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010. [PubMed]|
|10.||Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357:2576-2588. [PubMed]|
|11.||Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-2455. [PubMed]|
|12.||Fung J, Lai CL, Yuen MF. New paradigms for the treatment of chronic hepatitis B. J Gastroenterol Hepatol. 2008;23:1182-1192. [PubMed]|
|13.||Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531. [PubMed]|
|14.||Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther. 2013;38:98-106. [PubMed] [DOI]|
|15.||Wong GL, Chan HL, Mak CW, Lee SK, Ip ZM, Lam AT, Iu HW, Leung JM, Lai JW, Lo AO. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58:1537-1547. [PubMed] [DOI]|
|16.||Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, Akuta N, Suzuki Y, Saitoh S, Arase Y. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98-107. [PubMed] [DOI]|
|17.||Kumada T, Toyoda H, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Niinomi T, Yasuda S, Andou Y. Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis. J Hepatol. 2013;58:427-433. [PubMed] [DOI]|
|18.||Schiff ER, Lee SS, Chao YC, Kew Yoon S, Bessone F, Wu SS, Kryczka W, Lurie Y, Gadano A, Kitis G. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2011;9:274-276. [PubMed]|
|19.||Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886-893. [PubMed]|
|20.||Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468-475. [PubMed]|
|21.||Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, Frederick D, Rousseau F. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48:750-758. [PubMed]|
|22.||Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743-1751. [PubMed]|
|23.||European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227-242. [PubMed]|
|24.||Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662. [PubMed] [DOI]|
|25.||Liaw YF, Kao JH, Piravisuth T, Chan HLY, Chien RN, Liu CJ, Gane E, Locarnini S, Lim SG, Han KH. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6:531-561. [DOI]|
|26.||Fung J, Lai CL, Tanaka Y, Mizokami M, Yuen J, Wong DK, Yuen MF. The duration of lamivudine therapy for chronic hepatitis B: cessation vs. continuation of treatment after HBeAg seroconversion. Am J Gastroenterol. 2009;104:1940-1946; quiz 1947. [PubMed]|
|27.||Liaw YF, Raptopoulou-Gigi M, Cheinquer H, Sarin SK, Tanwandee T, Leung N, Peng CY, Myers RP, Brown RS, Jeffers L. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study. Hepatology. 2011;54:91-100. [PubMed] [DOI]|
|28.||Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, Chang TT, Horban A, Wang C, Kwan P, Buti M, Prieto M, Berg T, Kitrinos K, Peschell K, Mondou E, Frederick D, Rousseau F, Schiff ER. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72. [PubMed] [DOI]|
|29.||Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, Davis R, Gardner SD, Brown NA. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002;123:719-727. [PubMed]|
|30.||Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology. 2011;53:774-780. [PubMed] [DOI]|
|31.||Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ. Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2010;52:176-182. [PubMed] [DOI]|
|32.||Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann H, Samuel D, Zeuzem S, Villeneuve JP. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007;13:349-360. [PubMed] [DOI]|
|33.||You CR, Jang JW, Choi JK, Bae SH, Yoon SK, Kay CS, Choi JY. Hepatic Failure Caused by Reactivation of YMDD Mutants Occurring during Preemptive Lamivudine Therapy. Gut Liver. 2010;4:262-265. [PubMed] [DOI]|
|34.||Joo MK, Yeon JE, Kim JH, Jung YK, Lee SJ, Kim JH, Yim HJ, Byun KS, Park JJ, Kim JS. Chronic cirrhotic hepatitis B patients with a high incidence of hepatic decompensation after viral breakthrough with lamivudine-resistant mutants and during rescue treatment. Scand J Gastroenterol. 2008;43:1514-1521. [PubMed] [DOI]|
|35.||Bottecchia M, Ikuta N, Niel C, Araujo NM, O KM, Gomes SA. Lamivudine resistance and other mutations in the polymerase and surface antigen genes of hepatitis B virus associated with a fatal hepatic failure case. J Gastroenterol Hepatol. 2008;23:67-72. [PubMed] [DOI]|
|36.||Suzuki Y, Yotsuyanagi H, Okuse C, Nagase Y, Takahashi H, Moriya K, Suzuki M, Koike K, Iino S, Itoh F. Fatal liver failure caused by reactivation of lamivudine-resistant hepatitis B virus: a case report. World J Gastroenterol. 2007;13:964-969. [PubMed]|
|37.||Fung SK, Andreone P, Han SH, Rajender Reddy K, Regev A, Keeffe EB, Hussain M, Cursaro C, Richtmyer P, Marrero JA. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol. 2005;43:937-943. [PubMed]|
|38.||Kagawa T, Watanabe N, Kanouda H, Takayama I, Shiba T, Kanai T, Kawazoe K, Takashimizu S, Kumaki N, Shimamura K. Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant. World J Gastroenterol. 2004;10:1686-1687. [PubMed]|
|39.||Ye XG, Su QM. Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta-analysis. World J Gastroenterol. 2013;19:6665-6678. [PubMed] [DOI]|
|40.||Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, Sarrazin C. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001-2006. [PubMed] [DOI]|
|41.||Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, de Silva HJ, Hamid SS, Jalan R, Komolmit P. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int. 2009;3:269-282. [PubMed] [DOI]|
|42.||Heemann U, Treichel U, Loock J, Philipp T, Gerken G, Malago M, Klammt S, Loehr M, Liebe S, Mitzner S. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology. 2002;36:949-958. [PubMed] [DOI]|
|43.||Jalan R, Sen S, Steiner C, Kapoor D, Alisa A, Williams R. Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis. J Hepatol. 2003;38:24-31. [PubMed]|
|44.||Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, Berger ED, Lauchart W, Peszynski P, Freytag J. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl. 2000;6:277-286. [PubMed] [DOI]|
|45.||Bañares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, Saliba F, Sauerbruch T, Klammt S, Ockenga J. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology. 2013;57:1153-1162. [PubMed] [DOI]|
|46.||Sun LJ, Yu JW, Zhao YH, Kang P, Li SC. Influential factors of prognosis in lamivudine treatment for patients with acute-on-chronic hepatitis B liver failure. J Gastroenterol Hepatol. 2010;25:583-590. [PubMed] [DOI]|
|47.||Lai J, Yan Y, Mai L, Zheng YB, Gan WQ, Ke WM. Short-term entecavir versus lamivudine therapy for HBeAg-negative patients with acute-on-chronic hepatitis B liver failure. Hepatobiliary Pancreat Dis Int. 2013;12:154-159. [PubMed]|
|48.||Sun QF, Ding JG, Xu DZ, Chen YP, Hong L, Ye ZY, Zheng MH, Fu RQ, Wu JG, Du QW. Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model. J Viral Hepat. 2009;16:464-470. [PubMed] [DOI]|
|49.||Zheng MH, Shi KQ, Fan YC, Li H, Ye C, Chen QQ, Chen YP. A model to determine 3-month mortality risk in patients with acute-on-chronic hepatitis B liver failure. Clin Gastroenterol Hepatol. 2011;9:351-356.e3. [PubMed]|
|50.||Fan HL, Yang PS, Chen HW, Chen TW, Chan DC, Chu CH, Yu JC, Kuo SM, Hsieh CB. Predictors of the outcomes of acute-on-chronic hepatitis B liver failure. World J Gastroenterol. 2012;18:5078-5083. [PubMed] [DOI]|
|51.||Lee WC, Chou HS, Wu TJ, Lee CS, Lee CF, Chan KM. Indicators and outcome of liver transplantation in acute liver decompensation after flares of hepatitis B. J Viral Hepat. 2011;18:193-199. [PubMed]|
|52.||Chan AC, Fan ST, Lo CM, Liu CL, Chan SC, Ng KK, Yong BH, Chiu A, Lam BK. Liver transplantation for acute-on-chronic liver failure. Hepatol Int. 2009;3:571-581. [PubMed] [DOI]|
|53.||Fung J, Lai CL, Yuen MF. Hepatitis B and C virus-related carcinogenesis. Clin Microbiol Infect. 2009;15:964-970. [PubMed]|
|54.||Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology. 2013;57:399-408. [PubMed] [DOI]|
|55.||Kurokawa M, Hiramatsu N, Oze T, Yakushijin T, Miyazaki M, Hosui A, Miyagi T, Yoshida Y, Ishida H, Tatsumi T. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection. J Gastroenterol. 2012;47:577-585. [PubMed] [DOI]|
|56.||Papatheodoridis GV, Manolakopoulos S, Touloumi G, Vourli G, Raptopoulou-Gigi M, Vafiadis-Zoumbouli I, Vasiliadis T, Mimidis K, Gogos C, Ketikoglou I. Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study. Gut. 2011;60:1109-1116. [PubMed]|
|57.||Gordon SC, Lamerato LE, Rupp LB, Li J, Holmberg SD, Moorman AC, Spradling PR, Teshale EH, Vijayadeva V, Boscarino JA. Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin Gastroenterol Hepatol. 2014;12:885-893. [PubMed] [DOI]|
|58.||Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008;28:1067-1077. [PubMed]|
|59.||Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010;53:348-356. [PubMed] [DOI]|
|60.||Zhang QQ, An X, Liu YH, Li SY, Zhong Q, Wang J, Hu HD, Zhang DZ, Ren H, Hu P. Long-term nucleos(t)ide analogues therapy for adults with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis. Virol J. 2011;8:72. [PubMed] [DOI]|
|61.||Shen YC, Hsu C, Cheng CC, Hu FC, Cheng AL. A critical evaluation of the preventive effect of antiviral therapy on the development of hepatocellular carcinoma in patients with chronic hepatitis C or B: a novel approach by using meta-regression. Oncology. 2012;82:275-289. [PubMed] [DOI]|
|62.||Thiele M, Gluud LL, Dahl EK, Krag A. Antiviral therapy for prevention of hepatocellular carcinoma and mortality in chronic hepatitis B: systematic review and meta-analysis. BMJ Open. 2013;3:e003265. [PubMed] [DOI]|
|63.||Yeo W, Mo FK, Chan SL, Leung NW, Hui P, Lam WY, Mok TS, Lam KC, Ho WM, Koh J. Hepatitis B viral load predicts survival of HCC patients undergoing systemic chemotherapy. Hepatology. 2007;45:1382-1389. [PubMed] [DOI]|
|64.||Toyoda H, Kumada T, Tada T, Sone Y, Fujimori M. Transarterial chemoembolization for hepatitis B virus-associated hepatocellular carcinoma: improved survival after concomitant treatment with nucleoside analogues. J Vasc Interv Radiol. 2012;23:317-322.e1. [PubMed] [DOI]|
|65.||Shin HS, Kim SU, Park JY, Kim do Y, Han KH, Chon CY, Baatarkhuu O, Ahn SH. Antiviral efficacy of lamivudine versus entecavir in patients with hepatitis B virus-related advanced hepatocellular carcinoma. J Gastroenterol Hepatol. 2012;27:1528-1534. [PubMed] [DOI]|
|66.||Lao XM, Luo G, Ye LT, Luo C, Shi M, Wang D, Guo R, Chen M, Li S, Lin X. Effects of antiviral therapy on hepatitis B virus reactivation and liver function after resection or chemoembolization for hepatocellular carcinoma. Liver Int. 2013;33:595-604. [PubMed] [DOI]|
|67.||Huang G, Lai EC, Lau WY, Zhou WP, Shen F, Pan ZY, Fu SY, Wu MC. Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels. Ann Surg. 2013;257:490-505. [PubMed] [DOI]|
|68.||Yang T, Lu JH, Zhai J, Lin C, Yang GS, Zhao RH, Shen F, Wu MC. High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study. Eur J Surg Oncol. 2012;38:683-691. [PubMed] [DOI]|
|69.||von Sengbusch A, Gassmann P, Fisch KM, Enns A, Nicolson GL, Haier J. Focal adhesion kinase regulates metastatic adhesion of carcinoma cells within liver sinusoids. Am J Pathol. 2005;166:585-596. [PubMed] [DOI]|
|70.||Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ, Lee SD, Lui WY. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol. 2009;51:890-897. [PubMed]|
|71.||Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am J Gastroenterol. 2008;103:1663-1673. [PubMed]|
|72.||Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection. JAMA. 2012;308:1906-1914. [PubMed]|
|73.||Wong JS, Wong GL, Tsoi KK, Wong VW, Cheung SY, Chong CN, Wong J, Lee KF, Lai PB, Chan HL. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther. 2011;33:1104-1112. [PubMed] [DOI]|
|74.||Qu LS, Liu JX, Kuai XL, Xu ZF, Jin F, Zhou GX. Significance of viral status on recurrence of hepatitis B-related hepatocellular carcinoma after curative therapy: A meta-analysis. Hepatol Res. 2014;44:750-760. [PubMed] [DOI]|
|75.||Fung J. Managing hepatitis B: Before and after liver transplantation. Ind J Transplant. 2011;5:77-80.|
|76.||Yasunaka T, Takaki A, Yagi T, Iwasaki Y, Sadamori H, Koike K, Hirohata S, Tatsukawa M, Kawai D, Shiraha H. Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis. Hepatol Int. 2011;5:918-926. [PubMed] [DOI]|
|77.||Chun J, Kim W, Kim BG, Lee KL, Suh KS, Yi NJ, Park KU, Kim YJ, Yoon JH, Lee HS. High viremia, prolonged Lamivudine therapy and recurrent hepatocellular carcinoma predict posttransplant hepatitis B recurrence. Am J Transplant. 2010;10:1649-1659. [PubMed] [DOI]|
|78.||Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W, Alessandria C, Franchello A, Salizzoni M, Rizzetto M. Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. Liver Transpl. 2005;11:402-409. [PubMed] [DOI]|
|79.||Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med. 1993;329:1842-1847. [PubMed] [DOI]|
|80.||Lo CM, Cheung ST, Lai CL, Liu CL, Ng IO, Yuen MF, Fan ST, Wong J. Liver transplantation in Asian patients with chronic hepatitis B using lamivudine prophylaxis. Ann Surg. 2001;233:276-281. [PubMed]|
|81.||Gane EJ, Angus PW, Strasser S, Crawford DH, Ring J, Jeffrey GP, McCaughan GW. Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology. 2007;132:931-937. [PubMed]|
|82.||Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology. 2008;48:1460-1466. [PubMed] [DOI]|
|83.||Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, Flaherty J, Dinh P, Rossi S, Subramanian GM. Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation. Liver Transpl. 2013;19:594-601. [PubMed] [DOI]|
|84.||Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, Dai WC, Chan AC, Cheung TT, Tsang S. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology. 2011;141:1212-1219. [PubMed]|
|85.||Gane EJ, Patterson S, Strasser SI, McCaughan GW, Angus PW. Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates. Liver Transpl. 2013;19:268-274. [PubMed] [DOI]|
|86.||Fung J, Chan SC, Cheung C, Yuen MF, Chok KS, Sharr W, Chan AC, Cheung TT, Seto WK, Fan ST. Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B. Am J Gastroenterol. 2013;108:942-948. [PubMed]|
|87.||Wesdorp DJ, Knoester M, Braat AE, Coenraad MJ, Vossen AC, Claas EC, van Hoek B. Nucleoside plus nucleotide analogs and cessation of hepatitis B immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective. J Clin Virol. 2013;58:67-73. [PubMed] [DOI]|
|88.||Wadhawan M, Gupta S, Goyal N, Taneja S, Kumar A. Living related liver transplantation for hepatitis B-related liver disease without hepatitis B immune globulin prophylaxis. Liver Transpl. 2013;19:1030-1035. [PubMed] [DOI]|
|89.||Yi NJ, Choi JY, Suh KS, Cho JY, Baik M, Hong G, Lee KW, Kim W, Kim YJ, Yoon JH. Post-transplantation sequential entecavir monotherapy following 1-year combination therapy with hepatitis B immunoglobulin. J Gastroenterol. 2013;48:1401-1410. [PubMed] [DOI]|
|90.||Cholongitas E, Vasiliadis T, Antoniadis N, Goulis I, Papanikolaou V, Akriviadis E. Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation. Transpl Infect Dis. 2012;14:479-487. [PubMed] [DOI]|
|91.||Stravitz RT, Shiffman ML, Kimmel M, Puri P, Luketic VA, Sterling RK, Sanyal AJ, Cotterell AH, Posner MP, Fisher RA. Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation. Liver Int. 2012;32:1138-1145. [PubMed] [DOI]|
|92.||Ahn J, Cohen SM. Prevention of hepatitis B recurrence in liver transplant patients using oral antiviral therapy without long-term hepatitis B immunoglobulin. Hepat Mon. 2011;11:638-645. [PubMed]|
|93.||Saab S, Desai S, Tsaoi D, Durazo F, Han S, McClune A, Holt C, Farmer D, Goldstein L, Busuttil RW. Posttransplantation hepatitis B prophylaxis with combination oral nucleoside and nucleotide analog therapy. Am J Transplant. 2011;11:511-517. [PubMed] [DOI]|