1Hepatitis B virus replication is associated with a severe outcome in patients with decompensated cirrhosis.
2Viral suppression induced by antivirals results in a clinical improvement that allows liver transplantation to be delayed or avoided.
3Early treatment intervention is mandatory in patients with decompensated cirrhosis because of the delay in the restoration of liver functions.
4Lamivudine is no longer the drug of choice because the initial enthusiasm has been tempered by the high rate of resistance development.
5Early add-on therapy with adefovir allows us to rescue lamivudine resistance, but its use may be limited by nephrotoxicity.
6Studies are ongoing with the newer generation of antivirals (telbivudine, tenofovir, entecavir, and emtricitabine) in monotherapy or in combination to determine the best strategy for achieving rapid and prolonged suppression of viral replication. These improved strategies should enhance treatment success enough to obtain clinical stabilization, to delay or prevent the need for transplantation, and to reduce the risk of hepatitis B virus recurrence on the graft.
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Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide. Indeed, chronically infected patients are exposed to the main complications of the disease, including liver cirrhosis, decompensation of cirrhosis (portal hypertension and variceal bleeding, ascites, jaundice, encephalopathy, and liver failure), and hepatocellular carcinoma. HBV-related decompensated cirrhosis was a treatment challenge until the development of specific antivirals that allowed us not only to control viral replication, therefore permitting liver transplantation, but also to improve liver function so significantly that patients could be removed from the transplant waiting list. The significant improvement in the management of decompensated cirrhosis over the past few years is described in this review.
NATURAL HISTORY OF HBV CIRRHOSIS
Liver cirrhosis is the end stage of the natural history of chronic HBV infection. It is associated with a poor prognosis because of the high incidence of complications, including decompensation of liver functions and development of hepatocellular carcinoma.1, 2
Several studies have evaluated the natural history of HBV liver cirrhosis. In a study, the survival of histologically proven hepatitis B surface antigen (HBsAg)–positive cirrhosis of the liver was assessed in a cohort of 98 patients followed up for a mean of 4.3 years. The overall survival probability was 92% at 1 year, 79% at 3 years, and 71% at 5 years. Variables significantly associated with the duration of survival were age, serum transaminase levels, presence of esophageal varices, and the Child-Pugh index. Multivariate analysis showed that age, bilirubin, and ascites were independently related to survival. The survival of patients with decompensated cirrhosis and those with compensated cirrhosis at 5 years was 14% and 84%, respectively. For patients with compensated liver cirrhosis, hepatitis B e antigen (HBeAg) positivity was also a prognostic factor, with a 5-year survival of 72% for HBeAg-positive cirrhosis and a 5-year survival of 97% for HBeAg-negative cirrhosis; the risk of death was decreased significantly when HBeAg seroconversion occurred during follow-up, and this suggested that spontaneous suppression of viral replication is a major outcome determinant.3
Another multicenter longitudinal study was performed to assess the survival of HBsAg-positive compensated cirrhosis, primarily in relation to HBV replication and hepatitis delta virus infection, and to construct a prognostic index. Three hundred sixty-six Caucasian HBsAg-positive patients with cirrhosis who had never had clinical manifestations of hepatic decompensation were enrolled and followed for a mean period of 72 months. At entry, 35% of the patients were HBeAg-positive, 48% of the tested patients were HBV-DNA–positive (according to low-sensitivity assays that were available at that time), and 20% were anti–hepatitis delta virus–positive. Death occurred in 84 (23%) patients, mainly because of liver failure (45 cases) or hepatocellular carcinoma (23 cases). The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively. Cox's regression analysis identified 6 variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin, and HBeAg positivity at the time of diagnosis. Termination of HBV replication and/or biochemical remission during follow-up correlated with significantly better survival. These data showed that in compensated cirrhosis B, HBV replication, age, and indirect indicators of poor hepatic reserve and established portal hypertension significantly worsen the clinical course of the disease. Because a significant improvement in life expectancy following cessation of HBV replication and biochemical remission was observed, antiviral therapy was proposed for these patients.4
For a long time, interferon alpha was the only available agent for the treatment of hepatitis B. In patients with decompensated cirrhosis, several centers reported clinical benefit in some patients.5 However, its use was restricted to reference centers because of its side effects, including an increased risk of infection and severe exacerbation of liver disease. The development of nucleoside analogs exhibiting a direct antiviral effect has dramatically improved the management of these patients in recent years.
The recent results of lamivudine (LAM) treatment for patients with advanced fibrosis have further demonstrated the concept that effective inhibition of viral replication decreases the rate of progression of liver disease in comparison with patients receiving placebo and that the emergence of LAM resistance resulting in the loss of viral replication control is associated with an increased rate of clinical deterioration.6
ADV, adefovir; ALT, alanine aminotransferase; CPT, Child-Pugh-Turcotte; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HIV, human immunodeficiency virus; LAM, lamivudine; NA, not applicable; OLT, orthotopic liver transplantation.
ANTIVIRAL THERAPY OF DECOMPENSATED HBV CIRRHOSIS
For many years, the presence of HBV replication was considered a contraindication to orthotopic liver transplantation (OLT) by most centers. Therefore, the main goal of pre-OLT antiviral treatment was to suppress HBV replication before OLT and thus decrease the risk of reinfection of the graft. Clearance of HBV DNA from serum before OLT may also result in significant clinical improvement allowing patients to be removed from the waiting list. An ideal antiviral treatment in this setting should have a rapid and potent antiviral action, which in turn should improve liver functions without delay.7, 8
LAM, a nucleoside analog inhibiting viral polymerase activity, is well tolerated even in decompensated cirrhosis and is effective by achieving rapid viral suppression within several weeks of therapy. However, long-term antiviral therapy is required to prevent viral relapse, but HBV drug–resistant mutants emerge in 20% of patients per year. The results in decompensated cirrhosis are summarized in Table 1. Villeneuve et al.9 reported on 35 patients with severely decompensated HBV cirrhosis associated with high HBV DNA levels who were treated with 100 or 150 mg of LAM daily. Within 6 months after treatment initiation, 7 patients underwent OLT, and 5 patients died. In 23 patients who were treated for at least 6 months, there was a slow but marked improvement in liver function in 22 of them. The rate of development of LAM resistance was 25% at 2 years. In another study, the outcome of LAM treatment in 23 consecutive patients with severely decompensated HBV cirrhosis was compared with a historical untreated control group of 23 patients matched for age, gender, and baseline Child-Pugh-Turcotte (CPT) score.10 Significant clinical response, defined as a decrease in the CPT score, was observed in 61% of treated patients versus none of the controls (P < 0.0001). Time to death or OLT was significantly longer in treated patients than in controls (P < 0.001). These results suggested that LAM significantly improves hepatic function in over half of patients with decompensated cirrhosis and replicating HBV and confers a survival advantage.10 Other uncontrolled studies have confirmed the slow improvement (3-6 months) of hepatic function in patients with decompensated cirrhosis treated with LAM, who have a survival advantage in comparison with a historical group of untreated controls. Fontana et al.11 found, in a retrospective multicenter study including 309 patients, that LAM did not improve overall pre-OLT or OLT-free survival. However, a subset of patients with less advanced liver failure may benefit from LAM treatment. These data suggest that antiviral treatment should be initiated as early as possible in patients with decompensated liver cirrhosis, as the improvement of liver functions may be delayed after the control of viral replication.
Table 1. Efficacy of Lamivudine Monotherapy in Transplantation Candidates with HBV Decompensated Cirrhosis
Duration of Treatment
HBV DNA–Positive Pre-Treatment
Improvement in CPT Score
HBV DNA–Positive at End of Treatment
Abbreviations: CPT, Child-Pugh-Turcotte; HBV, hepatitis B virus; NA, not applicable.
In a prospective multicenter study, 154 patients listed for OLT received LAM for a median duration of 16 months.12 During study observation, 32 of the 154 (21%) patients died, with most of the deaths (25 of 32; 78%) occurring within the first 6 months of therapy. The estimated actuarial 3-year survival of patients who survived at least 6 months was 88% on continued treatment. In multivariate modeling, the severity of liver disease at the time of starting therapy was a better predictor of early mortality than the virologic response to LAM. Thus, it was recommended that patients with advanced liver failure should be prioritized for OLT, regardless of LAM response.
All these results consistently indicated that antiviral therapy should be started as early as possible because of the significant clinical improvement provided by treatment-induced viral control and because of the lag time observed between viral suppression and restoration of liver functions.
However, because of the high rate of resistance to LAM, which hampers the clinical benefit, a question that emerged was when to initiate LAM therapy in patients listed for OLT. Prolonged administration of LAM is necessary to obtain significant clinical benefits, but the risk for developing drug-resistant mutations increases with the duration of treatment and may be associated with worsening of liver failure. Cases of liver transplantation in patients with LAM-resistant mutants have been reported with controversial results.13-15 Recurrence of HBV infection on a liver graft was observed in some patients despite the administration of a prophylaxis combining hepatitis B immune globulins (HBIGs) and LAM post-transplant. This suggests that transplantation should be performed only after viral suppression is obtained before transplantation, as either a first-line therapy or a second-line therapy.
Another question was whether pre-emptive LAM administration before and after liver transplantation might allow HBIG administration to be avoided. However, because of the high rate of LAM resistance and a higher risk of recurrence on the graft versus the combination of LAM and HBIG post-transplant, this strategy was abandonned.7, 8
Clearly, LAM has provided an important treatment option in these difficult-to-treat patients, but it has turned out not to be the optimal drug because of its resistance profile. A new generation of drugs has shown an added clinical benefit in the management of patients with decompensated cirrhosis.
ADV, a nucleotide analog of adenosine monophosphate, is an inhibitor of the wild-type and LAM-resistant mutants of HBV.16-18 Thus, ADV was approved not only as a first-line therapy but also as a rescue therapy for patients with LAM resistance. Schiff et al.19 used ADV administered at doses of 10 mg/day for a median of 18 weeks in 128 patients with decompensated cirrhosis who failed LAM therapy pre-OLT. They achieved a median reduction of serum HBV DNA levels of 3.1 Log 10 copies/mL after 24 weeks and 4.1 Log 10 copies/mL after 48 weeks; 81% of patients achieved undetectable HBV DNA by polymerase chain reaction. Control of viral replication was associated with normalization in serum alanine aminotransferase (ALT) in 76% of patients who had abnormal baseline ALT. The CPT score stabilized or improved in over 90% of patients. Survival after 1 year of ADV treatment was 84%, and this compared favorably with historical controls. Dose reductions of ADV were required for patients with preexisting renal dysfunction.
A follow-up study was performed in which wait-listed (n = 226) or post–liver transplantation (n = 241) chronic hepatitis B patients with LAM-resistant HBV were treated with adefovir dipivoxil for medians of 39 and 99 weeks, respectively.20 Among wait-listed patients, serum HBV DNA levels became undetectable in 59% and 65% at weeks 48 and 96, respectively. After 48 weeks, serum ALT, albumin, bilirubin, and prothrombin time normalized in 77%, 76%, 60%, and 84% of wait-listed patients, respectively. Among posttransplantation patients, serum HBV DNA levels became undetectable in 40% and 65% at weeks 48 and 96, respectively. After 48 weeks, ALT, albumin, bilirubin, and prothrombin time normalized in 51%, 81%, 76%, and 56% of posttransplantation patients, respectively. The median change from the baseline Model for End-Stage Disease score was −2.0 at week 48 (n = 63; P < 0.001 Wilcoxon signed rank test) and −3.0 at week 96 (n = 13; P < 0.001). Of patients who were categorized as CPT class B or C at baseline, 91% (29/32) had a decrease of at least 1 point in the CPT score at week 48. Along with an antiviral effect and clinical improvement, treatment with adefovir dipivoxil was associated with high probabilities of survival. A total of 32 deaths (32/226, 14%) were reported while patients were wait-listed or within 30 days of the last dose of the study drug. Kaplan-Meier estimates of survival for wait-listed patients on ADV were 86% by week 48 and 78% by week 96. A survey was conducted in 100 patients; 43 patients underwent liver transplantation. Of the 57 patients who did not undergo liver transplantation, 21 (21/100, 21%) were able to be removed from the wait list by the time of the survey as a result of clinical improvement. The Kaplan-Meier probability of survival among posttransplantation patients treated with adefovir dipivoxil was 87% at 3 years. In comparison, among patients with untreated HBV infection post-transplantation, survival was 44% at 3 years.
Among wait-listed patients who underwent on-study liver transplantation, protection from graft reinfection over a median of 35 weeks was similar among patients who did or did not receive HBIG. HBsAg was detected on the first measurement only in 6% and 9% of patients who did or did not receive HBIG, respectively. Serum HBV DNA was detected on consecutive visits in 6% and 0% of patients who did or did not receive HBIG, respectively. Specific studies should be performed, especially with the newer generation of antivirals, to investigate whether prophylaxis of HBV recurrence can rely on nucleoside analog administration pre-transplant and post-transplant without HBIG.
Only 4% of patients discontinued adefovir dipivoxil because of nephrotoxicity, and hepatorenal syndrome or multiorgan failure was a contributing factor in the majority of cases. In patients with baseline renal insufficiency, proper adjustment of dosing is essential. Cumulative probabilities of resistance were 0%, 2%, and 2% at weeks 48, 96, and 144, respectively.20 The rtN236T mutation in the D domain of the reverse transcriptase was the only resistance mutation observed in this study. Emergence of resistance to ADV was delayed and developed only after discontinuation of LAM; patients could be rescued by the readministration of LAM in addition to ADV, and this confirmed that an add-on strategy is a better treatment strategy than a sequential monotherapy.21 One of the major problems with using sequential treatment with nucleoside analogs when complete viral suppression is not achieved is the risk of emergence of multiresistant viral strains that may escape the antiviral pressure of nucleoside analogs (LAM followed by LAM/ADV) and HBIG, as recently described.22 The lack of cross-resistance of the LAM-resistant and ADV-resistant strains to these compounds strongly suggests the use of de novo combination therapy, especially in patients with severe liver disease in whom the selection of multiple drug–resistant strains may be deleterious.23
NEW ANTIVIRAL DRUGS
A new generation of nucleoside analogs has been developed. They exhibit stronger antiviral efficacy and a lower resistance rate. Experience with these drugs is still limited in the setting of decompensated cirrhosis and liver transplantation. Because of the rapidity of their antiviral activity, which may be an added value in the management of patients with liver failure, studies are ongoing to determine the clinical benefit associated with their administration in this setting. Clearly, the antiviral activity profile of these drugs opens new perspectives in the management of these difficult-to-treat patients.
This is a nucleoside analog with strong antiviral potency that has been found to be comparable to that of entecavir in phase III clinical trials in both HBeAg-positive and HBeAg-negative patients.24-26 Unfortunately, its administration is associated with a resistance rate of approximately 10% per year. Phase III clinical studies have helped to identify on-treatment predictive factors for virologic response and drug resistance, with primary importance given to persisting viremia at 24 weeks of treatment. Telbivudine mainly selects for the rtM204I mutation, which is also resistant to LAM and entecavir but sensitive to ADV and tenofovir. Importantly, it can be used against ADV-resistant mutants. Its use in a combination regimen should also be evaluated in clinical trials, especially in patients with severe liver disease and decompensated liver cirrhosis.
This nucleoside analog is a very potent anti-HBV agent that induces a dramatic decline in the viral load in both HBeAg-positive and HBeAg-negative patients.27, 28 In naive patients, because of a high genetic barrier of resistance, the rate of emergence of entecavir-resistant strains seems to be very low even after 5 years of therapy.29 In contrast, entecavir administration in patients with LAM failure gives rise to entecavir-resistant mutants in more than 35% of patients after 4 years of therapy.30, 31 This is due to a particular mode of selection of entecavir strains that follows a 2-step process, with the selection of primary resistance mutations at position rt204 (which are also resistant to LAM) followed by the addition of secondary resistance mutations on the same viral genomes.32-34 Once these secondary substitutions occur, high-level resistance to entecavir occurs. Because of its antiviral potency and low rate of resistance, entecavir represents an interesting first-line treatment option in patients with decompensated cirrhosis. Studies are ongoing to determine its efficacy and safety profile in this clinical situation.
Tenofovir belongs to the same family of nucleotide analogs as ADV. It exhibits potent inhibitory activity against the wild-type and drug-resistant mutants (ie, LAM-resistant and entecavir-resistant strains).35, 36 Clinical experience has been mainly in patients coinfected with human immunodeficiency virus (HIV) and HBV as tenofovir is also active against the HIV reverse transcriptase.37-40 In this setting, it has been shown that tenofovir can control HBV replication in the majority of patients and can rescue HBV LAM failure. Moreover, clinical studies have demonstrated it to be effective when there is primary nonresponse to ADV in non–HIV-infected patients. In HIV-coinfected patients, it has been prescribed mainly as an add-on therapy with LAM and more recently in combination with emtricitabine, another nucleoside analog with an antiviral activity profile that is similar to that of LAM for both HBV and HIV. This may be the reason that until now there has been no definite observation of HBV resistance to tenofovir. It will be interesting to see whether this holds true when tenofovir is prescribed as monotherapy. Recent results of ongoing phase III studies in chronic hepatitis B patients negative for HIV have shown that tenofovir has better antiviral efficacy than ADV, even in patients with cirrhosis (Marcellin et al., Heathcote et al., Buti et al., and Abstracts of the 2008 European Association for the Study of the Liver Meeting). Approximately 75% and 90% of HBeAg-positive and HBeAg-negative patients, respectively, achieved undetectable HBV DNA by quantitative polymerase chain reaction after 1 year of therapy.
A few case studies have shown encouraging preliminary results with tenofovir in patients with decompensated cirrhosis. In a first study, a patient with cirrhosis developed sequentially LAM resistance and an incomplete response to ADV with the emergence of the rtN236T and rtA181T ADV-resistant mutations. ADV resistance resulted in viral breakthrough with hepatitis flare-up and liver decompensation. Tenofovir had an excellent antiviral effect allowing sustained control of viral replication and reversal of hepatic failure.41 In another study, 6 patients with HBV-related cirrhosis, viral breakthrough during LAM therapy, and viral breakthrough or nonresponse during ADV therapy were treated daily with tenofovir plus LAM for at least 6 months. Within 12 months, HBV DNA levels became undetectable in all patients, and ALT levels were normalized in 4 of 6 patients. The CPT scores improved in 2 of 3 patients with hepatic decompensation. Kidney tolerance was correct as no significant changes in serum creatinine were observed.42
Because of its spectrum of antiviral activity, tenofovir can be recommended for use in both naive patients and those with first-line treatment failure. Indeed, there is in vitro and in vivo evidence suggesting that it is active against LAM-resistant, entecavir-resistant, telbivudine-resistant, and even ADV-resistant mutants. In this setting, an add-on strategy or a switch to a combination of tenofovir plus emtricitabine might be recommended. Because of its favorable cross-resistance profile and the first experience in patients with cirrhosis, controlled trials are ongoing in patients with decompensated cirrhosis to compare the efficacy and safety of tenofovir versus the combination of tenofovir plus emtricitabine.
DISCUSSION AND PERSPECTIVES
The current aim of antiviral therapy for hepatitis B patients on the liver transplantation waiting list is to achieve rapid and prolonged suppression of viral replication in order to obtain clinical stabilization, to delay or prevent the need for transplantation, and to reduce the risk of HBV recurrence on the graft.2, 7, 8, 43 The management of patients with decompensated cirrhosis, from the perspective of liver transplantation, has been continuously improving with the successive approval of LAM and ADV, which have allowed better control of viral replication and rescue of drug resistance. All studies have also emphasized the need for early treatment intervention in patients with decompensated cirrhosis.
Several studies have shown that despite efficient antiviral treatment, a biphasic survival pattern has been observed, with most deaths occurring within the first 6 months of treatment because of complications of liver failure.12 In multivariate modeling, elevated pretreatment serum bilirubin and creatinine levels as well as the presence of high HBV DNA levels before treatment were significantly associated with 6-month mortality; survival was independent of early treatment efficacy (ie, rapid virologic response). These observations led to the recommendation of early antiviral treatment followed by liver transplantation in those patients with a high risk of mortality despite viral load suppression, or long-term treatment in patients who can be stabilized with suppressive antiviral therapy (Fig. 1).
The recent approval of 5 nucleoside/tide analogs—entecavir, telbivudine, and tenofovir—is providing new hope for improved management of pretransplant and posttransplant hepatitis B patients.2 These new drugs should provide better options for safe and effective rescue therapy for patients with LAM-resistant strains and alternative first-line antiviral therapy with more rapid and potent antiviral activity and a lower rate of resistance for treatment-naive patients.
Tenofovir has been shown to inhibit replication of wild-type and LAM-resistant HBV more potently than ADV. Tenofovir is potentially nephrotoxic but has a better therapeutic ratio and may be superior to ADV in patients who need dose adjustments because of renal insufficiency. It can be used in combination with emtricitabine in a single pill to prevent antiviral drug resistance, as shown in HIV-infected patients. Entecavir is approved for the treatment of wild-type and LAM-resistant HBV. However, its activity against LAM-resistant HBV is lower than its activity against wild-type HBV, despite the use of a higher dose (1 mg of entecavir daily). These data indicate that entecavir is not an ideal rescue therapy for patients with LAM-resistant HBV. Telbivudine is more effective against wild-type HBV than LAM; it inhibits ADV-resistant mutants but not LAM-resistant strains. It has, however, a higher resistance rate than entecavir and tenofovir. Clinical trials are ongoing to determine the respective roles of all these new antivirals and the best treatment regimen in patients with decompensated cirrhosis.
In the last few years, the availability of the first oral anti-HBV agents has allowed us to stabilize most patients with decompensated cirrhosis for liver transplantation and to improve significantly the prophylaxis of HBV recurrence on the graft. The approval of the new generation of antivirals is opening new perspectives for finding the optimal antiviral treatment for patients with decompensated cirrhosis, preventing antiviral resistance, and decreasing the need for HBIG in the posttransplant setting. A combination of antivirals may be one of the future strategies for fulfilling these goals, and all these new developments are providing a clearer horizon for the management of these severely ill patients.