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Patients with advanced liver disease and cirrhosis are at an increased risk of developing HCC and death, and therefore, effective therapy is crucial in this patient population as noted by guidelines from the AASLD and the EASL. It is essential to note that the risk of HCC is still considerable, approaching 20% to 25% after 5 years of treatment, in several studies of patients with (decompensated) cirrhosis.[16,19,20] HCC risk prediction models developed for untreated patients may also be used among those treated with entecavir or tenofovir DF,[190,191] although the discriminatory performance is limited particularly in white patients.
Although treatment with peginterferon can be effective in patients with advanced fibrosis and compensated cirrhosis, it is contraindicated in patients with decompensated liver disease because of the risk of worsening liver disease and infectious complications.[3,4,192] Nucleos(t)ide analogue treatment is, therefore, the best option in this patient population, and use of tenofovir DF or entecavir, agents with high potency and low risk of resistance, is recommended by the AASLD and the EASL. AASLD guidelines further note that tenofovir AF would be a reasonable choice in this population despite lack of data when adverse events from tenofovir DF prevent its use and entecavir is not an option.
In a pivotal study, prolonged lamivudine treatment was shown to reduce the probability of disease progression in patients with advanced liver disease, although the risk of antiviral resistance was substantial (~ 49%). Lamivudine therapy was also shown to improve hepatic function in a subset of these patients.[145,193] Of importance, development of resistance was associated with a reduction in clinical benefits associated with treatment, illustrating the importance of using agents with a high genetic barrier to resistance, and arguing against the use of lamivudine in this population.[145,194]
Adefovir has been extensively used in patients with advanced liver disease with low rates of resistance (2% at 144 weeks of follow-up), and is generally safe, despite the risk of nephrotoxicity. Nevertheless, the antiviral potency of adefovir is limited, and the risk of nephrotoxicity may be especially important in patients with decompensated cirrhosis.
Entecavir treatment is safe and effective in patients with advanced fibrosis or cirrhosis and may reverse cirrhosis in a subset of patients.[28,29,198] Long-term entecavir treatment of patients with cirrhosis is associated with excellent survival, although HCC risk remains considerable. In a direct comparison, prolonged treatment with entecavir had superior virologic efficacy compared with adefovir in 191 decompensated patients (Child-Turcotte-Pugh ≥ 7) with a similar safety profile. Indeed, 57% of subjects in the entecavir arm vs only 20% of subjects in the adefovir arm achieved HBV DNA < 57 IU/mL at Week 48 of therapy (P < .0001). Treatment with either agent resulted in improvement or stabilization of a patient’s Child-Turcotte-Pugh status.[197,199] Notably, these data have led to an expansion of the approved indication of entecavir to specifically include its use in patients with decompensated cirrhosis. In an investigator-initiated cohort study, viral suppression with entecavir was shown to reduce the incidence of disease progression (decompensation, HCC, death) among patients with cirrhosis.[17,200] HCC risk remains above that observed for patients with inactive disease despite antiviral suppression.[15,18] HCC occurrence during entecavir therapy may be predicted using established prediction models for nontreated patients such as the REACH-B calculator or, for white patients, using the PAGE-B predictor.
Entecavir resistance does occur in patients with resistance to lamivudine, and given the risks associated with viral breakthrough in decompensated patients, entecavir monotherapy may not be optimal in patients with previous lamivudine failure. Several case series have also shown the potential risk of lactic acidosis in entecavir-treated patients with severely impaired hepatic function.[92,197,202] Of note, the risk may not be specific to entecavir. All reported cases had Model for End-Stage Liver Disease scores of ≥ 21. Lactic acidosis was self-limiting or resolved after entecavir discontinuation in the majority of cases, although 1 fatality was reported.
Tenofovir DF, whether alone or in combination with emtricitabine, results in potent viral suppression in patients with decompensated liver disease, and has a similar safety profile to entecavir. After 48 weeks of treatment, HBV DNA was < 69 IU/mL in 70.5% of patients treated with tenofovir DF and in 87.8% of patients treated with emtricitabine/tenofovir DF. Long-term tenofovir DF therapy through 5 years was shown to reduce fibrosis and may even reverse cirrhosis in a subset of patients. Long-term tenofovir DF treatment of patients with cirrhosis is associated with excellent survival, although HCC risk remains considerable. However, the clinical benefits of combination therapy are currently unclear. It is also important to note that the risk of nephrotoxicity with tenofovir DF is unknown but may be a greater concern in patients with decompensated liver disease. HCC risk remains above that observed for patients with inactive disease despite antiviral suppression.[16,18] HCC occurrence during tenofovir DF therapy may be predicted using established prediction models for untreated patients such as the REACH-B calculator or, for white patients, using the PAGE-B predictor.