The present study indicates that both adefovir dipivoxil monotherapy and adefovir dipivoxil/lamivudine combination therapy for 24 weeks resulted in significant virologic and clinical improvements in patients with decompensated liver disease and lamivudine-resistant HBV, who were not candidates for liver transplantation. Both therapies led to marked and rapid suppression of viral replication. At week 24, 83% of adefovir dipivoxil monotherapy group and 86% of combination therapy group had undetectable HBV DNA level. ALT levels normalized in 78% of adefovir dipivoxil group and 82% of adefovir dipivoxil/lamivudine group at week 24. 72% and 64% of each group, respectively, had improvement in liver function, as evidenced by a ≥2 point improvement in CPT score. Furthermore, 22% and 28% of each group achieved HBeAg loss, while HBeAg seroconversion occurred in 17% and 21% respectively at week 24. The rate of HBeAg loss or HBeAg seroconversion in our study is little bit higher than those achieved in patients with compensated liver disease and lamivudine-resistant HBV, in which only 16% of adefovir dipivoxil group and 17% of adefovir dipivoxil/lamivudine group were HBeAg negative and 11% and 6% of each group achieved HBeAg seroconversion at week 48 (21
). These findings may be related to the high baseline ALT levels of decompensated patients in our study, which is suggested in previous studies showing that chronic hepatitis B patients with higher pretreatment ALT levels have significantly enhanced HBeAg seroconversion rates during lamivudine treatment (27
Our results of adefovir dipivoxil/lamivudine combination therapy are in agreement with the findings of other uncontrolled studies in which the addition of adefovir dipivoxil to lamivudine treatment were evaluated in patients with decompensated chronic hepatitis B resistant to lamivudine and in pre- and post-liver transplantation patients with active liver disease due to lamivudine-resistant HBV respectively (22
). Moreover, in the present controlled study, adefovir dipivoxil monotherapy was as effective as adefovir dipivoxil/lamivudine combination in suppressing viral replication. These findings suggest that the continuation of lamivudine has no additional or synergistic effect over adefovir dipivoxil monotherapy in these patients, which are similar to the findings of the study performed in patients with compensated chronic hepatitis B and lamivudine-resistant HBV (21
). Because wild-type HBV emerges rapidly over HBV mutants after the discontinuation of lamivudine or a switch to adefovir dipivoxil monotherapy, the virologic responses observed in adefovir dipivoxil monotherapy group in our study support the findings of previous studies that adefovir dipivoxil is active against both wild-type and lamivudine-resistant HBV (19
In patients with chronic hepatitis B with lamivudine-resistant HBV, it is reported that about 16% of patients experience ALT flares after the withdrawal of lamivudine by reversion of wild-type HBV and 5% of patients with ALT flare experience severe acute exacerbation of chronic hepatitis B (29
). In the previous study of compensated patients with lamivudine-resistant chronic hepatitis B, about one-third of patients receiving the adefovir dipivoxil monotherapy experienced ALT flares within 12 weeks. However, these ALT flares were not accompanied by concurrent elevations of HBV DNA levels and/or signs of reduced hepatic function, or even associated with reversion to wild-type HBV (21
). In the present study, only one patient receiving adefovir monotherapy had higher ALT level than the baseline at week 24, and undetectable HBV DNA level and improved CTP score. However, because the number of patients receiving adefovir dipivoxil monotherapy was relatively small and laboratory data were recorded every 8 weeks, it is possible that the ALT flares within the eight-week period might not be detected in our study.
Although adefovir dipivoxil was effective in improving liver function in our patients, approximately 28% of adefovir dipivoxil monotherapy group and 36% of combination therapy group failed to show significant clinical responses, as evidenced by the improvement of CPT scores ≥2 point, despite the overall virologic and biochemical improvement. These observations could result from the differences in the severity of pre-existing liver damage rather than the differences in virologic response, indicating that there may be a point in the natural history of decompensated HBV infection after when the application of antiviral therapy may be of limited benefit.
In the present study, CPT score improvement of ≥2 point was significantly associated with higher baseline ALT levels. Furthermore there was a significant correlation between the baseline ALT levels and the improvement of CPT or MELD score. This suggests that the hepatic function is more likely to be reversible in decompensated patients with higher necroinflammatory activity resulting from active viral replication. Thus, the effective suppression of the viral load by adefovir dipivoxil may result in a decrease of the necroinflammatory activity of the liver and eventually lead to clinical improvement.
Adefovir dipivoxil was generally well-tolerated during the 24-week treatment period in the current study, as shown in other studies (22
). No patient discontinued adefovir dipivoxil due to drug-related adverse events. Furthermore, there was no development of nephrotoxicity due to adefovir dipivoxil in our patients with decompensated liver disease and normal renal function.
It can be argued that this study does not prove the efficacy of adefovir dipivoxil because we did not include a control group with lamivudine monotherapy matched for the severity of hepatic decompensation due to lamivudine-resistant HBV. However, considering the current knowledge of the poor prognosis of decompensated cirrhosis and diminished clinical and virologic response of continued lamivudine monotherapy in patients with YMDD mutant HBV (4
), such an approach would raise critical ethical concerns especially in patients with decompensated liver function due to lamivudine-resistant HBV.
Our study has other limitations. First, the treatment period was relatively short for only 24 weeks. However, previous experiences with lamivudine therapy for decompensated HBV-cirrhosis have suggested that six-month survival rates with antiviral treatment might be sufficient to predict substantially longer survival rates (6
). Second, because patients were not randomly assigned into two groups, there were slight differences in baseline characteristics such as MELD score between the two groups. However, the differences were not statistically significant. Finally, HBV polymerase gene mutation within the YMDD motif was not performed in all patients.
In summary, the current study shows that a 24-week course of adefovir dipivoxil alone or in combination with lamivudine results in significant suppression of HBV replication, normalisation of ALT levels, HBeAg loss or seroconversion, and overall improvement in CPT and MELD score without any significant treatment-related adverse events in decompensated patients with lamivudine-resistant HBV. The virologic, biochemical and clinical responses of the two adefovir dipivoxil containing regimens seems to be similar suggesting that continuation of lamivudine may not confer any further benefit over adefovir dipivoxil monotherapy in these patients. A further study is warranted to confirm the long term effect and safety of adefovir dipivoxil monotherapy in patients with lamivudine-resistant decompensated chronic hepatitis B.