Although LAM is not recommended as first line therapy for CHB in the American Association for Study of Liver Disease (AASLD) CHB guidelines, and the European Association for Study of Liver (EASL) CHB guidelines, which recommend oral nucleosides or nucleotides with high genetic barrier (entecavir and tenofovir) as first line monotherapy, LAM is still widely used in Asia due to cost constraints. Thus, it is necessary for us to concern about the re-treatment issues of patients with viral relapse after discontinuation of LAM monotherapy. Unfortunately, the retreatment options for viral relapse are still in doubt. In clinical practice, a variety of retreatment strategies have been applied, including back to their original drug, switch to another drugs, or two or more drugs in combination.
Theoretically, if there were no evidence of antiviral resistance of original agent, it seemed reasonable to back to their original drug for retreatment. However, this hypothesis was recently questioned by clinicians. Evidence already had showed that HBV exists in form of quasi-species in patients with chronic hepatitis B, and because of the sensitivity and specificity limitation of detection, drug-resistance strains sometimes could not be detected in time, especially when its proportion was less than 20% in the pool of viral quasi-species[16, 17]. Thus, it is not difficult to conclude that before the drug-resistance strains reach a high number, they may not be detected in patients with viral relapse after cessation of antiviral treatment. But it is worth mentioning that those inferior strains would be easily developed to predominant strains with antiviral resistance by positive selection of antiviral agents [18, 19]. Taking into account of the above reasons, when viral relapse occurred after cessation of treatment, switch to agents with high genetic barrier or combination of two or more agents without cross-resistance may be good options for preventing the occurrence of drug resistance[9, 20].
In this study, we explored and compared retreatment options for chronic hepatitis B patients with viral relapse after cessation of LAM. After 1 year retreatment, the proportion of undetectable HBV DNA was achieved in 80% of patients receiving LAM plus ADV as compared to 42.9% of patients receiving LAM alone. Moreover, higher proportion of ALT normalization and HBeAg seroconversion were also reached in LAM plus ADV retreatment group. Several other studies also had reported that the combination of LAM and ADV could lead to effective viral suppression in most cases after development of viral breakthrough due to LAM monotherapy[21, 22]; and patients receiving LAM plus ADV combination therapy have a lower risk of developing genotypic resistance to ADV. In our study, patients receiving combination therapy of LAM and ADV were well tolerated, and no viral breakthrough was reported and no LAM- or ADV-associated resistant strains were detected. In contrast, among 28 patients receiving LAM alone, five patients experienced a viral breakthrough and LAM-associated resistant strains were detected in all of them. Those findings gave us another hint that the combination of LAM plus ADV was associated with lower antiviral resistance compared with LAM alone. In fact, for some special populations with chronic hepatitis B, the combination of agents without cross-resistance had been clearly put forward by authoritative guidelines[4, 13], and data from many clinical observational trials also suggested combination therapy would bring more benefits to nucleosides or nucleotides-refractory CHB patients.
At present, majority of clinical studies on LAM plus ADV combination therapy were for HBeAg-negative patients, and few studies on HBeAg-positive patients reported the combination of these agents had no synergistic on HBeAg seroconversion. But in our study, among 25 patients receiving combination therapy of LAM plus ADV, we delighted to found that 9 patients obtained HBeAg loss and 7 patients obtained HBeAg seroconversion, which were significant higher to that of patients receiving LAM alone. However, because of the limited sample size and short observation time, we currently cannot conclude that the combination of ADV plus LAM could increase the rate of HBeAg seroconversion as compared to single nucleoside or nucleotide analogue.
In conclusion, the current study showed that CHB patients with viral relapse after cessation of LAM retreated by LAM plus ADV exhibited significantly greater virological, biochemical and serological responses compared with LAM alone. These findings indicated that combination of LAM plus ADV would be a good option for the retreatment of CHB patients with viral relapse after cessation of LAM.