Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs

The goal of oral nucleos(t)ide analog (NA) therapy for chronic hepatitis B (CHB) is to suppress hepatitis B virus (HBV) replication in a sustained manner, preventing disease progression to decompensated cirrhosis and hepatocellular carcinoma (HCC) [1‐5]. However, the duration of oral NA treatment required once complete virologic suppression is achieved has not been conclusively established. Although loss of HBsAg is the ideal endpoint associated with sustained off-treatment virologic suppression [6], HBsAg is cleared in a minority of CHB patients after antiviral therapy; only 5.6–11% of patients treated with pegylated interferon alpha clear HBsAg [7, 8], and the probability of clearance is even lower with oral NA therapy [6, 9]. HBeAg loss and/or seroconversion has been widely used as a surrogate endpoint of CHB therapy, and several practice guidelines suggest that oral NA treatment may be stopped after 6–12 months of consolidation therapy following HBeAg seroconversion [4, 5, 10, 11]. However, the study of off-treatment virologic response (VR) has been somewhat neglected. Although previous reports indicate that HBeAg seroconversion may not be durable [12‐15], these data are from trials with lamivudine, a drug which is no longer recommended as initial therapy because of high resistance rates. Entecavir is widely used as a first-line therapy for CHB, but little is known about off-treatment VR. It is also yet to be elucidated whether re-treatment with the same oral NA can successfully re-induce complete VR.

The aims of this study were to assess off-treatment virologic relapse rates, identify predictive factors in CHB patients who achieved complete VR with NA therapy, particularly in those treated with entecavir, and to characterize the outcomes of antiviral therapy for off-treatment relapses.

One of the unresolved issues in the management of CHB is how long oral NA must be maintained once patients have achieved complete virologic suppression. Current American Association for the Study of Liver Diseases (AASLD) guidelines recommend at least 6 months of additional treatment after HBeAg seroconversion [5]. However, about a quarter of patients experience relapse within 2 years of completing 6 months of lamivudine consolidation [12‐15]; at 4 years, the relapse rate is increased to 82% after cessation of lamivudine [18]. In our study, about three quarters of CHB patients demonstrated off-treatment virologic relapse within 12 months of treatment termination. Although we used HBeAg loss rather than HBeAg seroconversion as a stopping criterion, subgroup analysis showed that the virologic relapse rates were not different between the seroconversion and HBeAg loss groups (Figure 1C; [13]). We believe that the high relapse rates in our study may be ascribed to different definitions of virologic relapse; previous studies used higher cut-off values of HBV DNA titer (10,000–100,000 copies/mL) whereas we used the 60 IU/mL (300 copies/mL) cut-off, determined by sensitive real-time PCR assays. Indeed, studies using similar cut-off values showed similar relapse rates in HBeAg-positive CHB [14, 19, 20]. These findings suggest that 6-month consolidation therapy is insufficient for preventing virologic relapse in HBeAg-positive CHB.

AASLD 2009 guidelines and European Association for the Study of the Liver (EASL) 2012 clinical practice guidelines do not recommend stopping NA treatment in HBeAg-negative CHB unless HBsAg is cleared [4, 5]. These recommendations are based on the observations that treatment duration of less than 1 year was universally associated with relapse [21, 22]. However, viral suppression may not have been complete at the time of treatment cessation in these studies as the cut-off for the definition of complete VR was relatively high (0.7 Meq/mL; 150,000 IU/mL). Indeed, more stringent stopping criteria with extended treatment duration resulted in up to 50% of remission rate in HBeAg-negative CHB [23, 24]. Asian-Pacific guidelines, conversely, state that treatment discontinuation can be considered after 12–24 months of consolidation therapy [11, 25]. We wanted to know the off-treatment remission rate after achieving complete viral suppression confirmed by a sensitive PCR method. Our data showed that 12-month consolidation therapy after serum HBV DNA loss was associated with high virologic relapse rates, similar to those of HBeAg-positive CHB with 6-month consolidation. Again, the high relapse rates in our study may be due to lower cut-off levels, determined by real-time quantitative PCR, compared with previous reports [23, 24].

Current guidelines recommend entecavir and tenoforvir as first-line drugs because of their high potency, high genetic barrier against resistance, and excellent long-term viral suppression [4, 5]. Patients in this study started oral antiviral therapy between 2004 and 2010; however, entecavir and tenofovir were not approved for the treatment of CHB in Korea until 2008 and 2013, respectively. Therefore, lamivudine was prescribed until 2008, after which entecavir was chosen as a first-line NA for the treatment of CHB, while tenoforvir was not available to these patients at any time. Although entecavir shows higher virologic suppression rates compared with lamivudine [26], off-treatment relapse was scarcely studied compared with lamivudine. Previous reports detailed relapse data after protocol-defined termination without consolidation therapy [19, 22, 26, 27]. We found that the off-treatment relapse rates were similar between entecavir and the less potent drug, lamivudine. Previous phase III clevudine trials showed delayed off-treatment virologic relapse [28, 29] but again, the off-treatment VR rate was similar. This result suggests that once complete virologic suppression is obtained, off-treatment remission rates are independent of the antiviral potency of the NA in question, and also suggests that the stopping criteria for entecavir should be as strict as those for less potent drugs. Because this study did not compare head-to-head off-treatment remission rates between entecavir and other NAs, further prospective studies with longer follow-up periods will be necessary to address this issue.

The univariate and multivariate logistic regression analyses showed that duration of NA therapy is an independent predictor of off-treatment sustained virologic remission in CHB. This finding is in line with previous studies of CHB patients treated with lamivudine [13‐15]. Considering the high off-treatment relapse rates in our study, 6 months of consolidation is insufficient in HBeAg-positive CHB patients, as recommended by the recent EASL guidelines [4]. However, the Kaplan–Meier analysis in our study did not show a significant difference in relapse rate according to treatment duration (<24 mo vs. >24 mo) in HBeAg-positive CHB, and consolidation of more than 12 months did not decrease relapse rates compared with a shorter consolidation period (data not shown). The reason that extension of consolidation failed to reduce virologic relapse in HBeAg-positive CHB is not clear at present, but our finding suggests that even longer consolidation may be necessary in this group. Off-treatment response is more difficult to predict in HBeAg-negative CHB because no surrogate markers are available, except for the rare event of HBsAg loss. We found that prolonged consolidation is more effective for induction of sustained virologic remission in HBeAg-negative CHB compared with HBeAg-positive disease. Thus, we suggest that duration of oral nucleos(t)ide therapy be no less than 2 years in HBeAg-negative CHB. Further prospective randomized controlled studies are needed, however, to determine the optimal duration of NA consolidation in CHB.

Because more than 60% of patients still experience virologic relapse after more than 2 years of NA therapy in HBeAg-negative CHB, current guidelines for long-term antiviral maintenance until HBsAg loss may be a safe approach, especially for patients with liver cirrhosis [4, 5]. However, because some patients show sustained off-treatment virologic remission in our study (10/54, 19%) and other reports [23, 24], cessation of oral NA might also be an clinical option in HBeAg-negative CHB patients with or without liver cirrhosis who show complete VR for more than 2 years [25] if significant adverse events can be prevented in relapsers. We closely monitored relapsers and NAs were resumed before biochemical relapse if HBV DNA increased over 2,000 IU/mL. Although about half of our study patients had liver cirrhosis, no hepatic decompensation was documented after virologic relapse. A similar study regarding the off-therapy durability of entecavir published recently reported that only one patient, who did not conform to the follow-up schedule, developed decompensation, which was successfully managed by a second course of entecavir treatment [30]. Thus, cessation of NAs may safely be tried in patients with cirrhosis on the condition of close monitoring.

There is no consensus on how to manage off-treatment HBV relapse. Our results revealed that about 10% of patients with off-treatment relapse failed to regain complete virologic suppression with the same NA regimen. Interestingly, all four patients with non-response to the initial NA regimen developed the rtM204I mutation during the course of secondary treatment. Therefore, drugs with high genetic barrier should be considered as a rescue therapy for off-treatment relapse in CHB, and early evaluation for genotypic resistance should be considered in these patients if the initial regimen shows inadequate response.

A relatively small sample size is the major limitation of our study. However, considering the current trend, which does not recommend early termination of NAs, results from larger prospective trials may not be readily available. In the meantime, our data may help when making clinical decisions where long-term maintenance of NAs is not feasible.

In summary, sensitive HBV DNA assays show high off-treatment VR rate in CHB patients who received consolidation therapy (6 and 12 months for HBeAg-positive and -negative CHB, respectively). Prolonged consolidation may reduce off-treatment relapse in HBeAg-negative CHB. Although most patients with virologic relapse regain complete virologic suppression with the same drug, some patients do not respond to re-treatment with the initial NA and develop genotypic resistance. Therefore, NA with a high genetic barrier should be considered as a rescue therapy for off-treatment relapse in CHB.