End-of-therapy hepatitis B surface antigen (HBsAg) levels, duration of consolidation therapy, and cirrhosis status are key determinants of relapse in patients with chronic hepatitis B (CHB) who discontinue nucleos(t)ide analogue (NA) therapy, according to study results published in Clinical Infectious Diseases.
In this retrospective study, researchers analyzed data from 488 patients with CHB to identify predictors of relapse in those who discontinued NAs and to determine if existing rules for stopping NA therapy can be improved. Virologic relapse was defined as serum hepatitis B virus DNA with a value of at least 2000 IU/mL after stopping treatment, and clinical relapse constituted virologic relapse along with alanine aminotransferase greater than 2 times the upper limit of normal. Researchers used the Asian Pacific Association for the Study of the Liver, European Association for the Study of the Liver, and American Association for the Study of Liver Diseases guidelines to assess whether NA treatment was stopped.
According to the Asian Pacific Association for the Study of the guidelines, 40% of patients (n=195) stopped antiviral therapy. Once NA therapy was stopped, the median follow-up period was 73.3 months. Follow-up at 1, 2, 5, and 10 year occurred in 93.0% (n=454), 84.2% (n=411), 59.0% (n=288), and 19.7% (n=96) of patients, respectively. A comparison of the 1, 2, 5, and 10-year cumulative rates of virologic relapse (54.1%, 65.0%, 73.5%, and 76.1%, respectively) and clinical relapse (33.2%, 45.0%, 54.7%, and 56.6%, respectively) showed a steep rise until year 2. Thus, researchers further analyzed the 2-year virologic and clinical relapse data.
In hepatitis B e antigen (HBeAg)-positive patients (n=262), end-of-therapy HBsAg levels (hazard ratio [HR], 1.93; 95% CI, 1.42-2.61) and consolidation duration of therapy of more than 2 years (HR, 0.31; 95% CI, 0.17-0.58) were independent predictors of virologic relapse; only consolidation duration of therapy of more than 2 years (HR, 0.49; 95% CI, 0.26-0.93) was an independent predictor of clinical relapse. Regardless of stopping rules, virologic relapse rate was significantly lower in patients attaining HBsAg levels less than or equal to 560 IU/mL than in those not attaining this level (with stopping rule, P =.007; without stopping rule, P =.027).
For HBeAg-negative patients (n=226), only HBsAg level was an independent predictor of both virologic (HR, 1.61; 95% CI, 1.24-2.11) and clinical relapse (HR, 1.16; 95% CI, 1.10-2.36). The virologic relapse rate was significantly lower when HBsAg levels was less than or equal to 800 IU/mL than in those not attaining this level when not meeting the stopping rule (P =.031) and only marginal when meeting the stopping rule (P =.096).
However, despite HBsAg levels of at least 800 IU/mL in HBeAg-negative patients, virologic relapse rates were significantly higher in patients with cirrhosis than in those without cirrhosis (P =.026). Cirrhosis was the only predictor of 2-year virologic relapse (P =.031). This finding supports the specific recommendations by the European Association for the Study of the Liver and American Association for the Study of Liver Diseases guidelines for continuing antiviral therapy in HBeAg-negative patients with cirrhosis.
Combining low HBsAg levels, consolidation therapy for more than 2 years, and ensuring that patients with cirrhosis stay on NA therapy even with low HBsAg levels not only significantly reduced post-treatment relapse but also improved performance of the stopping rules. As such, these “parameters should be added to the components of the NA stopping rules,” the researchers concluded.
Since this study only included patients from Korea mostly treated with lamivudine and entecavir, further studies are necessary to validate findings for different ethnicities and patients treated with tenofovir. In addition, researchers will need to further evaluate the optimal cut-off values of HBsAg levels.
Song DS, Jang JW, Yoo SH, et al. Improving the prediction of relapse after nucleos(t)ide analogue discontinuation in patients with chronic hepatitis B. Clin Infect Dis. Published online January 8, 2021. doi:10.1093/cid/ciab007