Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients

Abstract

The optimal duration of nucelos(t)ide analog (Nuc) treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B virus (HBV) infection is unknown. The Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend that treatment can be discontinued if undetectable HBV-DNA has been documented on three occasions 6 months apart. This study aimed to test this stopping rule in HBeAgnegative chronic hepatitis B (CHB) patients treated with entecavir (ETV). Ninety-five patients (39 cirrhosis) were treated with ETV for a median of 721 (395-1,762) days before stopping therapy and were then monitored with serum HBV DNA and alanine aminotransferase (ALT) at least every 3 months. Within 1 year after stopping ETV therapy, "clinical relapse" (an episode of ALT elevation >2 3 upper limit of normal plus HBV-DNA >2,000 IU/mL) occurred in 43 (45.3%) of the 95 patients. Of the 39 cirrhosis patients, 17 (43.6%) relapsed and one (2.6%) developed decompensation. The median duration until relapse was 230 days (74.4% >6 months). Logistic regression analysis showed that baseline HBV-DNA 2 3 10 5 IU/mL was the only significant independent factor for sustained response. The 1-year relapse rate was 29% in patients with a baseline HBV DNA 2 3 10 5 IU/mL versus 53% in those with HBV DNA >2 3 10 5 IU/mL (P 5 0.027). For the latter, consolidation therapy >64 weeks reduced the relapse rate to 33.3% in patients without cirrhosis. Conclusion: With an overall 1-year relapse rate of 45% and 29% in those with a baseline serum HBV DNA 2 3 10 5 IU/mL, the APASL stopping rule for HBeAg-negative CHB patients with proper off-therapy monitoring is adequate even in patients with cirrhosis. Consolidation therapy >64 weeks seems more appropriate for those with higher baseline HBV DNA.

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…Since overt hepatitis flares and life-threatening episodes have been rarely reported in patients with pre-existing cirrhosis who discontinue NAs, 98 treatment discontinuation is currently discouraged in patients with cirrhosis. Moreover, NAs may be discontinued only in patients who can be followed closely with ALT and HBV DNA determinations at least during the first year following NAs cessation.…”

Oral Antiviral Therapy for Chronic Hepatitis B Virus Infection: Is Continuous Treatment Needed?

“…However, a recent study followed 95 patients with HBeAg-negative chronic HBV infection who took entecavir with at least 3 consecutive HBV DNA negative 6 months apart by PCR, who terminated treatment as suggested by APASL guidelines. Within 12 months of stopping treatment, 55 patients (58%) showed virological relapse and 45% showed clinical relapse [22]. This suggests that the virological relapse rate is still high even when following APASL guidelines.…”

“…As the above studies show, the post-treatment relapse rate appears to be approximately 50%, regardless of the suppressive ability of antiviral treatment or the likelihood of drug resistance [16,[18][19][20]22,[24][25][26]. Therefore, it may be important to apply APASL guidelines for stopping antiviral treatments to patients who find long-term treatment financially burdensome or who are experiencing side effects associated with long-term usage of drugs or treatments.…”

Virus and Host Testing to Manage Chronic Hepatitis B

“…Virological breakthrough, defined as a 10-fold increase in HBV DNA during NUC treatment, is the first signal of drug resistance or poor drug adherence. Although the Asian-Pacific guideline recommends stopping NUCs among HBeAg-negative patients who have undetectable HBV DNA for at least 3 times at 6 months apart [6], 43%-91% of patients developed virological relapse (HBV DNA >2000 IU/mL) and 45% developed clinical relapse (HBV DNA >2000 IU/mL and ALT >2 times the ULN) within 1 year after stopping treatment [29,59,60]. It is therefore better to continue NUC treatment until HBsAg seroclearance in HBeAgnegative patients [5,7].…”