Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B

Abstract

Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on-treatment patient-months. The frequency was estimated as 3.2 per 100 person-years (95% CI 2.2-4.7). Lamivudine (LAM)-treated patients demonstrated the highest frequency (4.9/100 person-years, 95% CI 3.2-7.4). Twenty (74%) of 27 on-therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post-treatment follow-up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on-therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease.

Hepatitis B flares in chronic hepatitis B: Pathogenesis, natural course, and management

“…The temporal relationship between HBV DNA and ALT levels is similar to that during spontaneous hepatitis B flares [33]. The off-therapy flares are also similar to spontaneous hepatitis flares in the spectrum of clinical presentation that hepatic decompensation and fatality may occur if not retreated in time [72][73][74][75]. Hepatitis flares may occur after cessation of Nuc therapy in the majority of the patients who remained HBeAgpositive [55,75].…”

“…The off-therapy flares are also similar to spontaneous hepatitis flares in the spectrum of clinical presentation that hepatic decompensation and fatality may occur if not retreated in time [72][73][74][75]. Hepatitis flares may occur after cessation of Nuc therapy in the majority of the patients who remained HBeAgpositive [55,75]. Even in patients who underwent HBeAg seroconversion during Nuc therapy, hepatitis flares with or without HBeAg reversion may occur, especially in older patients, those infected with genotype C HBV, and if the consolidation duration of therapy is not long enough [76][77][78].…”

Long-term outcomes after nucleos(t)ide analogues discontinuation in chronic hepatitis B patients with HBeAg-negative

“…This suggests that the safety risk of discontinuation is acceptable. In a recent study, the frequency of NUCs withdrawal flares was estimated as 3.2 per 100 person-years in 17 (11%) of 149 therapy discontinuations [14]. …”

Close Monitoring of Hepatitis B Surface Antigen Levels Helps Classify Flares During Peginterferon Therapy and Predicts Treatment Response

“…However, flares that occur during or after discontinuation of nucleo(s)tide analogues therapy hardly ever lead to virological remission and may result in hepatic decompensation [19, 20]. Flares that occur after nucleo(s)tide analogue discontinuation do not trigger an adequate immune response [10], suggesting these flares are different from flares that induce disease remission in untreated patients.…”

“…This study shows that these virus-induced flares occur more frequently in patients where PC and BCP mutants are present before PEG-IFN initiation. Because these mutants have a reduced production of HBeAg, they are less susceptible to a PEG-IFN–induced immune response against HBeAg, which could result in positive selection and a subsequent virus-induced flare not unlike those observed in patients with viral breakthrough during nucleo(s)tide analogue–based therapy [19]. A relationship between type of flare and the host immune system should also be investigated.…”