Is stopping long-term nucleotide analogue treatment beneficial in chronic HBV?
A subgroup of patients with HBeAg-negative chronic hepatitis B virus (HBV) infection who ceased their long-term nucleotide analogue treatment maintained virological suppression, pointing to a group of patients who may be suitable for treatment cessation, according to a recent study.
The study cohort comprised 124 adults age 18–69 years from the GS-US-174-0102 and GS-US-174-0103* trials who had completed ≥8 years of treatment with nucleotide analogues**, were HBsAg-positive with HBV DNA concentrations <29 IU/mL, and were enrolled in a treatment-free follow-up (TFFU) phase for 24 weeks.
Of these, 106 were HBeAg-negative and 18 were HBeAg-positive, of whom 63 and seven completed the 24-week follow-up, respectively. Successful therapy cessation was defined as HBV DNA <2000 IU/mL, HBV DNA <29 IU/mL, alanine aminotransferase (ALT) concentrations below the upper limit of normal (ULN), and HBsAg loss at week 24.
Among the patients who were HBeAg-negative, five patients experienced HBsAg loss or seroclearance (functional cure), 42 patients had HBV DNA <2000 IU/mL, and 43 patients had below ULN concentrations of ALT at week 24. [Lancet Gastroenterol Hepatol 2019;4:296-304]
“These findings appear to be in accordance with current guidance that discontinuation of nucleotide analogue therapy should be considered only in selected HBeAg-negative patients who have achieved stable HBeAg seroconversion while on therapy and in whom close monitoring after therapy can be guaranteed,” said the researchers.
Among patients who were HBeAg-positive, at week 24, none experienced HBsAg loss or had HBV DNA <2000 IU/mL, while one patient had ALT concentrations below ULN.
Thirty-two patients (26 percent) experienced an adverse event (AE), 12 and 20 TFFU completers and non-completers, respectively. Five patients experienced serious AEs, specifically increase in ALT concentrations (n=2), hepatic flare (n=2), and lipase increase (n=1).
Thirty-eight patients (31 percent) experienced grade ≥3 laboratory abnormalities, chiefly increases in ALT (n=36). However, there were no signs of hepatic decompensation among those with ALT elevations and no deaths during the TFFU phase. Both HBV DNA and ALT levels fluctuated following treatment discontinuation.
Patients aged <40 years (compared with ≥40 years) at TFFU baseline had a lower likelihood of achieving HBV DNA <2000 IU/mL at 24 weeks after TFFU initiation (odds ratio [OR], 0.22; p=0.02), though the small number of patients aged <40 years precludes any conclusion from being drawn from this association.
HBV DNA concentration at treatment initiation was a predictor of HBV DNA <2000 IU/mL (OR, 0.67; p=0.04, respectively) and HBV DNA <29 IU/mL (OR, 0.60; p=0.02 per 1 log10 IU/mL increase) at 24 weeks after TFFU initiation. Asian race (OR, 3.60; p=0.04) and age <40 years (OR, 0.27; p=0.04) were significant predictors of ALT <ULN at 24 weeks.
Despite the tolerable safety profile while off treatment, the researchers recommended stringent follow up in order to identify ALT flares that could be linked to liver failure, and subsequent restart of treatment. However, they also pointed out that ALT flares could be a sign of HBsAg loss which treatment re-initiation could hinder.
“Not enough is known about this mechanism to provide clinical guidance on when to restart therapy and when to withhold it to increase the chance of achieving HBsAg loss,” they said, highlighting this as potential avenue for research.
More research is also needed to determine which patients would benefit from treatment cessation, said the researchers.
“[I]t is important to understand whether the patient would have a good chance of maintaining off-treatment response and low risk of fatal outcome before making the decision to stop nucleos(t)ide analogues,” said Drs Henry Chan, Grace Wong, and Vincent Wong from The Chinese University of Hong Kong, Hong Kong, in a commentary. [Lancet Gastroenterol Hepatol 2019;4:260-262]