1University of Michigan Ann Arbor MI. 2Hospices Civils de Lyon and INSERM Unit 1052 Lyon France. 3Kings College Hospital University College London Medical School London United Kingdom. 4Chinese University of Hong Kong Hong Kong S.A.R. 5Vall d'Hebron Hospital Barcelona Spain. 6National Institutes of Health Bethesda MD. 7Gilead Sciences, Inc. Foster City CA. 8Victorian Infectious Diseases Reference Laboratory Melbourne Australia. 9Hôpital Beaujon Université de Paris Diderot Clichy France.
In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg-IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti-HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg-IFN-containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative-qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile [Q]1, Q3, 46, 135) weeks follow-up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti-HBs seroconversion was observed during follow-up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti-HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off-treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). Conclusion: HBsAg loss after NUC or Peg-IFN-containing regimens was durable in 82% of patients with CHB. Anti-HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.
Jacobson, I. (2020) Lok AS, Zoulim F, Dusheiko G et al. Durability of hepatitis B surface antigen loss with nucleotide analogue and peginterferon therapy in patients with chronic hepatitis B. Hepatology Communications. 2020;4:8-20.
Hepatitis B surface antigen (HBsAg) clearance occurs all too infrequently in patients treated with antiviral therapy for chronic hepatitis B, accounting for the need for indefinite therapy in the most patients and fueling enormous interest in the development of new treatments that can effect what has come to be called a “functional cure.” Nevertheless, clinicians do sometimes encounter HBsAg clearance, often years after oral nucleos(t)ide therapy has been started, raising questions of practical import: (1) What is the risk of seroconversion after treatment is stopped? ? (2) Does the appearance of anti-HBs, representing “seroconversion”, affect the incidence of HBsAg recurrence and should it have an impact on the duration of consolidation therapy? (3) Is the risk of seroconversion affected by the duration of therapy after HBsAg loss has been noted, and what should be the duration of “consolidation” therapy?
The present study addresses all these questions by analyzing outcomes from the two pivotal trials of tenofovir disiproxil fumurate (TDF) in HBeAg-positive and HBeAg-negative patients treated for as long as 10 years, and a third trial of peginterferon monotherapy for one year or two regimens of combination therapy given for one year with different timing of TDF initiation. Of 1381 adult patients, 55 (4%) had confirmed HBsAg loss, defined as two or more consecutive HBsAg-negative results with at least one repeat result after end of treatment. Forty-seven of the 55 patients who lost HBsAg did so while still on treatment, 8 after discontinuation. Forty-three of the 55 patients who lost HBsAg (78%) had anti-HBs seroconversion, with similar rates of seroconversion whether or not peginterferon had been used. Of the 55 patients with confirmed HBsAg loss, 45(82%) had durable HBsAg loss through a median 96 weeks after initial HBsAg loss, while 10 (18%) had HBsAg reversion at some point after discontinuation of treatment, usually (80%) within 24 weeks of the end of treatment. Patients with anti-HBs seroconversion had a higher rate of durable HBsAg loss (86%) than those without anti-HBs seroconversion (67%), but this difference was not statistically significant. The authors could not identify a significant relationship between HBsAg loss and the duration of consolidation therapy, but referenced a study by Yip et al (J Hepatology 2017) suggesting that HBsAg seroconversion is less frequent with > 12 months of consolidation therapy than 6-12 months.
This large study puts a quantitative face on the frequency of HBsAg loss with long term antiviral therapy. Although over 70% of the patients across the 3 studies were HBeAg-positive at baseline, the paper does not distinguish between HBsAg clearance rates in patients who started therapy as HBeAg-posiitve versus HBeAg-negative. Although warranting further study, anti-HBs seroconversion does not appear to be necessary for clinicians to have confidence that they can stop therapy in patients who clear HBsAg. Continuation of treatment for 6-12 months of treatment after the first HBsAg negative test appears to be advisable. Further studies would help to determine whether longer periods of consolidation therapy are desirable for selected patients, and whether patients initially HBeAg-positive who clear HBeAg and later clear HBsAg on treatment can be approached differently from those who started treatment in the HBeAg-negative state.