Low HBsAg Levels During Nucleotide Analog Therapy Brings Favorable Prognostic Outcomes

A new study showed patients with chronic hepatitis B who achieve low hepatitis B surface antigen levels (HBsAG) during nucleot(s)ide analog therapy have favorable long-term outcomes.¹ The research also suggested patients could safety discontinue the therapy, as low antigen levels were linked to a reduced risk of relapse.

A previous study demonstrated patients with hepatitis B who have low levels of HBsAG, such as 100 IU mL or 10 IU/mL when they stop taking nucleot(s)ide analog medications, tend to have better long-term health outcomes. Investigators conducted a retrospective study to evaluate the duration of nucleot(s)ide analog therapy and the factors linked to achieving these low HBsAg levels.² The team also assessed the relationship between HBsAg and hepatitis B core-related antigen (HBcrAg) levels at the time of nucleot(s)ide analog therapy discontinuation and later clinical outcomes.¹

“The novelty of this study is that we investigated the cumulative rates of achieving low HBsAg levels and factors associated with achieving these low HBsAg levels in CHB patients treated with [nucleot(s)ide analog],” wrote investigators, led by Takanori Suzuki, from the department of gastroenterology and metabolism at Nagoya City University Graduate School of Medical Sciences in Japan.

The study included 153 patients (median age: 45 years; 92 males) with chronic hepatitis B who started nucleot(s)ide analog therapy at Nagoya City Hospital between January 2004 and May 2024. All patients met the Japan Society of Hepatology Guidelines for the Management of HBV infection and initiated nucleot(s]ide analog therapy with HBV DNA levels ≥ 3.3 log IU/mL (medium 6.8 log IU/mL).

Participants were followed up for > 1 year, approximately every 3 months during their nucleot(s)ide analog therapy and every 1 – 3 months after nucleot(s)ide analog discontinuation until their last visit. The median duration from the start of therapy to the last observation was 89 months (IQR, 43 – 150).

Most participants had the genotype C (n = 118), followed by B (n = 15), A (n = 10), and D (n = 2), with 8 patients having unknown genotypes. Nucleot(s)ide analog medicines received included entecavir (n = 87), tenofovir alafenamide (n = 30), tenofovir disoproxil fumarate (n = 24), and lamivudine (n = 12)

Low HBsAg was defined as either < 100, < 10, or < .05 IU/ML. HBV DNA > 2000 IU/mL was considered a virological response, and a virological response accompanied by ALT levels > 2 times the upper limit was normal (40 U/L) was considered a clinical relapse.

The team found cumulative rates of achieving low HBsAg levels at 5 and 10 years following nucleot(s)ide analog therapy were 19% and 29.2% for HBsAg < 100 IU/mL, 13.8% and 17.6% for HBsAg < 10 IU/mL, and 9.5% and 13.5% for HBsAg < .05 IU/mL, respectively.

“In our study, the cumulative incidence rates for achieving HBsAg <100 IU/mL continued to rise beyond 10 years of NA therapy initiation,” investigators wrote.

Furthermore, hepatitis B virus genotypes, excluding genotype C (hazard ratio [HR], 3.47; P < .001), and an HBsAg level < 1000 IU/mL at the start of nucleot(s)ide analog therapy (HR, 2.49; P = .008), were significantly associated with achieving HBsAg levels < 100 IU/mL.

The threshold of HBcrAg for stopping nucleot(s)ide therapy was set at 3 log U/mL, and the study showed a combination of HBcrAg and HBsAg levels at stopping nucleot(s)ide medications was a useful indicator of the decision to the discontinue nucleot(s)ide therapy.

A total of 27 patients discontinued nucleot(s)ide therapy. Among these patients, 5 patients with HBsAg levels < 100 IU/mL and HBcrAg levels < 3 U/mL did not have a virological relapse.

“It may be feasible to consider discontinuing NA therapy based on these HBsAg and HBcrAg cut-off levels,” wrote investigators. “Future studies with a large number of patients will need to examine whether the threshold of HBcrAg <2.1–3.0 log U/mL at cessation of NA is useful for predicting subsequent VR or HBsAgSC.”

Investigators wrote the findings were limited by an insufficient duration of nucleot(s)ide analog therapy and how future studies need longer observational periods.

“Our findings suggest that [nucleot(s)ide analog] discontinuation could be considered based on HBsAg and HBcrAg levels during treatment,” investigators concluded. “Further prospective studies are needed to confirm these results.”

References

1. ^{Suzuki T, Matsuura K, Inoue T, Kawamura H, Fujiwara K, Kataoka H, Tanaka Y. Factors associated with low hepatitis B surface antigen levels in chronic hepatitis B patients treated with nucleot(s)ide analogs. Hepatol Res. 2024 Oct 26. doi: 10.1111/hepr.14129. Epub ahead of print. PMID: 39460959.}
2. ^{Sonneveld MJ, Park JY, Kaewdech A, Seto WK, Tanaka Y, Carey I, Papatheodoridi M, van Bömmel F, Berg T, Zoulim F, Ahn SH, Dalekos GN, Erler NS, Höner Zu Siederdissen C, Wedemeyer H, Cornberg M, Yuen MF, Agarwal K, Boonstra A, Buti M, Piratvisuth T, Papatheodoridis G, Maasoumy B; CREATE Study Group. Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE). Clin Gastroenterol Hepatol. 2022 Apr;20(4):e784-e793. doi: 10.1016/j.cgh.2020.12.005. Epub 2020 Dec 10. PMID: 33309804.}