Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B

Rinker, F.; Zimmer, C.; Siederdissen, Christoph Höner zu; Manns, Michael P.; Kraft, Anke; Wedemeyer, Heiner; Björkström, Niklas K.; Cornberg, Markus

doi:10.1016/j.jhep.2018.05.004

Cited by 104 publications

(111 citation statements)

References 29 publications

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“…In the face of acute hepatitis flare, a delayed retreatment may fail to abort severe exacerbation that can rapidly deteriorate into fatal outcomes . On the other hand, clinical relapse without anti‐viral retreatment was associated with a higher chance of HBsAg seroclearance and an enhanced T ‐cell response against the virus …”

Section: Discussionmentioning

confidence: 99%

Combining hepatitis B core‐related and surface antigens at end of nucleos(t)ide analogue treatment to predict off‐therapy relapse risk

Hsu

Nguyen

et al. 2018

Aliment Pharmacol Ther

131

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Summary Background There remains an unmet need for convenient biomarkers to assess the risks of discontinuing nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Aim To investigate if hepatitis B core‐related antigen (HBcrAg) is an independent of surface antigen (HBsAg) for risk prediction of NA cessation. Methods This prospective multicentre study enrolled 135 CHB patients who stopped entecavir or tenofovir after achieving viral remission for a median of 25.2 months. All patients stopped NA with negative HBeAg and undetectable viral DNA, and were then observed for clinical relapse and HBsAg loss. Predictors including HBsAg and HBcrAg levels were explored using Cox proportional hazard model and weighted to develop a risk score. Results During a median follow‐up of 25.9 months, clinical relapse and HBsAg loss occurred in 66 and eight patients, respectively, with a 5‐year cumulative incidence of 56.1% (95% CI 46.7‐66.0%) and 8.8% (95% CI 4.3‐17.4%), respectively. HBcrAg was an independent relapse predictor, as well as HBsAg, age, ALT and tenofovir use. A score (SCALE‐B) was calculated by the equation of 35*HBsAg (log IU/mL) + 20*HBcrAg (log U/mL) + 2*age (year) + ALT (U/L) + 40 for tenofovir use. The concordance rates for clinical relapse were 0.87, 0.88, 0.87, 0.85 and 0.90 at 1, 2, 3, 4 and 5 years, respectively. Moreover, HBsAg loss occurred exclusively in low‐risk patients predicted by the score. Conclusions Serum HBcrAg and HBsAg levels were independent predictors of off‐NA relapse and can be factored into a risk score to guide treatment cessation in patients with CHB.

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Section: Discussionmentioning

confidence: 99%

Combining hepatitis B core‐related and surface antigens at end of nucleos(t)ide analogue treatment to predict off‐therapy relapse risk

Hsu

Nguyen

et al. 2018

Aliment Pharmacol Ther

131

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“…In fact, patients with vigorous immune clearance represented by severe reactivation of HBeAg‐negative hepatitis were more likely to develop early HBsAg decline . Viral relapse after NA cessation may induce immune responses, which could be beneficial for viral clearance by inducing plasma tumour necrosis factor, interleukin (IL) 10, IL‐12p70, CXCL10 and hence subsequent decline in HBsAg level . Nonetheless, despite more than half (572/1076; 53.2%) of the patients of this study had raised ALT, only 6 of these 572 patients had HBsAg seroclearance.…”

Section: Discussionmentioning

confidence: 78%

“…Serial serum HBV DNA and ALT levels of HBeAg-negative patients with chronic hepatitis B who had stopped nucleos(t)ide analogues (NA): A, serial HBV DNA; B, serial HBV DNA in the subgroup of patients with negative HBVDNA upon NA cessation; C, serial ALT; D, serial ALT in the subgroup of patients with negative HBV DNA upon NA cessation. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ULN, upper limit of normal20,21 Nonetheless, despite more than half (572/1076; 53.2%) of the patients of this study had raised ALT, only 6 of these 572 patients had HBsAg seroclearance. This means 97% of patients who had hepatitis flare could not achieve HBsAg seroclearance.A recent study showed that after 8 years of TDF at a 24-week period of treatment-free follow-up (TFFU) phase in 124 patients recruited in two randomized, controlled studies, a small yet notable…”

mentioning

confidence: 65%

The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg‐negative chronic hepatitis B

Wong

Chan

Yuen

et al. 2019

Liver International

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Background The rates of hepatitis B surface antigen (HBsAg) seroclearance after stopping nucleos(t)ide analogues (NA) in European (19% in 2 years) and Asian (13% in 6 years) patients with chronic hepatitis B (CHB) vary dramatically. We evaluated the incidence of hepatitis flare and HBsAg seroclearance in hepatitis B e antigen (HBeAg)‐negative Chinese CHB patients who had stopped NA. Methods This was a territory‐wide retrospective study in Hong Kong. We identified HBeAg‐negative CHB patients from January 2000 to December 2017 who had stopped NA treatment for more than 3 months. Hepatitis flare was defined as ALT >2×ULN. Results The 1076 patients were predominantly middle‐aged men (mean age 52 years, male 74.8%) when starting NA; they stopped NA after 82 ± 35 months of treatment. At 44.3 ± 24.6 months after stopping NA, 147 (13.6%) patients had hepatitis flare, which led to resumption of NA; whereas 77 (7.2%) patients had flare but did not resume NA. Decompensation occurred in 7/914 (0.8%) patients. A total of 695 (64.6%) patients remained on NA treatment at the last visit. Eleven patients had achieved HBsAg seroclearance (6 of them had hepatitis flare and 1 of these 6 patients achieved HBsAg seroclearance after NA was restarted). Hepatic events developed in 75/695 (10.8%) patients who had NA resumed vs 43/381 (11.3%) patients who did not resume NA (P = .677). Conclusions Hepatitis flare and retreatment were common in HBeAg‐negative CHB patients who stopped NA treatment; whereas HBsAg seroclearance rarely occurred. Stopping NA to achieve functional cure should not be recommended at this moment.

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“…Impaired function of T cells in patients with CHB was due to increased FOXP3 + CD127 − regulatory T cells and expression of programmed cell death protein 1 (PD‐1) and CTLA4 on CD4 + T cell . T cells from HBeAg‐negative patients with HBsAg loss expressed low levels of PD‐1 at the end of long‐term NAs therapy and 12 weeks thereafter . PD‐1 was traditionally considered to have an unappreciated role in long‐term survival of HBV‐specific T cell, but Rivino et al suggested that the increase of PD‐1 was associated with the population of HBV‐specific CD8 + T cell in patients who successfully discontinued NAs therapy.…”

Section: Relationship Between Host and Hbvmentioning

confidence: 99%

Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection

Guo

Zeng

et al. 2020

Journal of Viral Hepatitis

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Covalently closed circular DNA (cccDNA), which is stably present in the nucleus of hepatocytes, is an important indicator for evaluating antiviral efficacy. Since cccDNA quantification requires an invasive procedure, serum biological markers that can effectively reflect the transcriptional activity of intrahepatic virus and the efficacy of treatment are required. Here, from the aspects of virus and host, we outline the focus of clinical research of HBV in recent years, including HBV RNA, empty virus, hepatitis B core‐related antigen and changes in the immune response. We briefly discuss their significance in predicting disease activity and monitoring treatment response in chronic hepatitis B. On this basis, some issues worthy of attention in laboratory diagnosis are proposed.

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Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B

Cited by 104 publications

References 29 publications

Combining hepatitis B core‐related and surface antigens at end of nucleos(t)ide analogue treatment to predict off‐therapy relapse risk

Combining hepatitis B core‐related and surface antigens at end of nucleos(t)ide analogue treatment to predict off‐therapy relapse risk

The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg‐negative chronic hepatitis B

Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection

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