Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss

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

doi:10.1093/infdis/jiy097

Cited by 62 publications

(52 citation statements)

References 46 publications

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“…HBsAg levels at discontinuation have been reported as a predictor of both post‐NA HBsAg loss and relapse, while various cytokines have been studied in small cohorts of CHB patients . Recently, alterations in the T‐cells phenotype were reported to enhance cellular immunity and reduce T‐cell exhaustion, contributing to HBsAg clearance . Interferon‐inducible protein‐10 (IP10) serum levels have been associated with HBsAg decline during therapy with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) in CHB patients, and they were recently proposed as the only significant predictor of HBsAg loss .…”

Section: Introductionmentioning

confidence: 99%

Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

Papatheodoridi

Hadziyannis

Berby

et al. 2019

Journal of Viral Hepatitis

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Reliable predictors of outcomes after treatment discontinuation in HBeAg-negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon-inducible protein-10 (IP10) and hepatitis B core-related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg-negative CHB patients who discontinued long-term antiviral therapy. All HBsAg-positive (n = 57) patients of the prospective DARING-B study were included and followed monthly for 3 months, every 2/3 months until month-12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE-B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18-month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month-1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100-1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month-1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE-B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg-negative CHB. | 119PAPATHEODORIDI ET Al.

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Section: Introductionmentioning

confidence: 99%

Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

Papatheodoridi

Hadziyannis

Berby

et al. 2019

Journal of Viral Hepatitis

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“…HBsAg is the most abundant HBV protein in CHB patients, and contributes to the depressed host immune response . In addition, the enhanced NK cell function that accompanies CHB therapy is associated with HBsAg sero‐clearance . Therefore, we identified whether HBsAg influences STAT3 activation and NK cell function in the CHB patients.…”

Section: Resultsmentioning

confidence: 99%

“…In CHB patients, the levels of activating receptors such as 2B4 and NKG2D were reduced by TGF‐β, while that of the inhibitory receptor NKG2A was elevated, resulting in dysfunctional IFN‐γ production and NK cell cytotoxicity . HBsAg sero‐clearance by pegylated‐IFNα‐2a and nucleos(t)ide analogues restored NK cell function in the HBeAg‐negative CHB patients . However, the mechanisms underlying CHB‐mediated NK cell dysfunction are not completely known.…”

Section: Introductionmentioning

confidence: 99%

STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients

Zheng

Yang

Han

et al. 2019

Journal of Leukocyte Biology

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NK cells play an important role in early control of HBV infection. The function of NK cells is inhibited in chronic hepatitis B virus (CHB) infection, although the underlying mechanism remains unknown. We found that the expression of STAT3 decreased in peripheral NK cells of CHB patients, and was associated with low levels of degranulation and IFN-secretion. In addition, STAT3 levels were positively correlated with cytolysis-associated molecules and antiviral cytokines, such as CD107a, granzyme B, perforin, and IFN-. HBsAg directly inhibited the expression and activation of STAT3 in NK cells, and knocking down STAT3 expression in NK cells inhibited proliferation, decreased cyclin d1 levels, and suppressed responsiveness to IL-21 stimulation.Furthermore, STAT3 directly bound to the promoter of NKp46, an important activating receptor of NK cells, to regulate its transcription and expression. Taken together, our findings indicate that STAT3 is an important positive regulator of NK cells, and provide a new mechanism of NK cell dysfunction in CHB. K E Y W O R D SCD107a, CHB, granzyme B, IFN-, natural killer cells, NKp46, perforin, STAT3 INTRODUCTIONChronic hepatitis B virus (HBV) infection is a major health problem worldwide, and can trigger a wide spectrum of liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), which are altogether responsible for approximately 1 million deaths annually. 1 The aims of anti-chronic HBV (CHB) therapy are persistent suppression of viral replication, and the prevention of fibrotic progression and oncogenesis. 2 CHB is divided into the hepatitis B envelope Ag (HBeAg)-positive and HBeAg-negative phases. 2 The HBeAg + patients have demonstrated immune tolerance, and HBeAg seroconversion used to be the ideal endpoint of CHB therapy. 3,4 However, recent studies indicate that the HBeAg − CHB patients, including the inactive hepatitis B surface Ag (HBsAg) carriers, have a high risk of progressing to HCC, 5,6 and do not show any immune regulatory mechanism. 2 NK cells are crucial mediators of the innate immune system, and respond to viral infection rapidly without Ag presentation via the Abbreviations: CHB, chronic hepatitis B virus; EGF, epidermal growth factor; HBeAg, hepatitis B envelope Ag; HBsAg, hepatitis B surface Ag; HD, healthy donor; HGF, hepatocyte growth factor; HIES, hyper-IgE syndrome. MHC. 7,8 NK cell functions are regulated by several surface recognition receptors, with both activating and inhibitory functions, 9 which need to be maintained in a balanced state for proper NK cell response. Blocking the activating receptors NKp46 and DNAM-1 impaired NK cell cytotoxicity against cytomegalovirus-infected M s. 10 In CHB patients, the levels of activating receptors such as 2B4 and NKG2D were reduced by TGF-, while that of the inhibitory receptor NKG2A was elevated, resulting in dysfunctional IFN-production and NK cell cytotoxicity. 11-13 HBsAg sero-clearance by pegylated-IFN -2a and nucleos(t)ide analogues restored NK cell function in the HBeAgnegative ...

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“…The same team suggested that other cell types might also be involved in the immune response after NAs discontinuation in CHB patients. Special natural killer (NK) cell compartment has been revealed by unsupervised stochastic neighbour embedding analysis; increased activity of NK cells correlated with post-NAs biochemical flares and was particularly enhanced in patients experiencing subsequent HBsAg loss [53].…”

Section: Markers Of Host Immune Activitymentioning

confidence: 99%

Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B

Papatheodoridi

Papatheodoridis

2020

Cells

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The aim of this review is to outline emerging biomarkers that can serve as diagnostic tools to identify non-cirrhotic chronic hepatitis B (CHB) patients who could safely discontinue nucleos(t)ide analogues (NAs) before HBsAg loss. Regarding possible predictors of post-NAs outcomes, a number of studies have evaluated numerous factors, which can be categorised in markers of hepatitis B virus (HBV) activity, markers of host immune response and markers of other patient characteristics. In clinical practice, the most important question for patients who discontinue NAs is to differentiate those who will benefit by achieving HBsAg loss or at least by remaining in remission and those who will relapse requiring retreatment. Most of the discontinuation studies so far came from Asian and only few from European populations and examined the rates and predictors of post-NA virological and/or combined relapses or HBsAg loss. To date, there is still controversy about predictors of post-NA relapses, while only HBsAg serum levels at NA discontinuation seem to be the most robust predictive marker of the probability of subsequent off-treatment HBsAg seroclearance. Newer viral markers such as HBV RNA and hepatitis B core-related antigen seem promising, but further research is required.

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Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss

Abstract: Increased NK cell function is associated with active hepatitis and HBsAg seroclearance following structured NA cessation. This adds to our knowledge of the immunological events that develop following cessation of NA treatment in CHB.

Cited by 62 publications

References 46 publications

Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients

Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B

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