Granulocyte-colony stimulating factor (G-CSF) to treat hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF): results from a retrospective real-world study

doi:10.21203/rs.3.rs-4685806/v1

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Granulocyte-colony stimulating factor (G-CSF) to treat hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF): results from a retrospective real-world study

https://doi.org/10.21203/rs.3.rs-4685806/v1

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Objective

Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) has a high mortality rate due to severe liver function disorder, extremely poor liver regeneration capacity, and dysregulated immune responses, thus new treatment measures are urgently needed to improve the therapeutic effect. This study aimed to evaluate the effectiveness of Granulocyte-colony stimulating factor (G-CSF) treatment in HBV-ACLF.

Methods

The data of patients with HBV-ACLF admitted to West China Hospital from January 2022 to October 2023 were collected retrospectively. They were divided into control group and treatment group according to whether they had received additional G-CSF treatment. The survival outcomes at 30-day and 90-day were analyzed between two groups. The change of disease severity score and alpha fetoprotein (AFP) after 14 days of hospitalization were observed between two groups. The control group received standard medical therapy, while the G-CSF group received G-CSF at a dose of 5µg/kg once daily for six days on the basis of standard medical therapy.

Results

In this retrospective study, a total of 136 HBV-ACLF patients were divided into two groups, with 47 in the G-CSF group and 89 in the control group. The 30-day survival rate of patients receiving G-CSF treatment was 85.1%, compared to 71.9% in the control group (P = 0.084). The 90-day survival rate for patients receiving G-CSF treatment was 76.6%, while it was 59.6% for the control group (P = 0.047). Additionally, on the 14th day of hospitalization, patients receiving G-CSF treatment showed a more reduction in Model for End-Stage Liver Disease (MELD) score (P = 0.001) and Child-Turcotte-Pugh (CTP) score (P = 0.021) compared to the control group. The decrease in serum AFP in the control group was greater than that in the G-CSF group, although there was no statistical difference (P = 0.112).

Conclusion

G-CSF significantly improves the survival rate of HBV-ACLF patients and further promotes the recovery of liver function during hospitalization for ACLF.

Acute-on-chronic liver failure

Hepatitis B virus

Granulocyte colony-stimulating factor

Liver failure resulting from advanced hepatic injury can be attributed to various causes. A noteworthy development in the classification of liver failure occurred in 1995 with the introduction of acute-on-chronic liver failure (ACLF)^[1]. ACLF is characterized by acute liver injury, marked by a high 28-day mortality rate, presenting as coagulopathy and jaundice. Within 4 weeks, it becomes complicated by clinical ascites and/or encephalopathy in patients with previously diagnosed or undiagnosed chronic liver disease/cirrhosis^[2–4].The primary causes of ACLF in Western regions are non-infectious, including hepatotoxic drugs, variceal bleeding, and alcoholic hepatitis. In contrast, infectious etiologies, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and superinfection with hepatitis E virus (HEV), dominate in Eastern regions^[5]. As per the consensus recommendations of the Asian Pacific Association, three main treatments for ACLF are medication, artificial liver, and orthotopic liver transplantation (OLT). OLT serves as the last resort for patients whose lives cannot be extended through supportive therapies. A clinical trial demonstrated the survival benefits of liver transplantation for some ACLF patients^[6]. However, the challenge lies in finding a suitable liver source before appropriate donors emerge, leading patients to endure prolonged therapies with limited effectiveness^[7]. In such cases, an artificial liver becomes a realistic and optional plan, although improvements in the effects of medicines and artificial liver treatment are necessary. Currently, efforts are focused on facilitating liver regeneration and reducing cell apoptosis.

Granulocyte colony-stimulating factor (G-CSF) treatment may serve as an effective buffer for patients awaiting OLT. The pivotal role of effective hepatocyte regeneration in the successful treatment of liver failure is underscored by animal experiments demonstrating that G-CSF can promote liver repair and induce endogenous hepatic oval cell migration and proliferation^[8]. Clinical results also indicate that G-CSF contributes to improving the survival rate and prognosis of patients with liver failure^[9–15]. Additionally, G-CSF has been reported to prevent complications such as sepsis and multi-organ failure, potentially attributed to enhanced neutrophil function and immunomodulation^{[10, 14]}. However, a recent study showed no significant survival benefit of G-CSF in individuals with ACLF^[16].Therefore, more well-conducted clinical studies are required. G-CSF may be a potentially effective treatment for ACLF, and clinical data must be further expanded. In order to further study the effectiveness and safety of G-CSF in the treatment of HBV-ACLF, this project simultaneously conducted a prospective cohort study.

Patients

This is a single center retrospective clinical study, which was carried out in West China Hospital of Sichuan University, with the purpose of evaluating the efficacy and safety of G-CSF for the treatment of patients with HBV-ACLF. Only cases who were diagnosed with HBV-ACLF and received the corresponding treatment in our hospital from January 2022 to October 2023 were considered eligible. The primary endpoint of current research was 30-day and 90-day survival differences between control and G-CSF groups. Moreover, relevant indicators in illustrating the corresponding liver function and regeneration, such as scores of liver function models [Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score] and alpha fetoprotein (AFP) on the 14th day of hospitalization, have also been evaluated. This study was conformed strictly to the ethics guidelines of the 1975 Declaration of Helsinki, and approved by the Institutional Review Board of the Medical School of Sichuan University [Ethics number: 2022 (1746)].

The definition of ACLF

ACLF patients are defined according to the Asia-Pacific Association for the Study of Liver (APASL) consensus as having hepatitis, rapidly developing jaundice, total bilirubin (TBIL) > 5 mg/dL (85 µmol/L), coagulation dysfunction [international normalized ratio (INR) ≥ 1.5 or prothrombin activity (PTA) < 40%], as well as ascites or encephalopathy occurring within 4 weeks^{[2, 3]}.

Inclusion criteria

1) Cases showed symptoms of weak, anorexia, nausea and abdominal distension, other serious gastrointestinal symptoms;

2) Cases diagnosed with ACLF accompanied with HBsAg and/or HBV DNA positive ≥ 6 months.

3) 18–70-year-old cases diagnosed with chronic hepatitis B (CHB) disease, regardless of gender.

Exclusion criteria

1) Cases who were detected with a combination with other types of infectious disease, including hepatitis A, B, C, D viruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus (HIV).

2) Cases who were detected with primary or secondary liver malignancies, such as hepatocellular carcinoma (HCC);

3) Cases who were detected with concurrent other serious illnesses or liver diseases, such as autoimmune liver diseases, alcoholic liver disease, drug-induced liver injury, or genetic metabolic liver diseases like Wilson's disease; Septicemia or other severe infections; Obstructive jaundice or hemolytic jaundice; Blood system disorders or other conditions that can lead to prolonged prothrombin time.

Therapeutic regimen

Cases in the control group only received standard medical therapy, including drug therapy and artificial liver treatment. In contrast to the control group, apart from the standard medical therapy as mentioned above, G-CSF treatment (starting from baseline blood sample collection upon admission, administering G-CSF at a dose of 5 µg/kg once daily for a total of six days) has also been applied in cases in the G-CSF group.

Date collection

This study collected detailed demographic data for all patients (including age, gender, disease course, pre-admission treatment, etc.), auxiliary examination results at admission and during hospitalization (including complete blood count, biochemical parameters, coagulation function, AFP, etc.), HBV-related virological markers, and various imaging reports. Adverse reactions potentially related to G-CSF reported during the treatment process, as well as 30-day and 90-day survival outcomes, were also recorded. Blood parameters, serum biochemical, and electrolyte indices were measured using a fully automated blood cell analyzer, a fully automated coagulation analyzer, and a fully automated biochemical analyzer (Olympus AU5400, Olympus Corporation, Tokyo, Japan) following standard procedures.

Statistical analysis

Statistical analysis was performed using IBM SPSS version 25.0 (IBM SPSS, Chicago, IL, USA) and GraphPad Prism 9. Categorical data were expressed as numbers (percentages). Chi-Squared and Fisher's exact tests were employed to assess categorical variables. Overall survival (OS) was defined as the duration from the initiation of G-CSF treatment to the date of death or the last follow-up. Survival differences were evaluated using Kaplan-Meier curves. The Cox proportional hazards model was utilized to construct a multivariate model for independent prognostic factors for survival, with Hazard Ratio (HR) and its 95% confidence interval (CI) presented. A significance level of p < 0.05 was considered indicative of statistical significance.

Baseline characteristics

This study included a total of 136 HBV-ACLF patients who met the inclusion criteria and exclusion criteria, including 89 patients in the control group and 47 patients in the G-CSF group (Fig. 1). There were no statistically significant differences in age, gender, cirrhosis, baseline blood biochemistry indicators, complete blood count, and other parameters between the two groups (P > 0.05). The MELD scores and CTP scores showed no statistical differences between the two groups (P = 0.642, P = 0.088). The baseline conditions were generally consistent between the two groups. (Table 1)

Table 1

Baseline characteristics of the entire HBV-ACLF patients
Variables	Groups	Total number	G-CSF group	Control group	P value
Variables	Groups	(n = 136)	(n = 47)	(n = 89)	P value
Age		45.00 [38.00, 52.00]	42.00 [33.50, 52.50]	47.00 [40.00, 52.00]	0.100
Sex (%)	Male	122 (89.7)	41 (87.2)	81 (91.0)	0.491
	Female	14 (10.3)	6 (12.8)	8 (9.0)
Cirrhosis (%)	No	55 (40.4)	16 (34.0)	39 (43.8)	0.269
	Yes	81 (59.6)	31 (66.0)	50 (56.2)
TBIL		342.30 [278.90, 428.45]	347.50 [266.25, 458.55]	341.70 [279.80, 417.90]	0.442
ALT		160.00 [71.00, 387.00]	132.00 [67.00, 332.00]	161.00 [75.00, 387.00]	0.564
AST		138.50 [89.00, 248.75]	129.00 [91.50, 207.50]	151.00 [89.00, 277.00]	0.373
ALB		31.70 [29.80, 34.08]	31.70 [29.05, 35.10]	31.60 [30.10, 33.90]	0.998
Cre		69.50 [58.75, 86.00]	67.00 [57.50, 75.00]	72.00 [59.00, 93.00]	0.149
Hb		122.50 [108.00, 137.00]	119.00 [107.00, 130.50]	124.00 [110.00, 137.00]	0.313
PLT		87.50 [62.00, 123.00]	81.00 [64.00, 124.50]	89.00 [62.00, 117.00]	0.621
WBC		6.80 [5.10, 8.21]	7.02 [4.92, 9.20]	6.49 [5.15, 8.00]	0.731
INR		1.94 [1.68, 2.41]	1.92 [1.65, 2.58]	1.95 [1.70, 2.30]	0.849
NEUN		4.41 [3, 11]	4.34 [4, 9]	4.43 [3, 11]	0.755
AFP		29.86 [11.90, 98.70]	30.10 [14.10, 126.50]	29.83 [9.25, 93.98]	0.677
MELD score		23.77 [20.44, 26.72]	23.10 [19.60, 27.03]	23.80 [21.11, 26.48]	0.642
CTP score		11.00 [10.00, 12.00]	11.00 [10.00, 11.00]	11.00 [11.00, 12.00]	0.088

All data were present as mean ± SD, median (IQR) or number (%). G-CSF, Granulocyte-colony stimulating factor; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Cre, creatinine; Hb, hemoglobin; PLT, platelet; WBC, white blood cell count; INR, international normalized ratio; AFP, alpha fetoprotein; NEUN, neutrophil; MELD score, the Model for End-Stage Liver Disease score; CTP score, Child-Turcotte-Pugh (CTP) scores.

Survival outcomes between two groups

We employed Kaplan–Meier curves (K-M curves) to analyze the differences in prognosis outcomes between HBV-ACLF patients treated with or without combined G-CSF therapy. At the 30-day follow-up endpoint for 136 patients, 104 were alive, and 32 had deceased, resulting in a 30-day survival probability of 76.5% (104/136). The cumulative survival rate for the control treatment group was 71.9% (64/89), and for the G-CSF group, it was 85.1% (40/47). According to the Log-rank test, the comparison between the two groups showed no statistical significance (P = 0.082). At the 90-day follow-up endpoint for 136 patients, 89 were alive, and 47 had deceased, resulting in a 90-day survival probability of 65.4% (89/136). The cumulative survival rate for the control treatment group was 59.6% (53/89), and for the G-CSF group, it was76.6% (36/47). According to the Log-rank test, the comparison between the two groups showed no statistical significance (P = 0.039). (Table 2) (Fig. 2)

Table 2

Survival outcomes of HBV-ACLF patients in each group.
Variables	Groups	Total number	G-CSF group	Control group	P value
Variables	Groups	(n = 136)	(n = 47)	(n = 89)	P value
Status30 (%)	Alive	104 (76.5)	40 (85.1)	64 (71.9)	0.084
	Dead	32 (23.5)	7 (14.9)	25 (28.1)
OS30		30.00 [30.00, 30.00]	30.00 [30.00, 30.00]	30.00 [26.00, 30.00]	0.072
Status90 (%)	Alive	89 (65.4)	36 (76.6)	53 (59.6)	0.047
	Dead	47 (34.6)	11 (23.4)	36 (40.4)
OS90		90.00 [32.00, 90.00]	90.00 [90.00, 90.00]	90.00 [26.00, 90.00]	0.24

All data were present as mean ± SD. G-CSF, granulocyte-colony stimulating factor; OS, overall survival.

Univariate and multi-variate analysis of overall survival.

As is summarized in Table 3 and Table 4, the results of univariate analysis indicate that, for the 30-day prognosis outcome, an increase in CTP (P = 0.013) and MELD scores (P <0.001) is an independent risk factor for the prognosis outcome of HBV-ACLF patients. For the 90-day prognosis outcome, an increase in CTP (P <0.001) and MELD scores (P <0.001) remains an independent risk factor for the prognosis outcome of HBV-ACLF patients, while standard treatment combined with G-CSF therapy is a protective factor (P = 0.043).

The results after multivariate analysis correction indicate that, for the 30-day outcome, MELD score (P = 0.003) is the sole risk factor for the prognosis. For the 90-day prognosis outcome, an increase in both CTP (P = 0.017) and MELD scores (P <0.001) is still an independent risk factor for the prognosis outcome of ACLF patients, and standard treatment combined with G-CSF therapy remains a protective factor for the prognosis (P = 0.009).

Table 3

Univariate and multi-variate analysis of overall survival of all patients in a 30-day.
Variables	Univariate analysis		Multivariate analysis
Variables	HR (95%CI)	P value	HR (95%CI)	P value
Age	1.014(0.979,1.050)	0.444	——	——
Sex	0.870(0.265,2.856)	0.818	——	——
CTP score	1.483(1.087,2.022)	0.013	1.284(0.922,1.788)	0.139
MELD score	1.113(1.053,1.177)	<0.001	1.095(1.031,1.163)	0.003
G-CSF	0.482(0.209,1.115)	0.088	——	——

Setting the control group (receiving standard treatment only), female gender as the control. A significance level of p < 0.05 was considered statistically significant.HR: hazard ratio; CI: confidence interval; MELD score, the Model for End-Stage Liver Disease score; CTP score, Child-Turcotte-Pugh (CTP) scores; G-CSF, granulocyte-colony stimulating factor.

Table 4

Univariate and multi-variate analysis of overall survival of all patients in a 90-day.
Variables	Univariate analysis		Multivariate analysis
Variables	HR (95%CI)	P value	HR (95%CI)	P value
Age	1.025(0.996,1.054)	0.088	——	——
Sex	1.499(0.671,3.347)	0.323	——	——
CTP score	1.646(1.271,2.132)	<0.001	1.427(1.066,1.910)	0.017
MELD score	1.110(1.059,1.163)	<0.001	1.116(1.052,1.185)	<0.001
G-CSF	0.498(0.253,0.978)	0.043	0.378(0.182,0.788)	0.009

Setting the control group (receiving standard treatment only), female gender as the control. A significance level of P < 0.05 was considered statistically significant.HR: hazard ratio; CI: confidence interval; MELD score, the Model for End-Stage Liver Disease score; CTP score, Child-Turcotte-Pugh (CTP) scores; G-CSF, granulocyte-colony stimulating factor.

The impact of co-administering G-CSF on the change in liver disease model scores and AFP level during the 14-day hospitalization.

We analyzed the impact of co-administering G-CSF on the improvement of liver function during hospitalization in HBV-ACLF patients. Specifically, we compared the reduction in MELD score (or CTP score) from baseline to the 14th day between the G-CSF group and the control group. The differences in the changes in liver disease model scores between the two groups were assessed for statistical significance through t-tests to evaluate whether the addition of G-CSF treatment promotes the improvement of liver function in HBV-ACLF patients. The results showed that, compared to the control group, the G-CSF group experienced a more significant decrease in MELD score on the 14th day of hospitalization (P = 0.001). Additionally, the CTP score in the G-CSF group decreased more than the control group on the 14th day of hospitalization (P = 0.007). These findings indicate that the addition of G-CSF to standard treatment can further promote the recovery of liver function during the hospitalization of HBV-ACLF patients. (Table 5) We also found that the decrease in serum AFP in the control group was greater than that in the G-CSF group, although there was no statistical difference (P = 0.112). This phenomenon probably prove that G-CSF promotes HOC proliferation.

Table 5. The change in liver disease model scores and AFP level during the 14-day hospitalzation between two groups.

Variables	Total number	G-CSF group	Control group	P value
Variables	(n=136)	(n=47)	(n=89)	P value
ΔMELD score	1.59 [-1.34, 3.53]	2.70 [0.77, 4.45]	0.86 [-3.40, 2.51]	0.001
ΔCTP score	0.00 [-1.00, 0.00]	0.00 [0.00, 1.00]	0.00 [-1.00, 0.00]	0.007
ΔAFP	10.80 [2.75, 23.42]	10.40 [1.90, 22.72]	15.00 [6.58, 26.45]	0.112

Δ= value before treatment – value after treatment. A significance level of P < 0.05 was considered statistically significant. MELD score, the Model for End-Stage Liver Disease score; CTP score, Child-Turcotte-Pugh (CTP) scores; AFP, alpha fetoprotein; G-CSF, granulocyte-colony stimulating factor.

In the G-CSF group, there were 3 cases of fever (6.3%), 2 cases of transient rash (4.2%), and 4 cases of lumbosacral pain (8.5%). All patients recovered from these symptoms after receiving appropriate treatment. No patients discontinued the use of G-CSF due to these potential adverse reactions.

This study aims to further investigate the application value of G-CSF in patients with HBV-ACLF by conducting a prospective cohort study in China. We found that adding G-CSF significantly increased the 90-day survival rate of HBV-ACLF patients compared to standard treatment alone. Cox regression analysis showed that combined G-CSF therapy is a protective factor for the prognosis of HBV-ACLF patients, significantly reducing the risk of death. Additionally, the evaluation of MELD scores and CTP scores on the 14th day of hospitalization for HBV-ACLF patients treated with combined G-CSF showed a more significant decrease, suggesting that combined G-CSF treatment can promote a faster recovery of liver function during hospitalization for HBV-ACLF.

These results are consistent with previous studies on the use of G-CSF in the treatment of ACLF patients. Studies conducted by Garg and colleagues in India suggested that combined G-CSF treatment could more than double the two-month survival rate of ACLF patients and significantly improve patients' CTP and MELD scores^[14]. Similar conclusions were drawn from a clinical application study of G-CSF in the Chinese ACLF population conducted by Duan et al^[9]. In a study by Spahr et al., G-CSF treatment for ACLF related to alcoholic hepatitis improved patient prognosis. Liver histological assessment revealed an increase of over 50% in hepatic oval cell (HOC) count in the liver tissue of patients receiving G-CSF compared to the control group. Moreover, the liver morphology showed better reconstruction in the G-CSF group, and this was positively correlated with peripheral blood hepatocyte growth factor (HGF) levels^[17].

However, there are also studies that conclude G-CSF treatment for ACLF may not have a significant effect. For example, a clinical study conducted by Engelmann et al. in Europe in 2021 suggested that G-CSF treatment did not significantly improve the survival rate, liver function, or infection rate of ACLF patients^[16]. It's important to note that the study population in that research primarily consisted of individuals of European descent, the diagnosis of ACLF was based on the EASL-CLIF criteria, and the primary underlying disease was alcoholic liver disease. These characteristics differ from the ACLF population in China, which is primarily characterized by HBV infection. Therefore, whether the results of that study can directly apply to the ACLF patient population in China remains debatable.

This study has limitations, including being a single-center study with a relatively small sample size, potentially leading to statistical fluctuations. Additionally, the specific mechanism of how G-CSF acts on HBV-ACLF patients remains to be elucidated and will be addressed in future basic experiments.

Existing research has preliminarily discovered that G-CSF can promote liver regeneration by inducing the proliferation of HOC and improve the prognosis of ACLF patients^{[8, 14, 18]}. Some recent studies have observed the proliferation of HOC in models of liver injury or failure in humans or animals, playing a crucial role in liver regeneration and repair^{[19, 20]}. In a mouse model undergoing extensive liver resection, inhibiting the proliferation of HOC resulted in impaired liver regeneration and reduced postoperative survival^[19]. HOC, as liver progenitor cells with bidirectional differentiation capability in the human liver, are considered the main contributors to compensatory liver repair, replacing the secondary mechanism of liver regeneration. Proliferation activation of HOC typically occurs in the early stages of diseases (within one week), and the process from proliferation activation to differentiation into mature liver cells and bile duct cells takes approximately one week^[21]. Previous studies have indicated that HOC expresses G-CSF receptors, providing a physiological basis for the regulation of HOC by G-CSF^[8]. Moreover, AFP is highly expressed in HOC and immature hepatocytes, and is lowly expressed in adult hepatocytes. In our study, it was found that the decrease in serum AFP in the G-CSF group was smaller than that in the control group. Whether this phenomenon is related to G-CSF promoting HOC proliferation and thereby increasing AFP expression deserves further study in the future.

In conclusion, this study provides preliminary evidence that G-CSF has potential application value in the treatment of HBV-ACLF. The addition of G-CSF to standard treatment resulted in survival benefits for patients with HBV-ACLF. While the dosage, duration, timing, and other aspects of G-CSF treatment need further investigation, these findings provide a rationale for continuing to explore the clinical use of G-CSF in HBV-ACLF patients.

Consent for publication

All authors approved the publication.

Competing interests

No potential conflict of interest was reported by the author(s).

Funding

This work was supported by the National Key Research and Development Program of China (No.2022YFC2304800) and 1.3.5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (ZYJC21014).

Author Contribution

W.H. and M.W. participated in the collection and analysis of data and the writing of the first draft of the article. L.B., L.D and H.T. designed the study. L.C. and Y.M. conducted the study supervision. L.Y., Y.Z. and X.Z. revised the manuscript. All authors contributed to the article and approved the submitted version.

Acknowledgements

None

Data Availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Granulocyte-colony stimulating factor (G-CSF) to treat hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF): results from a retrospective real-world study

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Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Methods

Patients

The definition of ACLF

Therapeutic regimen

Date collection

Statistical analysis

Results

Baseline characteristics

Survival outcomes between two groups

Discussion

Declarations

Consent for publication

Competing interests

Funding

Author Contribution

Acknowledgements

Data Availability

References

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