Artificial Liver Support Systems for Hepatitis B Virus-associated Acute-on-Chronic Liver Failure

A Meta-analysis of the Clinical Literature

Guotao Li; Pan Zhang; Yumeng Zhu

J Viral Hepat. 2023;30(2):90-100.

Abstract and Introduction

Abstract

To evaluate the short-term and long-term survival efficacy of an artificial liver support system (ALSS) in patients with acute-on-chronic liver failure (ACLF). A systematic search was performed for relevant published data in PubMed, Web of Science and Cochrane Library databases. Studies that evaluated the efficacy of ALSS in patients with ACLF and provided the short-term or long-term survival rate were included. A total of 10 studies involving 3685 patients were included in this analysis. The pooled 28-day survival rate and 90-day survival rate were 68.7% (95% CI: 64.5%–72.9%) and 53.4% (95% CI: 45.5%–61.4%), respectively. The pooled estimates of the OR for the 28-day and 90-day survival rates between the ALSS group and the control group were 1.91 (95% CI: 1.21–3.04) and 1.41 (95% CI: 1.17–1.70), respectively. Subgroup analysis showed that patients treated with lower levels of TBIL and MELD scores had a higher 28-day survival rate (χ ² = 15.75, p < 0.01; χ ² = 13.80, p < 0.01). The present meta-analysis suggests that ALSS treatment could remarkably improve short-term survival rates in HBV-ACLF patients, which implies that treatment with ALSS may help to reduce high mortality. Further prospective randomized trials are needed to validate these findings.

Introduction

Acute-on-chronic liver failure (ACLF) is a complicated clinical syndrome manifesting as acute and severe hepatic dysfunction resulting from virus, alcohol or drugs and chronic decompensation in any type of end-stage liver disease.^[1] Hepatitis B virus (HBV) infection accounts for the majority of ACLF in Asians.^[2] China has been recognized as an HBV high-prevalence area with approximately 130 million carriers and 30 million chronically infected individuals.^[3] ACLF is characterized by jaundice, coagulopathy, hepatic encephalopathy (HE) and a high incidence of short-term (28-day) mortality of 30%–40%.^[4] Although the most useful therapy for ACLF is liver transplantation (LT), healthy livers are extremely lacking, and the operation is very costly.^[5] Unfortunately, many ACLF patients will die prior to suitable organ availability and/or evolve to multisystem organ failure, at which point LT is contraindicated. Furthermore, due to medical or psychosocial reasons, many ACLF patients are ineligible for LT.

The artificial liver support system (ALSS) was first applied in the treatment of liver failure in the 1970 s.^[6] In the past several decades, many types of ALSS have been developed to bridge patients to LT or to support the failing liver temporarily until it is able to regenerate.^[7] Specifically, ALSS should be able to selectively remove accumulating toxins propagating liver failure and provide temporary support of liver and kidney function. Plasma exchange (PE) represents complete detoxification but may result in a risk of allergy and infection owing to exposure to exogenous plasma.^[8] Albumin dialysis allows the removal of albumin-bound toxins and soluble toxins with external albumin in MARS (molecular adsorbent recirculating system)^[9] or the patient's own albumin in FPSA (fractionated plasma separation and adsorption).^[10] Although some meta-analyses of clinical trials have demonstrated the beneficial effects of ALSS on ACLF,^[11,12] systematic studies on survival outcomes of HBV-ACLF are deficient. Several cohort studies have reported a positive association of ALSS with short-term or long-term survival of HBV-ACLF.^[13,14] Meanwhile, inclusive evidence, namely negative association, no relation or positive without significance, was suggested in other cohort studies. Moreover, few meta-analyses focusing on the association of ALSS and HBV-ACLF have been reported. Thus, it is imperative to perform a more comprehensive and systematic meta-analysis to re-evaluate the effects of ALSS on the survival outcomes of patients with HBV-ACLF.

In this study, a meta-analysis was conducted to evaluate the short-term and long-term survival efficacy of ALSS in patients with ACLF and compare the effects of ALSS plus standard medical treatment (SMT) versus SMT alone on survival and to evaluate the safety profile of therapy.

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Baseline characteristics of selected studies
No	Author year	Study design	Design summary	ALSS type	Sample size		Age^a (years)	Gender (Male/female)	TBiL^a	MELD score^a	Treatment of hepatitis B infection	Endpoints	Follow-up
No	Author year	Study design	Design summary	ALSS type	ALSS group	SMT group	Age^a (years)	Gender (Male/female)	TBiL^a	MELD score^a	Treatment of hepatitis B infection	Endpoints	Follow-up
1²²	Gang Qin 2014	Prospective controlled study	An open-label, randomized, controlled parallel group design was conducted at single centre. Patients were randomly assigned to ALSS combined with SMT (ALSS group) or only SMT (control group).	PE	104	130	44.13 ± 17.03	86/18	17.95 ± 8.25	28.56 ± 4.52	During the first week after admission, 34 patients received 100 mg lamivudine (LAM) daily, 3 patients received 100 mg LAM plus 10 mg adefovir (ADV), 6 patients received 0.5 mg entecavir (ETV) daily. Forty-three patients (18 in ALSS group and 25 in the control group) received early nucleos(t)ide analogues (NUCs) treatment during the first week after admission.	Primary endpoint of the study was 90-day survival, and secondary endpoint was supposed to be 5-year or 10-year survival	90 days and 5 years
2²⁵	Pi-QiZhou 2015	Retrospective cohort study	A retrospective cohort, including 181 patients with ACLF hospitalized (single-centre) between January 1, 2012 and December 31, 2014. ACLF patients were randomly divided into either a PBA plus PE group or a PE only group.	PE plus other ALSS	113	/	44.6(22–81)	94/19	24.8(5.9–51.8)	24(12–44)	Lamivudine (LAM), telbivudine, or entecavir (ETV).	Laboratory Parameters and their correlation with clinical outcomes; 90 days and 270 days survival.	90 days and 270 days
3²⁰	Jiajia Chen 2016	Prospective cohort study	Nationwide prospective multicentre study; From December 1, 2009 to December 31, 2011, 250 patients at different stages of HBV-ACLF; unified PE treatment.	PE	250	/		221/29	24.57 ± 8.71	21 ± 6	Antiviral treatment (no details were available).	Laboratory parameters; 30 days survival.	30 days
4¹⁸	Yuemeng Wan 2016	Prospective cohort study	Enrolled patients were divided into TPE group (n = 33), and DPMAS group (n = 27), respectively. All patients received standard medical therapy (SMT) in combination with TPE or DPMAS.	PE + SMT	33	/	50.7 ± 9.2	20/13	18.23 ± 5.51	22.02 ± 2.07	Entecavir (ETV).	Key liver function parameters (i.e., albumin, ALT, AST, TBA, TBIL, and DBIL) and serum inflammatory markers (i.e., PCT, IL-6, and hsCRP); 12-week survival.	84 days
4¹⁸	Yuemeng Wan 2016	Prospective cohort study		DPMAS+SMT	27	/	55.1 ± 7.7	20/7	20.06 ± 6.47	22.71 ± 2.70	Entecavir (ETV).		84 days
5²¹	Zeng Fan 2017	Prospective cohort study	Single centre 560 patients were included. 338 were treated with ALSS combined with SOC (ALSS group) and 222 were given only SOC (SOC group).	PE plus other ALSS	338	222	42.1 ± 11.5	312/26	22.4(15.9–28.1)	23.9(21.9–28.9)	Antiviral treatment (no details were available).	Neutrophil ± lymphocyte ratio and its correlation with mortality; an inflammation marker; 30 days mortality.	30 days
6¹⁹	Jia Yao 2019	Retrospective cohort study	Total of 131 patients who were diagnosed with HBV-ACLF and underwent DPMAS+PE (n = 54) or PE (n = 77) were retrospectively analysed.	PE	77	/	43.8 ± 14.2	54/23	24.54 ± 8.83	24.3 ± 5.4	Antiviral treatment (no details were available).	Changes in serum biochemical parameters; survival at 28-days; adverse effects.	28 days
6¹⁹	Jia Yao 2019	Retrospective cohort study		PE plus other ALSS	54	/	47.6 ± 11.5	38/16	26.18 ± 9.88	23.8 ± 6.2	Antiviral treatment (no details were available).		28 days
7²³	Kaizhou Huang 2019	Prospective cohort study	Patients were screened at two different medical centres operating identical medical record systems. A total of 699 hospitalized HBV-ACLF patients were initially screened and enrolled; 365 patients in the derivation cohort and 124 in the validation cohort were ultimately included.	PE plus other ALSS	365	/	46.52 ± 11.38	325/40	24.85 ± 7.20	25.40 ± 5.55	Single or combination of antiviral drugs (no details were available).	28-day mortality; factors prognostic of survival.	28 days
7²³	Kaizhou Huang 2019	Prospective cohort study		PE	124	/	45.31 ± 11.97	99/41	23.52 ± 7.72	26.17 ± 7.54		28-day mortality; factors prognostic of survival.	28 days
8¹⁴	Lanlan Xiao 2019	Retrospective cohort study	Nationwide, multicentre, retrospective study; total, 790 patients with HBV-ACLF were included; 412 patients received SMT only (SMT group), and 378 patients received SMT and ALSS treatment (ALSS group).	PE plus other ALSS	310	310	46.8 ± 11.3	274/36	23.9 ± 7	24.9 ± 5.6	Nucleos(t)ide analogues (NUCs).	Changes in laboratory parameters at Day 7 and Day 28; survival rates at day 28 and day 90; risk factors on 28-day survival	28 days
9¹⁷	Zhongyang Xie 2018	Retrospective cohort study	Total of 304 HBV-ACLF patients who received PE-based ALSS were retrospectively analysed (single centre).	PE + SMT	304	/	47.77 ± 11.32	268/36	19.3(15.5–25.6)	22.7(19.8–25.6)	Antiviral treatment (no details were available).	Survival rates at days 28; prognostic factors.	28 days
10¹³	Lingling Yang 2020	Case–control matched study	The clinical data of HBV-ACLF patients receiving SMT plus ALSS (ALSS group, n = 507) or only SMT (SMT group, n = 417) were collected for survival assessment.	PE	507	417	44 ± 17	454/53	24.3 ± 9.4	23.91	Nucleos(t)ide analogues (NUCs).	End-points were cumulative survival rates at days 21, 28, and 90.	21 days, 28 days, and 90 days

Abbreviations: ACLF, acute-on-chronic liver failure; ALSS, artificial liver support system; DPMAS, double plasma molecular absorption system; HBV-ACLF, hepatitis B virus–related acute-on-chronic liver failure; MELD, model for end-stage liver disease; PBA, plasma bilirubin adsorption; PE, plasma exchange; SMT, standard medical treatment; SOC, standard of care; TBiL, total bilirubin; TPE, therapeutic plasma exchange.
^aData were displayed by mean ± standard deviation or mean (range).