Review Article

Current and Emerging Therapies for the Management of Cirrhosis and its Complications

Elliot B. Tapper; Nneka N. Ufere; Daniel Q. Huang; Rohit Loomba

Aliment Pharmacol Ther. 2022;55(9):1099-1115.

Abstract and Introduction

Abstract

Background: Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes.

Methods: We conducted a narrative review of the literature focusing on the most recent advances.

Results: We review the aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, and the current landscape of clinical trials for non-alcoholic steatohepatitis. We review the current standard of care and latest developments in the management of hepatic encephalopathy (HE), ascites and hepatorenal syndrome. We evaluate the promise and drawbacks of chemopreventative therapies that have been examined in trials and observational studies which may reduce the risk of hepatocellular carcinoma and cirrhosis complications. Finally, we examine the therapies which address the non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue.

Conclusion: The improvement of clinical and patient-reported outcomes for patients with cirrhosis is possible by applying evidence-based pharmacotherapeutic approaches to the prevention and treatment of cirrhosis complications.

Introduction

Cirrhosis is common and morbid. Its prevalence exceeds >1 million persons in the United States (US) alone,^[1] rising by 50% in the past 20 years.^[2] Hospitalisations for cirrhosis have increased by 90% and their rate now exceeds that for heart failure.^[3] Cirrhosis mortality has risen by 65% since 2008.^[4] Despite these poor indicators, there has been substantial progress in supportive care for cirrhosis with interventions that enrich quality of life and prevent the development of cirrhosis complications. Effort to optimise therapy for cirrhosis care and prevention will improve public health. Herein, we provide a narrative review of the state-of-the art for the pharmacotherapeutic management and prevention of cirrhosis complications.

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Abstract and Introduction
Aetiologic Therapies
Conclusion
References

Table 1. Selected studies of drugs for NASH cirrhosis in Phase II/III development
Agent	Mechanism	Phase	ClinicalTrials.gov number	Progress/results	Date of completion or expected completion
Simtuzumab⁴²	Monoclonal antibody against lysyl oxidase-like 2	IIb	NCT01672879	Ineffective in decreasing hepatic venous pressure gradient	Jan 2017
Selonsertib⁴¹	Selective inhibitor of ASK1	III	NCT03053063	Ineffective in improving fibrosis without worsening NASH	May 2019
Emricasan⁴⁴	Pan-caspase inhibitor	II	NCT03205345	No reduction in composite outcome of mortality, decompensation or rise in MELD-NA score ≥4 points	Aug 2019
Pegbelfermin ⁴⁵	PEGylated fibroblast growth factor 21 (FGF21) analogue	IIa	NCT03486912	Ineffective in improving fibrosis without worsening NASH	Oct 2021
Aldafermin	Fibroblast growth factor 19 analogue	II	NCT04210245	Ongoing; primary outcome: ≥ 1-stage improvement in fibrosis without worsening NASH	Sep 2022
Belapectin	Inhibitor of galectin 3	IIb/3	NCT04365868	Ongoing; primary outcome: proportion of patients who develop new oesophageal varices	Dec 2023
Semaglutide ± Cilofexor/Firsocostat	Glucagon-like peptide-1 receptor agonist (semaglutide)	II	NCT04971785	Ongoing; primary outcome: ≥1-stage improvement in fibrosis without worsening NASH	Mar 2024
Efruxifermin	Fc- fibroblast growth factor 21 fusion protein	IIb	NCT05039450	Ongoing; primary outcome: change from baseline in fibrosis regression with no worsening steatohepatitis	Apr 2024
BMS-986263	siRNA designed to degrade HSP47 mRNA	II	NCT04267393	Ongoing; primary outcome: ≥ 1-stage improvement in fibrosis without worsening NASH	Jul 2024

Abbreviations: MELD, model for end-stage liver disease; NASH, non-alcoholic steatohepatitis.

Table 2. Therapies associated with reduced risk of cirrhosis complications
Study type	Outcome	Exemplar study	Threats to validity from study design
Study type	Outcome	Exemplar study	Specific	General
Observational studies	Aspirin
	Hepatocellular carcinoma	Simon 2020	Implausible 50% absolute risk reduction, largely non-cirrhotic cohort	Retrospective cohort	Administrative data	Confounding by indication	Immortal time bias
	Beta-blockers
	Hepatocellular carcinoma	Wijarnpreecha⁹⁴	Implausible 39% relative risk reduction
	Statins
	Variceal bleeding	Mohanty⁹⁹	Low event rates (1%–2%)
	Ascites	Mohanty⁹⁹	Unreliable diagnostic codes
	Hepatocellular carcinoma	Simon¹⁰⁰	Implausible 70% absolute risk reduction
	Hepatocellular carcinoma	Simon¹⁰⁰	Largely non-cirrhotic cohort
	Hepatic encephalopathy	Tapper⁹⁸	Did not use new-user design
Randomised trials	Carvedilol
	Variceal bleeding	Sinagra 2014 (meta-analysis of RCTs)¹⁶³	Optimal method of patient selection unknown	None
	Ascites	Villaneuva 2018⁹¹	Highly adherent patients; most with viral untreated hepatitis C
	Statins
	Mortality	Abraldes⁹⁷	Small sample (N = 158) powered to detect the difference in bleeding but not mortality	All patients were on Non-selective Beta-Blockers

Table 3. Therapeutic agents for the control of symptoms common to patients with cirrhosis
Symptom	Therapy	RCT	Dosing	Patient population	Duration of treatment	Outcome	Reported side effects
Pruritus	Cholestyramine	Di Padova¹¹⁵	Cholestyramine (3 mg TID) vs placebo	10 patients with either intra- or extra- hepatic cholestasis	4 weeks	Improvement in itching intensity in cholestyramine group	No reported major/minor adverse effects
	Colesevelam	Kuiper¹¹⁶	Colesevelam (1875 mg twice daily) vs placebo	35 patients with cholestatic pruritus (PBC: 14, PSC: 14, Other: 7)	3 weeks	No difference in pruritus (VAS), quality of life (SF-36 and LDSI), or itching severity between both groups	No reported major/minor adverse effects
	Gabapentin	Bergasa¹¹⁷	Gabapentin (300–2400 mg daily) vs placebo	16 women with chronic liver disease (PBC: 9, PSC: 1, HCV: 6) and chronic pruritus	4 weeks	Increased perception of pruritus (VAS) in gabapentin group	Minor: Pruritus, fatigue, dizziness, worsening symptoms of carpal tunnel syndrome, vomiting
	Rifampin	Ghent¹⁶⁴	Rifampin (300–450 mg daily in divided doses) vs placebo	Nine patients with compensated PBC and chronic pruritus	4 weeks (randomised crossover: 2 weeks rifampin, 2 weeks placebo with washout period)	Improved pruritus scores (VAS) during rifampin therapy	No reported major/minor adverse effects
	Rifampin	Podesta¹⁶⁵	Rifampin (300 mg twice daily) vs placebo	14 patients with PBC	2 weeks (randomised crossover: 1 week rifampin, 1 week placebo with washout period)	Improved pruritus severity (VAS) during rifampin therapy	No reported major/minor adverse effects
	Naltrexone	Wolfhagen¹¹⁹	Naltrexone (50 mg daily) vs placebo	16 patients (PBC: 13, PSC: 2, Other: 1) and chronic pruritus	4 weeks	Improved daytime and nighttime itching (VAS) in naltrexone group	Minor: Opioid withdrawal-like phenomena, nausea, dizziness, flushing, drowsiness, headache, tremors, abdominal cramps
	Naltrexone	Terg³³	Naltrexone (50 mg daily) vs placebo	20 patients (PBC: 15, PSC 1, Other: 4)	1–3 months	Improved pruritus severity (VAS) in naltrexone group
	Sertraline	Mayo¹²²	Sertraline (75–100 mg daily) vs placebo	12 patients with cholestatic liver disease (PBC: 9, PSC: 2, Other: 1; 4 with MELD >15) and chronic pruritus	12 weeks (randomised crossover: 6 weeks sertraline, 6 weeks placebo with washout period)	Improved itch scores (VAS) in sertraline group	Minor: Dizziness, loose stools
	Bezafibrate	De Vries¹²³	Bezafibrate (400 mg daily) vs placebo	70 patients with cholestatic liver disease (PSC: 44, PBC 24, Other: 2) with itch intensity of ≥5 on VAS	3 weeks	Higher rates of ≥50% reduction of moderate to severe pruritus (VAS) in bezafibrate group	Minor: Pain in the mouth, lower back pain, general malaise, intensified itch and jaundice after stop of treatment
Muscle cramps	Taurine	Vidot¹²⁷	Taurine (500–1000 mg twice daily) vs placebo	30 patients (CTP A: 6, CTP B: 20, CTP C: 4, 43% with prior or present HE) experiencing ≥3 cramps/week	8 weeks (randomised crossover: 4 weeks taurine, 4 weeks placebo)	Reduced frequency, duration and intensity of muscle cramps (patient self-report, VAS) in taurine group	No reported major/minor adverse effects
	Branched-chain amino acids (BCAA)	Hidaka¹²⁸	Daytime BCAA (one sachet after each meal) vs Nocturnal BCAA (one sachet after breakfast and two sachets before bedtime)	37 patients with cirrhosis and serum albumin 3.1–3.5 g/dl (CTP A: 21, CTP B: 16)	12 weeks	Decreased occurrence of muscle cramps (HRQOL survey) in nocturnal group	Minor: Bloating, itching
	Quinidine	Lee¹³⁰	Quinidine sulphate (400 mg daily) vs placebo	31 patients with cirrhosis (CTP A: 23, CTP B: 7, CTP C: 1) and muscle cramps	4 weeks	Reduced frequency of cramps (patient self-report) in quinidine group	Minor: diarrhoea *Not approved for use in the United States due to side effect profile
	Baclofen	Elfert¹³¹	Baclofen (10–30 mg total daily dose) vs placebo	100 patients with cirrhosis (CTP score 5–9) without HE experiencing ≥3 cramps/week	12 weeks	Decreased frequency, severity and duration of muscle cramps (patient self-report) in baclofen group	Minor: Drowsiness, constipation, nausea
	Methocarbamol	Abd-Elsalam¹³²	Methocarbamol (500 mg twice daily) vs placebo	100 patients with HCV cirrhosis (CTP A: 21, CTP B: 42, CTP C: 37) experiencing ≥3 cramps/week	4 weeks	Decreased frequency and duration of muscle cramps (patient self-report) in methocarbamol group	Minor: Dry mouth, drowsiness
	Orphenadrine	Abd-Elsalam¹³³	Orphenadrine (100 mg twice daily) vs placebo	124 patients with cirrhosis (CTP A: 61, CTP B: 24, CTP C: 39) experiencing ≥3 cramps/week	4 weeks	Decreased frequency and duration (patient self-report) of muscle cramps in orphenadrine group	Minor: Dry mouth, drowsiness, nausea
Sexual dysfunction	Tadalafil	Jagdish¹³⁶	Tadalafil (10 mg daily) vs placebo	140 men with cirrhosis (CTP < 10) and erectile dysfunction (erectile function score <25 on IIEF)	12 weeks	Improved erectile function (>5-point increase in erectile function score of IIEF) in the tadalafil group	Minor: Dizziness, congestion, mild headache, bloating, peri-orbital swelling, itching
Sleep Disturbances	Melatonin	De Silva¹⁴⁴	Melatonin (3 mg nightly) vs placebo	60 patients with cirrhosis (CTP A or B) with sleep disturbances, without present or prior overt HE	2 weeks	Improved sleep quality (PSQI) and daytime sleepiness (ESS) in the melatonin group	Minor: Abdominal pain, headache, dizziness
	Zolpidem	Sharma¹⁴³	Zolpidem (5 mg nightly) vs placebo	52 patients with cirrhosis (CTP A or B) with PSQI >5 without present or prior overt HE	4 weeks	Increased total sleep time, sleep efficiency, subjective sleep quality (PSQI) and improvement in parameters of sleep initiation and maintenance (polysomnography) in zolpidem group	Minor: Excessive daytime sleepiness, constipation, dry mouth
	Hydroxyzine	Spahr¹⁴⁵	Hydroxyzine (25 mg nightly) vs placebo	35 patients with cirrhosis with minimal HE, >3 months of sleep difficulties, and ESS score >10	10 days	Improved sleep behaviour (VAS, wrist actigraphy) in hydroxyzine group	Major: 1 patient developed acute overt hepatic encephalopathy while receiving hydroxyzine
Fatigue	Fluvoxamine	ter Borg¹⁴⁹	Fluvoxamine (75 mg twice daily) vs placebo	33 patients with cholestatic liver disease (PBC: 22, PSC: 11; CTP < 6) with self-reported fatigue	6 weeks	No statistically significant beneficial effect of fluvoxamine on fatigue (VAS, FFSS, MFI) or quality of life (SF-36)	Minor: Headache, nausea, insomnia, dizziness
Fatigue	Modafinil	Silveira (2017)¹⁵⁰	Modafinil (100 mg daily) vs placebo	33 patients with PBC receiving UDCA >6 months before study enrolment. Excluded: MELD >15, recurrent variceal bleeding, diuretic-refractory ascites or spontaneous HE	12 weeks	No significant improvement in fatigue severity (≥50% improvement in FFSS) in modafinil compared to placebo	Minor: Headaches, diarrhoea, rash

Abbreviations: CTP, Child-Turcotte-Pugh; ESS, Epworth Sleepiness Scale; FFSS, Fick Fatigue Severity Scale; HAS, Hourly scratching activity; HE, Hepatic encephalopathy; HRQOL, Health-related quality of life; IIEF, International Index of Erectile Function; LDSI, Liver Disease Symptom Index; MELD, Model for End-stage Liver Disease; PBC, Primary biliary cholangitis; PSC, Primary sclerosing cholangitis; PSQI, Pittsburgh Sleep Quality Index; SF-36, Short-Form 36 Questionnaire; UDCA, Ursodeoxycholic acid; VAS, visual analogue scale.