Gastrointestinal and hepatic side effects of potential treatment for COVID-19 and vaccination in patients with chronic liver diseases

Man Fai Law, Rita Ho, Kimmy Wan Tung Law, Carmen Ka Man Cheung

Man Fai Law, Carmen Ka Man Cheung, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

Rita Ho, Department of Medicine, North District Hospital, Hong Kong, China

Kimmy Wan Tung Law, West Island School, Hong Kong, China

Abstract The outbreak of coronavirus disease 2019 (COVID-19) is a global pandemic.Many clinical trials have been performed to investigate potential treatments or vaccines for this disease to reduce the high morbidity and mortality.The drugs of higher interest include umifenovir, bromhexine, remdesivir, lopinavir/ritonavir, steroid, tocilizumab, interferon alpha or beta, ribavirin, fivapiravir, nitazoxanide, ivermectin, molnupiravir, hydroxychloroquine/chloroquine alone or in combination with azithromycin, and baricitinib.Gastrointestinal (GI) symptoms and liver dysfunction are frequently seen in patients with COVID-19, which can make it difficult to differentiate disease manifestations from treatment adverse effects.GI symptoms of COVID-19 include anorexia, dyspepsia, nausea, vomiting, diarrhea and abdominal pain.Liver injury can be a result of systemic inflammation or cytokine storm, or due to the adverse drug effects in patients who have been receiving different treatments.Regular monitoring of liver function should be performed.COVID-19 vaccines have been rapidly developed with different technologies including mRNA, viral vectors, inactivated viruses, recombinant DNA, protein subunits and live attenuated viruses.Patients with chronic liver disease or inflammatory bowel disease and liver transplant recipients are encouraged to receive vaccination as the benefits outweigh the risks.Vaccination against COVID-19 is also recommended to family members and healthcare professionals caring for these patients to reduce exposure to the severe acute respiratory syndrome coronavirus 2 virus.

Key Words: COVID-19 treatment; Gastrointestinal side effects; Hepatic side effects; COVID-19 vaccine; Chronic liver disease; Liver transplantation

INTRODUCTION

The outbreak of coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).It is a very contagious virus and has infected millions of people worldwide causing numerous deaths.There are many clinical trials investigating potential treatments or vaccines for this disease to reduce the high morbidity and mortality.

Drugs with potential utility include remdesivir, lopinavir/ritonavir (LPV/r), steroids, tocilizumab, interferon alpha or beta, ribavirin, hydroxychloroquine/chloroquine alone or in combination with azithromycin, and baricitinib.Gastrointestinal (GI) symptoms and liver dysfunction are frequently seen in COVID-19 which can make it difficult to differentiate disease manifestations from treatment side effects[1,2].

The common GI symptoms in patients with COVID-19 include anorexia, dyspepsia, nausea, vomiting, diarrhea and abdominal pain[3-11].The pooled prevalence of GI symptoms is 17.6% according to a recent meta-analysis[12].The hepatic manifestations of COVID-19 include elevated liver enzymes and less commonly elevated bilirubin levels.The incidence of liver injury ranges from 14.8% to 53% as indicated by abnormal alanine transaminase (ALT)/aspartate aminotransferase (AST) levels with slight elevation of bilirubin levels[2,7].Patients with liver dysfunction also tend to have severe COVID-19, and the liver injury in these patients can be a result of systemic inflammation or cytokine storm, or due to the adverse drug reactions in severe COVID-19 patients who have been receiving different treatments.While cholangiocytes may contribute to hepatic regeneration and immune response, it has been suggested that bile duct epithelial cells play a greater role in hepatic injury due to SARS-CoV-2 infection than cholangiocytes do[13].The aim of the current article is to review the GI and hepatic side effects associated with the potential agents for the treatment of COVID-19, focusing particularly on redemsivir, LPV/r and steroids which have shown beneficial effects in the treatment of COVID-19.COVID-19 vaccines are now available in many countries and an increasing number of people are getting vaccinated.We will discuss their side effects and the current views on whether patients with chronic liver diseases (CLD), liver transplantation or inflammatory bowel disease (IBD) should receive the vaccine.

COVID-19 TREATMENTS

The agents used for COVID-19 treatment can be classified according to the type of agents, such as antiviral, antiparasitic, antibacterial and immunomodulatory agents, or according to the site of action on the SARS-CoV-2 virus such as blocking the entry of virus, inhibition of viral replication and anti-inflammatory effect.

Viral entry can be blocked by proteins, peptides, or small molecule compounds that bind to the viral S protein, thereby preventing the virus from interacting with the host membrane.Examples are umifenovir and bromhexine[14].

Inhibitors of viral nucleic acid synthesis are the best represented class of antiviral drugs that suppress viral replication in host cells[15].Examples include lopinavirritonavir, remdesivir, ribavirin, chloroquine or hydroxychloroquine, favipiravir, nitazoxanide, ivermectin and molnupiravir.

The RNA-dependent RNA polymerase (RdRp) is found in the core of the coronavirus replication machinery, nsp12 protein, and has an important role in the viral life cycle[16].Inhibition of RdRp is a possible target for therapeutic interventions.Examples of RdRP inhibitors include favipiravir and ribavirin.

Excessive inflammatory responses and cytokine release are found in patients with severe cases of COVID-19.This mechanism contributes to the worsening of the disease and stimulates lung and other systemic injuries.The early modulation of these responses can reduce the risk of acute respiratory distress[17].Examples of agents that target the inflammatory response include steroids, tocilizumab [an anti-interleukin (IL)-6 monoclonal antibody] and baricitinib.The mechanisms of agents used for the treatment of COVID-19 are shown in Figure 1.

Figure 1 The mechanism of potential treatment of coronavirus disease 2019.

AGENTS AGAINST THE ENTRY OF VIRUS

Umifenovir

Umifenovir is used for the treatment of some enveloped and non-enveloped viral infection.It can also effectively block SARS-CoV-2 entry into cells and inhibits postentry stages of infection[18].The efficacy of the drug was assessed in an open-label randomized controlled trial (RCT).One hundred patients were randomly assigned to two treatment groups receiving either hydroxychloroquine followed by LPV/r or hydroxychloroquine followed by umifenovir[19].The primary outcome was hospitalization duration and clinical improvement 7 d after admission.

Umifenovir significantly improved clinical and laboratory parameters including peripheral oxygen saturation, intensive care unit (ICU) admission rate, duration of hospitalization, white blood cell (WBC), and erythrocyte sedimentation rate when compared with LPV/r.The duration of hospitalization in the umifenovir group was significantly shorter than in the LPV/r arm (7.2 dvs9.6 d;P= 0.02)[19].

Nausea, vomiting and liver function test (LFT) derangements are the major GI and hepatic abnormalities that can occur in patients receiving umifenovir.Clinicians should use the drug with caution in those patients with hepatic impairment.

Bromhexine

SARS-CoV-2 invades the human body through the angiotensin-converting enzyme 2 (ACE-2)/transmembrane protease serine 2 (TMPRSS2).In addition to host cell entry, TMPRSS2 is involved in the maturation and release of the virus, which ultimately increase the viral infectivity[20].Therefore, a possible useful therapeutic approach for COVID-19 is the inhibition of TMPRSS2[21].

Bromhexine has strong inhibitory effect on TMPRSS2 and can be used to block pulmonary virus infection[22].Therefore, it may exert a protective effect against COVID-19-induced acute lung injury.The effect and safety of bromhexine was assessed in patients with mild or moderate COVID-19 who were randomly assigned to a bromhexine group or a control group at a 2:1 ratio[22].The primary end points were the time to clinical recovery and the rate of deterioration after initiation of medications.

There were no significant differences in the outcomes between the two treatment groups.The side effects include LFT derangement (38.9%), gingivitis (11.1%), insomnia (11.1%), headache (5.6%), and elevated WBCs in urine (5.6%).However, all side effects were mild and no patient stopped the treatment because of the adverse effects[22].

Another randomized, open-label clinical trial study involving 78 patients was performed to assess the efficacy of bromhexine.Patients were randomized to the bromhexine group or the control group.The primary outcomes were the rate of ICU admissions, intubation and then mechanical ventilation, and 28-d mortality[23].When compared with the standard treatment group, the bromhexine-treated group showed a significant reduction in ICU admissions (5.1%vs28.2%,P= 0.006), intubation (2.6%vs23.1%,P= 0.007) and death (0vs5,P= 0.027)[23].

INHIBITORS OF VIRAL REPLICATION

LPV/r

LPV/r is a co-formulation of two structurally related protease inhibitor (PI) antiretroviral agents widely used to treat HIV infections[24].Ritonavir substantially increases the half-life of lopinavir by inhibiting cytochrome P450 (CYP) isoenzyme 3A4[25].PIs prevent cleavage of gag and gag-pol protein precursors in infected cells, arresting maturation and inhibiting the formation of infectious virions, thereby preventing subsequent waves of infection[26].

Lopinavir demonstratedin vitroinhibitory activity against SARS-CoV and Middle East respiratory syndrome coronavirus[27-29].Addition of LPV/r to ribavirin in treating SARS patients showed a reduction of adverse outcomes [death or development of acute respiratory distress syndrome (ARDS) requiring intensive care] compared to ribavirin alone[30].Conflicting results of published data have stirred controversy concerning the use of LPV/r in COVID-19 patients.Caoet al[31] conducted a RCT in Wuhan, China to assess the efficacy and safety of LPV/r in 199 severe COVID-19 patients.Patients were randomly assigned in a 1:1 ratio to receive either LPV/r (400/100 mg, orally) twice daily or supportive care alone.Treatment with LPV/r was not associated with a difference from standard care in the time to clinical improvement [hazard ratio (HR) for clinical improvement, 1.31; 95% confidence interval (CI): 0.95 to 1.80].The 28-d mortality rate and the percentages of patients with detectable viral RNA at various time points were similar.In a modified intention-totreat analysis, which excluded three patients with early death, antiviral treatment shortened the median time to clinical improvement by 1 day compared with standard care (15 dvs16 d, HR, 1.39; 95%CI: 1.00 to 1.91)[31].Another RCT included 86 patients with mild to moderate disease; the use of LPV/r did not shorten the time of positiveto-negative conversion of SARS-CoV-2 nucleic acid in respiratory specimen, nor symptoms or radiological improvement[32].On the other hand, Yanet al[33] reported data from a retrospective study including 129 non-critically ill patients with COVID-19.They showed that the median duration of SARS-CoV-2 shedding in the LPV/r treatment group was 22 d [interquartile range (IQR) 18-29], which was significantly shorter than in group that did not receive LPV/r treatment (28.5 d, IQR 19.5-38) (logrankP= 0.009).Subgroup analysis revealed that the administration of LPV/r treatment within 10 d of symptom onset, but not later administration, could shorten the duration of SARS-CoV-2 RNA shedding compared with no LPV/r treatment[33].Yeet al[34] studied the clinical efficacy of LPV/r in 47 patients and showed that patients in the active treatment group returned to normal body temperature in a shorter time compared with the control group (4.8 ± 1.94 dvs7.3 ± 1.53 d,P= 0.0364).

GI adverse events were common in patients receiving LPV/r.The most common GI adverse event in patients receiving LPV/r was diarrhea (occurring in 20% of patients); others included nausea, vomiting abdominal pain and gastroenteritis[35].In the study by Caoet al[31], 14% of patients were unable to complete the full 14-d course of LPV/r because of GI adverse events (Table 1).In the study by Liet al[32], one patient withdrew from the study due to severe diarrhea.Twice-daily dosing of LPV/r is associated with a reduced frequency of moderate to severe diarrhea compared with once daily[36].The majority of patients who develop diarrhea can be managed conservatively and may not require antidiarrheal treatment[37].Hypokalemia, secondary to diarrhea or emesis, should be treated according to standard local protocols[38].If patients develop significant adverse effects, lower dosages of LPV/r (e.g., 200/100 mg twice a day) can be considered, with the understanding that lower doses may not markedly alleviate toxicities[34].

Table 1 Gastrointestinal adverse events in key studies investigating treatments for coronavirus disease 2019

Ritonavir use is associated with a 5-fold higher incidence of severe hepatotoxicity compared with other PIs[39].Hepatitis including elevation of AST, ALT, and gammaglutamyl transferase levels has been reported in 3.5% of patients taking LPV/r, according to the package insert[35].This drug is principally metabolized by the hepatic CYP3A4 isoenzyme[40] and therefore, caution should be exercised when administering this drug to patients with hepatic impairment.Safety data on LPV/r use in patients with cirrhosis do exist[41].Coinfection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) increases the risk hepatotoxicity and patients with such infections should be monitored closely[42].Patients with severe liver disease such as cirrhosis or those with significant elevation of liver enzyme were excluded from RCTs[31,32].Concomitant use of tenofovir with LPV/r is not recommended since this will lead to elevated levels of tenofovir.Physicians may consider switching from tenofovir to entecavir during treatment with LPV/r.

Remdesivir

Remdesivir was initially under clinical development for the treatment of Ebola virus disease[43].It is a monophosphoramidate prodrug of an adenosine analog, which is then metabolized in cells to an active nucleoside triphosphate that inhibits viral RdRp early in the viral infectious cycle.It has demonstrated antiviral activity against coronavirus including SARS-CoV-2[44-47].Other potential antiviral mechanisms involve lethal mutagenesis and chain termination[48,49].

Remdesivir was used to treat the first case of COVID-19 infection in the United States[3].Thereafter, numerous clinical trials focusing on its efficacy and safety have been published.In a multicenter RCT led by Beigelet al[50] including 1059 hospitalized patients with evidence of lower respiratory tract involvement, remdesivir was administered intravenously as a 200-mg loading dose on day 1, followed by 100-mg daily on days 2 through 10 or until hospital discharge or death.Patients who received treatment had a shorter time to recovery than patients who received placebo (median 11 dvs15 d; rate ratio for recovery, 1.32; 95%CI: 1.12 to 1.55;P< 0.001).Recovery was defined as patients not requiring supplemental oxygen or ongoing medical care except for infection-control reasons.Mortality was numerically lower in the treatment group than the placebo group, but the difference was not significant (HR for death, 0.70; 95%CI: 0.47 to 1.04)[50].Another RCT from China enrolled 237 patients, but failed to demonstrate a significant difference in the time to clinical improvement with remdesivir in severe patients [21.0 d in remdesivir groupvs23.0 d in the control group, HR 1.23 (95%CI: 0.87 to 1.75)][51].Nevertheless, the results should be interpreted with caution as the power of this study was limited by failure to complete full enrolment due to control of the outbreak in Wuhan.

Several studies have compared the efficacy and safety of 5 dvs10 d of remdesivir treatment in patients with COVID-19[52,53].Goldmanet al[52] enrolled 397 COVID-19 patients with evidence of pneumonia and reduced oxygen levels but not requiring mechanical ventilation or extracorporeal membrane oxygenation.Similar clinical improvement was observed in the 5-d group and 10-d group based on assessment on day 14 (P= 0.14).The most common GI/hepatic adverse events were nausea (10% in the 5-d groupvs9% in the 10-d group), increased ALT (6%vs8%), and constipation (7% in both groups)[52].Spinneret al[53] randomized 596 patients with moderate COVID-19 to a 10-d course of remdesivir, a 5-d course of remdesivir, or standard care in a 1:1:1 ratio.At 11 d after starting treatment, those randomized to the 5-d course of remdesivir had a statistically significant difference in clinical status compared with standard care[53].However, those receiving the 10-d course of remdesivir did not have a statistically significant difference in clinical outcome compared with standard care.Common side effects included nausea, hypokalemia, and headache.Elevated liver enzymes were observed in one-third of patients, and were of grade ≥ 3 severity in 2% of patients[53].

GI/hepatic adverse events were similar in the treatment and control arms of the two RCTs described above[50,51].One patient receiving remdesivir developed a hemorrhage of the lower digestive tract and three patients discontinued treatment as aresult of liver enzyme elevation in the study by Wanget al[51].No serious grade 3 or 4 liver dysfunction was reported in either arm[51].

AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; inf: Infusion; IQR: Interquartile range; IV: Intravenous; NA: Not available; Tx: Treatment.

GI and hepatic adverse events have also been reported in case series of patients receiving remdesivir.In a remdesivir compassionate use program (n= 53), 12 patients (23%) developed elevated hepatic enzymes, and 5 (9%) had diarrhea[54].Two patients (3.8%) discontinued remdesivir prematurely because of elevated aminotransferases[54].In another case series in 35 patients who received compassionate remdesivir treatment in Italy, hepatotoxicity was the most frequent adverse event, with a grade 3 to 4 increase in transaminase levels observed in 42.8% of the patients[55].In the first 12 COVID-19 patients in United States, all 3 patients who received remdesivir experienced transient transaminitis and GI symptoms including nausea, vomiting, gastroparesis or rectal bleeding[56].Another case series of critically ill patients receiving remdesivir in Italy reported that three of these four patients had elevated ALT and AST levels, ranging from 5 times to 8 times the upper limit of normal[57].

Hepatic adverse events are not unexpected with nucleoside analogues; these agents can cause direct hepatotoxicity by inducing mitochondrial dysfunction and/or idiosyncratic hepatotoxicityviaan acute hypersensitivity reaction or the production of toxic intermediates[58].Asymptomatic grade 1 or 2 ALT elevations were observed in healthy individuals who received remdesivir in phase 1 studies[59].Pharmacokinetic studies in patients with hepatic impairment were limited, but remdesivir should be used with caution in patients with existing liver disease, and only if the potential benefit outweighs the risk[60].Regular monitoring of liver function should be performed if possible[61].

Hydroxychloroquine/chloroquine ± azithromycin

Hydroxychloroquine/chloroquine are drugs commonly us ed in the management of rheumatoid arthritis, systemic lupus erythematosus and malaria.SARS-CoV-2 enters cells by binding to the ACE-2 receptor.Chloroquine may inhibit terminal glycosylation, thus preventing the virus from binding to the ACE-2 receptor[62].Hydroxychloroquine prevents SARS-CoV-2 from binding to gangliosides which in turn prevents the virion from engaging with the ACE-2 receptor[63].

The use of hydroxychloroquine/chloroquine in the treatment of COVID-19 is controversial[64-71].A multicenter, RCT was conducted in 504 hospitalized patients with COVID-19 who were receiving either no supplemental oxygen or a maximum of 4 L/min of supplemental oxygen.Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine 400 mg twice daily, or standard care plus hydroxychloroquine 400 mg twice daily and azithromycin 500 mg once daily for 7 d[70].Active treatment had no effect on patients’ clinical status at 15 d compared with standard care.The proportional odds of having a higher score on the seven-point ordinal scale at 15 d was not increased by either hydroxychloroquine alone [odds ratio (OR) 1.21; 95%CI: 0.69 to 2.11;P= 1.00] or hydroxychloroquine plus azithromycin (OR, 0.99; 95%CI: 0.57 to 1.73;P= 1.00).In addition, a higher proportion of patients receiving hydroxychloroquine alone (8.5%) or with azithromycin (10.9%) developed elevated liver enzymes compared those who did not receive either agent (3.4%)[70].Further randomized studies are needed to clarify the efficacy of hydroxychloroquine or chloroquine in the treatment of COVID-19.

These drugs also have a number of side effects.Apart from the well-known arrhythmogenic cardiotoxicity of the drugs, the most common adverse events of hydroxychloroquine and chloroquine are GI, including GI upset, nausea, vomiting, diarrhea, abdominal cramps, and a metallic taste[72-74].In a study evaluating the use of chloroquine, nearly 24% of patients suffered from nausea or abdominal cramps and 17% reported diarrhea as side effects[75].Up to 50% of patients receiving hydroxychloroquine in another study reported some GI side effects; the frequency was dosedependent with GI events occurring more commonly with loading doses of 800 mg or higher[76].

Chloroquine and hydroxychloroquine should be administered with food to reduce nausea and vomiting.At the same time, chloroquine can be crushed and mixed with flavored syrups to mask the bitter taste.It is also recommended to avoid taking antacids within 4 h of chloroquine because of a potential for chelation and reduced bioavailability, but this drug interaction does not occur with hydroxychloroquine.

Azithromycin is a semisynthetic macrolide antibiotic that is commonly prescribed to treat infections with Gram-positive, Gram-negative and atypical pathogens.It has been used for the treatment of COVID-19 in combination with hydroxychloroquine or chloroquine and has produced synergistic effects in the context of combination therapy[77].Azithromycin may cause GI side effects such as nausea and vomiting.

Ribavirin

Ribavirin is a guanine derivative used for the treatment of respiratory syncytial virus and HCV infections.It has been used in combination with other agents for the treatment of COVID-19[78].In a prospective study of patients with mild to moderate COVID-19, the combination of interferon-beta, oral LPV/r and ribavirin produced a significantly shorter median time from start of study treatment to negative nasopharyngeal swab compared with LPV/r alone[78].Patients in the combination group also had earlier relief of symptoms compared with the control group (4 dvs8 d,P< 0.0001).This study suggests that combination therapy is more potent than singleagent antiviral therapy against COVID-19[78].

The common side effects observed in the combination therapy group included diarrhea (40%), fever (37%), nausea (35%) and elevated ALT levels (13%)[78].Since CYP enzymes are not involved in the metabolism and elimination of ribavirin, there is minimal potential for drug-drug interactions.

Favipiravir

Favipiravir is an RdRp inhibitor[79].Once inside cells, favipiravir is converted into an active phosphoribosylated form, which acts as a substrate for viral RNA polymerase, and then inhibits RNA polymerase activity.It is a broad-spectrum antiviral drug approved in Japan for the treatment of influenza.It has also been used for the treatment of Ebola and Lassa virus infection.

Chenet al[80] conducted a prospective, randomized, open-label multicenter clinical trial involving 240 adult patients with COVID-19 comparing the efficacy and safety of favipiravirvsumifenovir.The clinical recovery rate on day 7 was better in the favipiravir arm than in the umifenovir arm (71.43%vs55.86%,P= 0.01).Favipiravir significantly shortened the latency to relief for pyrexia and cough compared with umifenovir, and dyspnea was significantly (P= 0.017) less common in the favipiravir group than in the umifenovir group.Deranged LFT is a common side effect of favipiravir and was found in 8.6% of patients.

Caiet al[81] conducted an open-label study in 80 patients with mild to moderate COVID-19 and assessed the effects of favipiravir in comparison with LPV/r for the treatment of COVID-19.Favipiravir was shown to have shorter viral clearance time (median 4 dvs11 d).In addition, a higher proportion of patients in the favipiravir than the LPV/r groups showed improvement in chest imaging (91.43%vs62.22%;P= 0.004), particularly in the group with viral clearance within 7 d of starting treatment.Multivariable Cox regression showed that favipiravir was significantly (P= 0.026) associated with faster viral clearance[81].

The most common side effects of favipiravir were liver enzyme abnormalities, GI symptoms like diarrhea, and serum uric acid elevations.We would be cautious about prescribing favipiravir in patients with abnormal LFT results.

Nitazoxanide

Nitazoxanide is an antiparasitic prodrug with antiviral properties that is approved by the U.S.Food and Drug Administration (FDA).The effects of nitazoxanide against COVID-19 were examined in a multicenter, randomized, double-blind, placebocontrolled trial recruiting 392 patients presenting up to 3 d after onset of symptoms including fever, dry cough, and/or fatigue.The patients were randomized in a 1:1 ratio to receive either nitazoxanide 500 mg 3 times/d or matching placebo for 5 d after the diagnosis of SARS-CoV2 infection was made by reverse transcription polymerase chain reaction (RT-PCR) on a nasopharyngeal sample[82].

Although there was no difference between the nitazoxanide and placebo groups in the resolution of symptoms at the 5-d study visit, a significantly higher proportion of patients in the nitazoxanide group (29.9%) returned a negative PCR result for SARSCoV-2 compared with the placebo group (18.2%;P= 0.009).There was also significantly greater reduction in viral load between the start and end of therapy in patients receiving nitazoxanide (55%) compared with placebo (45%;P= 0.013).GI side effects included nausea (14.4%), vomiting (4.6%), diarrhea (29.4%), and abdominal pain (5.2%) were reported in patients receiving nitazoxanide in the study[82].

Ivermectin

Ivermectin is an antiparasitic drug and was found to have a broad range of antiviral activity against many RNA and DNA virusesin vitro.It was also shown to be highly effectivein vitroagainst SARS-CoV-2[83].

It was shown that the combined use of ivermectin, nitazoxanide and ribavirin plus zinc supplement achieved better clearance of the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy in a non-RCT[84].The viral clearance rates on the 7thday were 0% and 58.1%, respectively, in the groups receiving supportive treatment and combined antiviral therapy, and were 13.7% and 73.1%, respectively, on the 15thday.The corresponding cumulative viral clearance rates on the 15thday were 13.7% and 88.7%, respectively.Overall, 11.3% of patients had elevation of LFTs and 22.6% of developed GI upset during the study period.

Rajteret al[85] performed a retrospective study of 280 COVID-19 patients to assess the efficacy of ivermectin, in which 173 had been treated with ivermectin and 107 had not.Most patients in both groups also received hydroxychloroquine, azithromycin, or both.Mortality was significantly lower in the ivermectin group (13.3%vs24.5%;P< 0.05).Mortality was also lower among ivermectin-treated patients with severe pulmonary involvement (38.8%vs80.7%;P= 0.001).Eleven percent of phas a broad range of antiviral activity against many RNA and DNA virusesin vitrohas a broad range of antiviral activity against many RNA and DNA virusesin vitro.Ivermectin has a broad range of antiviral activity against many RNA and DNA virusesin vitro.

Molnupiravir

Molnupiravir is an oral, direct-acting antiviral agent which was shown to be highly effective in reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA.It is well absorbed after oral administration.Fischeret al[86] randomized 202 patients to molnupiravir (200, 400 or 800 mg) or placebo twice-daily for 5 d.Antiviral activity was assessed as time to undetectable levels of viral RNA by RT-PCR and time to elimination of infectious virus isolation from nasopharyngeal swabs.

The results showed a significant reduction in virus isolation in participants receiving 800 mg molnupiravir (1.9%)vsplacebo (16.7%) at day 3 (P= 0.02).Virus was not isolated from any patient receiving 400 mg or 800 mg molnupiravir while 11.1% of patients receiving placebo had virus isolated at day 5 (P= 0.03).

There was decrease in the time to viral RNA clearance in patients given 800 mg molnupiravir compared with placebo (14 dvs27 d,P= 0.001).There was also a higher rate of overall clearance in patients receiving molnupiravir.The side effects of molnupiravir include headache, insomnia, and increased ALT.We would be cautious using molnupiravir in patient with hepatic dysfunction.

Immunomodulatory agents

Cytokine storm is an important pathogenic process in COVID-19 patients[87].SARSCoV-2 binds to the toll-like receptor, activating the nuclear factor (NF)-κB pathway and pro-inflammatory cytokines[88].Cytokines are signalling molecules that recruit immune cells to the site of inflammation, induce vascular leakage and exudation, and stimulate the generation of free radicals and proteases[89].Pro-inflammatory cytokines induce alveolar injury and reduced alveolar fluid clearance resulted in ARDS[90].Compared with mild or moderate cases, patients with severe COVID-19 have higher levels of circulating IL-2, IL-6, IL-7, IL-10, interferon gamma, granulocyte colony stimulating factor, interferon-inducible protein 10, monocyte chemoattractant peptide , macrophage inflammatory protein-1A, and tumor necrosis factor (TNF)-α[7,91-93].This raises the possibility of using immunomodulatory agents to control the inflammatory response, and thereby improve the prognosis of COVID-19[94].

Corticosteroids

Corticosteroids inhibit NF-κB signalling and various pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, TNF-α, and IL-17.It also reduces the proliferation, activation, differentiation, and survival of T cells and macrophages[95].Steroids may play a protective role in the respiratory and digestive systems by activating ACE-2 and suppressing the cytokine storm, in particular reducing IL-6 levels, in patients with severe or critical COVID-19[96].Corticosteroids were used in early reports from Wuhan, China, where they were used in an attempt to reduce inflammation-induced lung injury[90].

Dexamethasone is the first treatment that has been shown to reduce mortality in severely ill COVID-19 patients[97,98].The randomized evaluation of COVID-19 therapy (RECOVERY) trial compared 2104 patients receiving oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 d with 4321 patients receiving usual care alone.The 28-d mortality rate was lower in the group receiving dexamethasone compared with usual care group in patients who were receiving invasive mechanical ventilation (29.3%vs41.4%; rate ratio, 0.64; 95%CI: 0.51 to 0.81) or receiving oxygen without invasive mechanical ventilation (23.3%vs26.2%; rate ratio, 0.82; 95%CI: 0.72 to 0.94).No survival benefit was seen among those who were receiving no respiratory support at randomization.Dexamethasone also reduced mortality in patients with symptoms for more than 7 d but not in those with more recent symptom onset[97].

The positive impact of steroids was confirmed in a prospective meta-analysis of seven clinical trials involving 1703 critically ill patients with COVID-19 conducted in 12 countries[99].The meta-analysis showed that the use of systemic corticosteroids reduced all-cause 28-d mortality compared with usual care or placebo.The number of deaths was 222 in those receiving corticosteroids compared to 425 deaths in the usual care or placebo group.Dexamethasone could significantly suppress the odds of allcause mortality.

The preliminary report of the RECOVERY study did not describe side effects.Previously reported side effects of steroids include hyperglycemia, hypokalemia, delayed viral clearance, risk of secondary bacterial infection, psychosis and avascular osteonecrosis[100-104].Corticosteroids may induce various GI adverse events such as gastritis, peptic ulcer formation and GI bleeding, with the risk of bleeding significantly increased by concomitant non-steroidal anti-inflammatory drug use[105,106].Direct SARS-CoV-2 invasion of the GI tract, causing erosion and ulcers in severe patients, may increase the risk further[1].Prophylactic proton pump inhibitors should be considered in patients who receive dexamethasone[107].

Steroids increase the risk of acute pancreatitis by an unknown mechanism[108].Steroids activate triglyceride synthesis and accumulation, increase fatty acid uptake and inhibit fatty acid beta-oxidation in the liver, while they also increase lipolysis, lipogenesis and the secretion of non-esterified fatty acids and adipokines in adipose tissue, which results in hepatic steatosis[109].Diabetes and obesity are associated with the development of non-alcoholic fatty liver disease[110].These metabolic risk factors may result in deleterious effects on host immunity, and are closely related to disease severity and mortality in patients with COVID-19[111-115].Regular monitoring of liver function and glucose level is recommended for this high-risk group of patients receiving dexamethasone.

Tocilizumab

COVID-19 can trigger aggressive an inflammatory response resulting in cytokine release syndrome (CRS), which is associated with an unfavorable prognosis[116].A meta-analysis of 6 studies including 1302 patients demonstrated 2.9-fold higher levels of IL-6 in patients with complicated COVID-19 compared with patients with noncomplicated disease[117].IL-6 is an important cytokine responsible for an inflammatory storm that leads to impaired oxygen diffusion in the lungs[7].Tocilizumab is a recombinant humanized monoclonal antibody against the IL-6 receptor and reduces the effects of CRS.This led to speculation that it could be used in the treatment of COVID-19, especially in severe patients with high IL-6 levels.

A retrospective, observational cohort study was carried out to investigate mortality in 544 patients with severe COVID-19 requiring support in the ICU; 179 patients received tocilizumab and 365 patients received standard care.There was an improvement in median overall survival from time of hospital admission in patients receiving tocilizumab when compared with the standard care cohort (20%vs7%;P< 0.001)[118].

Another multicenter retrospective cohort study investigated outcomes in 4485 adults with COVID-19 admitted to ICU in 68 hospitals.Among critically ill patients, the risk of in-hospital mortality was lower in patients treated with tocilizumab in the first 2 d of ICU admission compared with patients whose early treatment did not include tocilizumab (HR, 0.71; 95%CI: 0.56 to 0.92)[119].

However, similar favorable results were not seen in a RCT involving 243 patients with hyperinflammatory states.Tocilizumab was not shown to be effective enough to prevent intubation or death in moderately ill, hospitalized COVID-19 patients in this trial[120].Further research in RCTs is needed.

Reports have emerged of liver injury with an increase in transaminase levels associated with tocilizumab use in COVID-19 patients[121], and increases in liver enzyme levels were seen in 5% of patients in one of the cohort studies described above and in 1% of patients in the RCT[118,120].In the cohort study by Guptaet al[119], 16.6% of patients receiving tocilizumab developed an AST of more than 250 U/L and 8.5% developed an ALT level of more than 500 U/L.Tocilizumab can interfere with serum concentrations of CYP3A4 substrates.It should be used with caution and liver function regularly monitored, especially when used in combination with another hepatotoxic drug or in patients receiving multiple concomitant medications.

Baricitinib

Baricitinib is a selective inhibitor of Janus kinase (JAK) 1 and 2, and orally administered.It was originally developed for the treatment of rheumatoid arthritis.Inhibition of JAK blocks intracellular signal transmission from cytokine or growth factor receptors and leads to reduced hematopoiesis[17].This inhibition of signal transmission prevents phosphorylation and then activation of signal transducers and activators of transcription.

Baricitinib was used in combination with remdesivir in a RCT involving 1033 patients with COVID-19.The rationale for combining these two therapies is that clinical outcomes would be improved by reducing the immune response and preventing a hyperinflammatory state[122].The combination was found to be significantly better than remdesivir alone in reducing recovery time and accelerating clinical improvement in patients with COVID-19.This effect was more marked in patients receiving high-flow oxygen or non-invasive ventilation.The time to recovery was 10 d in patients who received combination treatment compared with 18 d in patients who received remdesivir alone.The 28-d mortality was 5.1% in the combination group and 7.8% in the control group (HR for death, 0.65; 95%CI: 0.39 to 1.09).

The combination was associated with fewer serious adverse events.Transaminases increased in 1.2% of patients receiving combination therapy and 2% of patients receiving remdesivir, and bilirubin increased in 0.4% and 1.6%, respectively.Regular monitoring of liver function is recommended, especially when used in combination with remdesivir.

A summary of the side effects of the potential treatments for COVID-19 is shown in Table 2.

Table 2 Gastrointestinal and hepatic side effects of potential treatments for coronavirus disease 2019

COVID-19 VACCINES AND LIVER AND GI DISEASES

Vaccination is an important method to protect the population from COVID-19 and is likely to be especially important in high-risk individuals, such as those with preexisting health conditions.A minimum vaccine efficacy of 50% is necessary to get regulatory approval from the World Health Organization (WHO).Patients with chronic diseases have a higher mortality when they get infected with COVID-19.Therefore, this group of patients will benefit more from the vaccination.However, the phase 1-3 studies of the COVID-19 vaccines mainly recruited healthy individuals, so data are limited in patients with chronic diseases.The decision to be vaccinated mayalso depend on the stability of the patient’s chronic illness and the prevalence of COVID-19 in the relevant country or region.

TYPES OF VACCINES

Different technologies were applied to the development of the vaccines including mRNA, viral vectors, inactivated viruses, recombinant DNA, protein subunits and live attenuated viruses.

The BNT162b2 mRNA vaccine (manufactured by Pfizer BioNTec) and the mRNA-1273 mRNA vaccine (manufactured by Moderna-NIH) was developed based on mRNAs that encode variants of the SARS-CoV-2 spike glycoprotein and are encapsulated into lipid nanoparticles[123-125].The ChAdOx1 nCoV-19 vaccine (manufactured by AstraZeneca) uses an adenoviral vector and is approved by the WHO is currently being used in Europe, the United States and many other countries[126].Another WHO-approved COVID-19 vaccine is Ad26.COV2.S, developed by Janssen (Johnson & Johnson); this is a single-dose viral vector vaccine based on a human adenovirus that has been modified to contain the gene for making the spike protein of the SARS-CoV-2 virus[127].However, the use of this vaccine was stopped by the WHO because of the risk of thrombotic complications.

The two mRNA vaccines described above got the earliest approval from the WHO and are now being used, but these vaccines must be stored in very low temperature freezers.Common acute side effects of the vaccines include myalgia, fatigue, lowgrade fever, headache, nausea and redness or soreness at the injection site.There do not appear to be many GI and hepatic side effects.

BNT162b2 was chosen by Pfizer/BioNTec as the most promising of two potential mRNA vaccine candidates based on safety and immunogenicity data from phase I studies in younger and older adults[123].A two-dose regimen of BNT162b2 confirmed a 95% protection rate against COVID-19 in persons 16 years of age or older.The side effect profile was characterized mainly by fatigue, mild to moderate pain at the injection site, and headache[124].

A phase III study of the mRNA-1273 vaccine was carried out in 30420 healthy individuals aged 18 or above randomly assigned in a 1:1 ratio to receive either vaccine or placebo.It showed an efficacy of 94.1% at preventing COVID-19 illness, including severe disease[125].There were no major safety concerns apart from transient local and systemic reactions.

The third approved vaccine is ChAdOx1 nCoV-19 vaccine (AZD1222) which was developed at Oxford University.It consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1 which contains the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene.After receiving two standard doses of vaccine, the efficacy of the vaccine was 62.1%vs1.6% of 4455 participants in the control group[126].

Recently, however, safety concerns have emerged about the thrombotic risk associated with the vaccine.A pathogenic PF4-dependent syndrome, which was unrelated to the use of heparin, was identified after the administration of the vaccine[128].Clinicians should pay particular attention to individuals with thrombotic risk factors.

The fifth vaccine is an inactivated vaccine developed by Sinovac Life Sciences and is being used in some countries.CoronaVac was well tolerated and induced humoral responses against SARS-CoV-2, and it was approved for emergency use in China and some other countries and regions.Efficacy and safety were demonstrated in two phase I/II double-blind, placebo-controlled RCTs in healthy adults aged 18-59 years and 60 years or older[129,130].A phase III, randomized, multicenter, double-blind, placebocontrolled clinical study is being carried out to assess the efficacy and safety of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac in two age groups: 18 years to 59 years and 60 years or more[131].

Another vaccine, Sinopharm, which is an inactivated vaccine developed in China, has been approved and used in some countries and regions.It showed promising results in phase I/II trials[132].The phase III trial data will provide more information on the safety, efficacy and immunogenicity of the vaccine.A summary of the available COVID-19 vaccines is shown in Table 3.There are ongoing studies for these and other vaccines and more choices will become available over time.

Table 3 Summary of the ata for the currently used coronavirus disease 2019 vaccines

COVID-19 VACCINES AND CLD

Patients with CLD, liver cirrhosis, hepatobiliary malignancies, and candidates for liver transplantation are at higher risk of COVID-19 infections.At the same time, these groups of patients have a lower immune response to vaccines.

The benefits and risks of vaccination for patients with chronic disease or immunocompromised patients should be weighed individually, taking into account the incidence of the infection in the country or community, the vaccine formulation, the type of immunosuppressive therapy (e.g., chemotherapy, transplantation) the patient is receiving, and the extent of their immunosuppression.

There is a reduction of immune memory against and immune responses to certain vaccines as patients age and their CLD progresses[133].Moreover, patients with alcohol-associated liver disease, CLD and cirrhosis may have an impaired immune response to vaccination.At the same time, they are more susceptible to infections and infection-related complications[134].

Patients with immunosuppressive conditions or liver diseases were usually excluded from the studies of the COVID-19 vaccines.A post-marketing study in a nationwide mass vaccination setting in Israel suggests that the BNT162b2 mRNA vaccine is effective for a wide range of COVID-19-related outcomes, a finding consistent with that of the randomized trial[135].All persons who were newly vaccinated were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics.Each study group included 596618 persons, and the vaccinated population included 9699 (1.6%) patients with liver disease and 435 (0.1%) patients with solid organ transplantation[135].

There are currently limited published data on specific patient subgroups.Investigators have performed subgroup analyses, each time restricting the matching process to persons with a specific condition of interest, in order to maximize the sample size[136].The results on the subgroup with CLD are not yet known.

Patients with CLD infected with SARS-CoV-2 infection have higher risk of adverse outcome than the general population.There are on-going trials in patients with liver diseases worldwide and the results are pending[137].

In view of the high rate of complications and decompensation caused by COVID 19 in CLD, we recommend SARS-CoV-2 vaccination in patients with CLD, and in candidates for liver transplantation, with prioritization of patients with risk factors for severe COVID-19.

In general, professional bodies like the European Association for the Study of the Liver and the American Association for the Study of Liver Disease recommendCOVID-19 vaccination for patients with CLD as the benefits likely outweigh the risks[138,139].

Rituximab may be used for the treatment of CLD such as autoimmune hepatitis and its efficacy is shown in a recent retrospective study[140].There is usually a blunted vaccine response after vaccination in patients with lymphoma[141-144] or autoimmune disorders[145-148] treated with rituximab.B cells are required for the development of humoral immune responses to neoantigens.Therefore, depletion of B cells following rituximab will likely reduce the humoral immune responses to the COVID-19 vaccine.Both T cell-dependent and -independent responses are also significantly impaired for at least 6 mo after rituximab treatment[148].

Assuming that immunological response to the COVID-19 vaccine correlates with disease protection, it is recommended that vaccination be performed at least 6 mo after rituximab infusion.

EFFICACY AND SAFETY OF VACCINES IN SOLID ORGAN TRANSPLANT RECIPIENTS

Solid organ transplant (SOT) recipients are on immunosuppression to prevent graft rejection, so they are at a higher risk of infection and infective complications.Vaccination is useful to prevent infections and the associated complications in transplant recipients.

COVID-19 vaccination is recommended for all SOT recipients including liver transplant recipients, and vaccination can be given 3-6 mo after SOT.Since the current approved vaccines do not contain live or attenuated virus, they are likely to be safe in immunosuppressed patients[139,149].

The immunogenicity of vaccines in SOT recipients is lower than in immunocompetent individuals because of the immunosuppressive therapy and the underlying chronic disease.Therefore, vaccination against COVID-19 is recommended for family members and healthcare professionals caring for these patients to reduce exposure to SARS-CoV-2[138].

COVID-19 VACCINE AND IBD

IBD is an umbrella term for the immune-mediated inflammatory conditions of Crohn’s disease and ulcerative colitis.

IBD patients may receive immunosuppressive drugs such as high-dose corticosteroids, immunomodulators (thiopurines, methotrexate, and calcineurin inhibitors), anticytokine therapies (including anti-TNF and anti-IL-12p40 biologics), anti-integrin therapies (vedolizumab), and small-molecule inhibitors of signalling (tofacitinib), which could leave them susceptible to infection.

Immunosuppressive drugs may reduce the humoral response to vaccines and thus their effectiveness, which could have major implications for the safety of immunosuppressed patients in the COVID-19 era.The risks associated with current COVID-19 vaccines are low, and guidelines recommend vaccination for patients with IBD[150,151].

COVID-19 vaccination is also advocated for IBD patients younger than 16 years.Although pediatric patients may experience milder illness if they get infected by SARS-CoV-2[152,153], they can be the source of ongoing outbreaks and transmission[154].The cessation of the COVID-19 pandemic relies on maximal community uptake of the COVID-19 vaccine in order to achieve herd immunity.On May 10, 2021, the U.S.FDA expanded the Emergency Use Authorization for the BNT162b2 mRNA vaccine to include people aged 12 years to 15 years[155].This is based on the results of an RCT enrolling 2260 adolescents (12-15-year-old) who were randomized 1:1 to receive the BNT162b2 or placebo[156].In 7 d after the second dose of BNT162b2, there were zero new case of COVID-19, translating into 100% vaccine efficacy, while there were 16 confirmed cases in the placebo group.Vaccinated adolescents 12- to 15-year-old had higher geometric mean titers of SARS-CoV-2 neutralizing antibodies (1239.5vs705.1) compared with recipients aged 16 years to 25 years.A favorable safety and side effect profile, similar to other age groups, was also demonstrated in the 12- to 15-year-old recipients of BNT162b2[156].

The use of COVID-19 vaccines is not recommended in pregnant women and there are no safety data of the vaccines in these women to date.

Another point to consider is that patients with IBD are at risk of thromboembolic complications, and COVID-19 increases the risk of thromboembolic events.Studies have shown that prophylactic anticoagulation can reduce the 30-d mortality risk in patients with COVID-19[157].

RECOMMENDATIONS

COVID-19 is a pandemic infection with a high burden of morbidity and mortality.Various drugs are under investigation for the treatment of the disease, but many are associated with GI and hepatic side effects.Caution and careful monitoring should be exercised when prescribing these therapies in patients with GI symptoms like diarrhea and vomiting.As liver impairment is a common observation among patients with COVID-19, we recommend that all patients with COVID-19 and liver impairment undergo investigations for potential causes of liver disease, including viral hepatitis serology, particularly in areas where HBV is prevalent.

Furthermore, increasing rates of liver dysfunction have been correlated with the severity of COVID-19[158].We need to maintain a high index of suspicion as hepatotoxic drug effects may be difficult to detect in this condition.

High-dose corticosteroids and tocilizumab have been used for the treatment of patients with severe COVID-19.There is a risk of HBV reactivation, hepatitis flare, and even acute liver failure in patients with chronic HBV infection receiving this regimen.Screening for HBsAg is recommended, and antiviral prophylaxis with nucleoside analogs should be given to patients with COVID-19 who are positive for HBsAg during steroid therapy.

COVID-19 vaccines have been rapidly developed.Patients with CLD or IBD and liver transplant recipients are encouraged to receive vaccination.The benefits will outweigh the risks.

Vaccination against COVID-19 is also recommended for family members and healthcare professionals caring for these patients to reduce exposure to SARS-CoV-2.The vaccination against COVID-19 is encouraged for all individuals at risk of SARSCoV-2 infection, including those with underlying chronic diseases.Recommendations by professional bodies, governments and health authorities will be important driver of COVID-19 vaccination[159].

CONCLUSION

Extensive research has been performed to identify potential treatments for SARS-CoV-2 infection.GI symptoms and liver dysfunction in COVID-19 patients could be due to disease manifestations or treatment side effects, which physicians should take into consideration when choosing the best therapeutic strategy.The development of effective and safe vaccines is the light at the end of the tunnel to end the pandemic and should be encouraged, including for patients with CLD, IBD, liver transplant recipients their family members, and healthcare professionals.