ClinicReview Article | DOI: https://doi.org/10.31579/2834-8664/058
Nitazoxanide in Self-limiting Viral Gastroenteritis a Systematic Review and Meta-Analysis
1Departement of Internal Medicine Siloam Hospitals Kebon Jeruk, Jakarta
2Magister Program of Esa Unggul University, Kebon Jeruk, Jakarta
3Division of Gastroentero Hepatologi Siloam Hospitals Kebon Jeruk, Jakarta
*Corresponding Author: Louis Edwin Wirya, Departement of Internal Medicine Siloam Hospitals Kebon Jeruk, Jakarta.
Citation: Louis E Wirya, Suryanti2, H Lie , Epistel P Simatupang,(2024), Nitazoxanide in Self-limiting Viral Gastroenteritis A Systematic Review and Meta-Analysis , International Journal of clinical and Medical Case Reports, 3(5); Doi:10.31579/2834-8664/058
Copyright: Louis E Wirya, Suryanti2, H Lie , Epistel P Simatupang,(2024), Nitazoxanide in Self-limiting Viral Gastroenteritis A Systematic Review and Meta-Analysis , International Journal of clinical and Medical Case Reports, 3(5); Doi:10.31579/2834-8664/058
Received: 06 September 2024 | Accepted: 18 September 2024 | Published: 30 September 2024
Keywords: Nitazoxanide, Viral, Gastroenteritis
Abstract
Introduction: Acute gastroenteritis (AGE) is a condition where there is an inflammation of the stomach and small and large intestines, with characteristic of vomiting, fever, abdominal pain, increased bowel movement and resulting in diarrhea. Mostly, AGE was cause by viral infection. Up to this date, AGE accounts for a burden in public health, especially in low-income and middle-income countries and also the eighth leading cause of mortality among all ages. This systematic review and meta-analysis aim to summarize the evidence regarding the use of Nitazoxanide in improving the outcome of viral gastroenteritis in all ages.
Methods: We conducted a systematic review and meta analysis, collecting studies from EuropePMC, Pubmed, Scopus, and clinicaltrial.gov. The inclusion criteria for selecting the study were as follows: (1) Types of studies: observational studies (cohort, case-control, cross-sectional), randomized or non-randomized clinical trials; (2) Types of participants: patients at any age who present with acute diarrhea or gastroenteritis caused by viral pathogens (rotavirus, norovirus, or adenovirus); (3) Types of intervention: received nitazoxanide in any dose and any formulations for the treatment of viral diarrhea/gastroenteritis; (4) Types of comparison: receiving only standard of care (rehydration solutions) or placebo; Studies in which diarrhea or gastroenteritis caused by other pathogens than virus (such as bacteria, parasite or fungal infections) were excluded. The primary outcome was duration of diarrhea and duration of hospitalization.
Results: A total of 874 studies were retrieved, resulting in the final number of six studies included, with a total of 580 patients. Out of 6 studies, 3 were double-blind RCTs, 1 was single-blind RCT, while the remaining 3 were retrospective cohort studies. Sample sizes ranged from 26 to 330. Three out of six studies include adults gastroenteritis patients, while the rest 3 articles were studies on paediatric populations. The majority of the causative viral pathogens in the included studies were rotavirus (dominant pathogens in 4 out of 6 studies), and the remaining two studies were dominated by norovirus infection. The doses of nitazoxanide used in the included studies were ranged from 7.5 mg/kg/day to 500 mg twice daily, administered for 3 days. The use of nitazoxanide was associated with shorter duration of diarrhea [Mean Difference -1.25 days, (CI 95% -1.68, -0.82), p < 0.00001) and shorter duration of hospitalization [Mean Difference -0.82 days, (CI 95% -1.10, -0.54), p < 0.00001). when compared with standard of care/placebo in patients with viral gastroenteritis.
Conclusion: The use of Nitazoxanide in viral gastroenteritis was associated with shorter duration of diarrhea and shorter duration of hospitalization when compared with standard of care/placebo in adult and child population. However, further randomized clinical trials are still needed to confirm the results of our study.
Introduction
Acute gastroenteritis (AGE) is a condition where there is an inflammation of the stomach and small and large intestines, with characteristic of vomiting, fever, abdominal pain, increased bowel movement and resulting in diarrhea.1,2 The focus on the prevention and control of AGE is on children, but it also needs to be remembered that AGE could happen in all ages, and most of the deaths caused by AGE in United States were in older adults. Based on data by the National Outbreak Reporting System, it is estimated that more than 350,000,000 cases of acute gastroenteritis occur annually in the United States.1,3 AGE also causes 1 million hospitalizations annually and accounts for more than 1.6 million deaths globally every year in all ages.3,4,5 Up to this date, AGE accounts for a burden in public health, especially in low-income and middle-income countries and also the eighth leading cause of mortality among all ages.5,6,7Meanwhile, AGE is also still one of the leading cause of morbidity and mortality in children and infants, and also still one of the most common infection in children and infants.8,9 Based on data published by the Global Health Data Exchange in 2016, diarrhea was the fifth leading cause of mortality among children younger than 5 years, which is 446,000 deaths. In South Asia and sub-Saharan Africa, diarrhea accounts for more than a quarter of leading cause of mortality in children younger than 5 years, which is 26.93%.5 There are numerous etiologies for GAE, which are viral, bacterial, and parasitic pathogens.10Norovirus and Rotavirus are the most common etiology of viral gastroenteritis. Other less common etiology of viral gastroenteritis are Astrovirus and Adenovirus.1,10,11 Incidence rate of Norovirus as the causative agent of AGE worldwide is 17–18%, especially among developed countries. Norovirus infection can occur in all ages, while Rotavirus is found as the most common causative agent of AGE in children. Rotavirus was mostly found in children aged 0–14 years old, with the highest incidence rate was in children less than 5 years.2,12Nitazoxanide or 2-(acetyloxy)-N-(5-nitro-2-thiazolyl) benzamide is a new thiazolide broad-spectrum antiviral agent which has been gaining more attention in recent years because of its ability as a broad-spectrum antiviral agent. Nitazoxanide plays a role through multiple mechanisms of action of virus and interfere with host-regulated pathways in viral replication.13,14 Nitazoxanide as a new broad-spectrum antiviral agent is expected to provide greater protection against virus and reduce the risks of resistance and costs associated with medication, and also prevent further viral infection and transmission so that eradication could occur.14,15,16Nitazoxanide’s antiviral mechanisms is through the inhibition of viral RNA and DNA replication and modulate host’s innate immune response when a pathogen has entered a susceptible cellular target.15This systematic review and meta-analysis aim to summarize the evidence regarding the use of Nitazoxanide in improving the outcome of viral gastroenteritis in all ages.
Materials & Methods
Eligibility Criteria
The inclusion criteria for selecting the study were as follows: (1) Types of studies: observational studies (cohort, case-control, cross-sectional), randomized or non-randomized clinical trials; (2) Types of participants: patients at any age who present with acute diarrhea or gastroenteritis caused by viral pathogens (rotavirus, norovirus, or adenovirus); (3) Types of intervention: received nitazoxanide in any dose and any formulations for the treatment of viral diarrhea/gastroenteritis; (4) Types of comparison: receiving only standard of care (rehydration solutions) or placebo; (5) Types of outcome: duration of diarrhea and duration of hospitalization. Studies in which diarrhea or gastroenteritis caused by other pathogens than virus (such as bacteria, parasite or fungal infections) were excluded. Studies without the control group, any other articles besides primary studies (review articles, editorials, correspondences), and articles in non-English language will also be excluded.
Literature Search And Study Selection
Literature search was done on EuropePMC, PubMed, Scopus, and ClinicalTrials.gov with English-language restriction until August 26th, 2022 with the following keywords “(nitazoxanide OR thiazolides OR alinia OR heliton OR daxon) AND (viral OR virus OR rotavirus OR norovirus OR adenovirus) AND (diarrhea OR gastroenteritis OR enteritis)”. The initial step was the identification of eligible articles through screening of titles and abstracts by two reviewers. Additional evaluation of references from found eligible studies were also conducted to search for more potential articles. Duplicate articles were removed. Finally, full-text articles were independently screened by 2 reviewers, with discrepancies resolved through discussion. Meta-analysis of Observational Studies in Epidemiology (MOOSE)17 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were employed for our study.18according to the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines
Materials & Methods
Eligibility Criteria
The inclusion criteria for selecting the study were as follows: (1) Types of studies: observational studies (cohort, case-control, cross-sectional), randomized or non-randomized clinical trials; (2) Types of participants: patients at any age who present with acute diarrhea or gastroenteritis caused by viral pathogens (rotavirus, norovirus, or adenovirus); (3) Types of intervention: received nitazoxanide in any dose and any formulations for the treatment of viral diarrhea/gastroenteritis; (4) Types of comparison: receiving only standard of care (rehydration solutions) or placebo; (5) Types of outcome: duration of diarrhea and duration of hospitalization. Studies in which diarrhea or gastroenteritis caused by other pathogens than virus (such as bacteria, parasite or fungal infections) were excluded. Studies without the control group, any other articles besides primary studies (review articles, editorials, correspondences), and articles in non-English language will also be excluded.
Literature Search And Study Selection
Literature search was done on EuropePMC, PubMed, Scopus, and ClinicalTrials.gov with English-language restriction until August 26th, 2022 with the following keywords “(nitazoxanide OR thiazolides OR alinia OR heliton OR daxon) AND (viral OR virus OR rotavirus OR norovirus OR adenovirus) AND (diarrhea OR gastroenteritis OR enteritis)”. The initial step was the identification of eligible articles through screening of titles and abstracts by two reviewers. Additional evaluation of references from found eligible studies were also conducted to search for more potential articles. Duplicate articles were removed. Finally, full-text articles were independently screened by 2 reviewers, with discrepancies resolved through discussion. Meta-analysis of Observational Studies in Epidemiology (MOOSE)17 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were employed for our study.18according to the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines
Data Extraction
Two independent authors performed data extraction process using a standardized form which included authors’ names, publication year, study design, sample characteristic, and outcomes measured. Sample characteristics will include sample size, type of participants, viral pathogens, age, and nitazoxanide dose. Extracted data were then compared with any discrepancies will be resolved through discussion. The quality of the included clinical trial studies will be assessed by using Risk of Bias version 2 (RoB v2) from Cochrane Collaborations.19 This tool includes five domains for methodological evaluation: (a) randomization process; (b) deviations from intended interventions; (c) missing outcome data; (d) measurement of the outcome; and (e) selection of the reported result. The RCT was classified as low risk of bias (low risk of bias for all domains), high risk (high risk of bias for one or more domains) or unclear risk (unclear risk of bias for one or more key domains). Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of case-control and cohort studies. The assessment process included reviewing the comparability, selection, and outcome of each study, then each research was assigned a total score beginning with zero until nine. Research is graded good if it scores ≥7.20
Statistical Analysis
Meta-analysis was done using Review Manager 5.4 (Cochrane Collaboration) software. Application of Mantel-Haenszel formula with random-effect models, regardless of heterogeneity was employed to calculate risk ratio (RR) and its 95% confidence interval (95% CI) for the dichotomous variable outcomes. Meanwhile, Inverse-Variance formula with random effect models was used to calculate standardized mean difference (SMD) and its standard deviations (SD) for the continuous variable outcomes. In this meta-analysis, heterogeneity between studies was assessed by I-squared (I2; Inconsistency). The I2 statistic with a value of <25>50% considered high degree of heterogeneity. I2 of at least 50% is considered substantial heterogeneity; it means that at least half of the total variability among effect sizes is due to true heterogeneity between studies. When data were reported as medians and interquartile ranges or as medians and minimum-to-maximum ranges, we converted them to means and standard deviations for meta-analysis pooling using the formula by Wan X et al.21 Funnel plot analysis was utilized to assess the qualitative risk of publication bias.
Results
Study Selection And Characteristics
A total of 874 studies were retrieved from Europe PMC, ClinicalTrials.gov, PubMed, and Scopus. After screening titles, abstracts and removing the duplicates, 18 articles were assessed for eligibility through reading the full-text form. Of these eligible studies, 12 articles were further excluded, seven articles did not have control or comparison group, three were review articles, and two articles were not exclusively performed on viral gastroenteritis populations, therefore resulting in the final number of 6 clinical trial and observational studies22-27 with a total of 580 patients with viral gastroenteritis for the analysis (Figure 1). Out of 6 studies, 3 were double-blind RCTs, 1 was single-blind RCT, while the remaining 3 were retrospective cohort studies. Sample sizes ranged from 26 to 330. Three out of six studies include adults gastroenteritis patients, while the rest 3 articles were studies on paediatric populations. The majority of the causative viral pathogens in the included studies were rotavirus (dominant pathogens in 4 out of 6 studies), and the remaining two studies were dominated by norovirus infection. The doses of nitazoxanide used in the included studies were ranged from 7.5 mg/kg/day to 500 mg twice daily, administered for 3 days through syrup or tablet formulations. The details of each included studies were summarized in Table.1
| Study | Sample size | Design | Participants | Viral pathogen | Age (years) | Nitazoxanide dose | Control group | |
NTZ | Control | |||||||
Brooks T et al.22 2021 | 26 | Retrospective cohort | Adults (age >18 years) who had either: 1) underwent stem cell transplantation; or 2) received myeloablative chemotherapy within 4 weeks of NV diagnosis by positive test on gastrointestinal pathogen panel | Norovirus (100%) | 68.2 ± 20.2 | 54.4 ± 18.9 | Not mentioned | Supportive care |
Ghosh N et al.23 2016 | 97 | Retrospective cohort | Immunocompromised and cancer patients with viral associated diarrhea (VAD) | Norovirus (50.5%) Rotavirus (35%) Adenovirus (14.5%) | 43.1 ± 18.3 | Not mentioned | Supportive care | |
Mahapatro S et al.24 2017 | 330 | Double-blind RCT | Children aged 12 months – 5 years with acute onset diarrhea of <48> | Rotavirus (100%) | 2.1 ± 0.7 | 2.1 ± 0.7 | 100 mg (12 – 47 months) or 200 mg (≥4 years), twice daily for 3 days in syrup formulation | Placebo |
Rossignol JF et al.25 2006 (a) | 38 | Double-blind RCT | Children aged <12> | Rotavirus (100%) | 1.4 ± 1.8 | 1.1 ± 0.4 | 7.5 mg/kg (<12> | Placebo |
Rossignol JF et al.26 2006 (b) | 45 | Double-blind RCT | Children aged >12 years presenting with gastroenteritis | Rotavirus (100%) | 34.1 ± 16.2 | 32.9 ± 12.9 | 500 mg, twice daily for 3 days in tablet formulation | Placebo |
Teran CG et al.27 2008 | 50 | Single-blind RCT | Infants aged 28 days to 24 months with a history of acute watery diarrhea positive for rotavirus of less than 72 h duration and a moderate to severe degree of dehydration | Rotavirus (100%) | 0.8 ± 0.5 | 0.9 ± 0.4 | 15 mg/kg/day divided into 2 doses for 3 days in syrup formulation | Oral or systemic rehydration solution |
Table 1. Characteristics of included studies
Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of the outcome | Selection of the reported result | Overall | ||
| Mahapatro S (2017) | +
| + | + | + | + | + Low risk | |
| Rossignol JF (2006) (a) | + | + | + | + | + | ? Some concerns | |
| Rossignol JF (2006) (b) | + | + | + | + | + |
| - High risk |
| Teran CG (2008) | - | + | + | + | + | - |
Table 2. Risk of Bias assessment of the included studies using RoB v2 tool
First author, year | Study design | Selectiona | Comparabilityb | Outcomec | Total score | Result |
| Brooks T et al.22 2021 | Cohort | *** | ** | ** | 7 | Good |
| Ghosh N et al.23 2016 | Cohort | *** | ** | ** | 7 | Good |
Table 3. Newcastle-Ottawa quality assessment of observational studies
a(1) representativeness of the exposed cohort; (2) selection of the non-exposed cohort; (3) ascertainment of exposure; (4) demonstration that outcome of interest was no present at start of study
b(1) comparability of cohorts on the basis of design or analysis, (maximum two stars)
c(1) assessment of outcome; (2) was follow-up long enough for outcomes to occur; (3) adequacy of follow up of cohorts
Quality Of Study Assessment
Risk of Bias version 2 (RoB v2) from Cochrane was used to evaluate the quality of randomized clinical trial studies. Three out of four included RCTs have low-risk of bias in all five domains of methodological evaluation, while one RCT have high-risk of bias because of randomization method was not described in details and there were some differences in the baseline characteristics (age and malnutrition status) among groups of patients which suggest some problems during randomization process (Table 2). NOS scale was used to evaluate the quality of cohort and case-control studies, which indicated all included studies had good quality (Table 3).
Nitazoxanide vs control
Duration of diarrhea (in days)
In overall six studies (n = 292) reported on the duration of diarrhea outcome, our pooled analysis showed that the use of nitazoxanide was associated with shorter duration of diarrhea when compared with standard of care/placebo in patients with viral gastroenteritis [Mean Difference -1.25 days (95% CI -1.68, -0.82), p < 0>I2 = 44%, random-effect modelling] (Figure 2).Three studies (n = 168) in adult population reported on the duration of diarrhea outcome. Our pooled analysis showed that the use of nitazoxanide was associated with shorter duration of diarrhea when compared with standard of care/placebo in adult population with viral gastroenteritis [Mean Difference -1.39 days (95% CI -2.50, -0.27), p=0.32, I2 = 0%, random-effect modelling] (Figure 2A).Three studies (n = 124) in child population reported on the duration of diarrhea outcome. Our pooled analysis showed that the use of nitazoxanide was associated with shorter duration of diarrhea when compared with standard of care/placebo in children population with viral gastroenteritis [Mean Difference -1.23 days (95% CI -1.81, -0.65), p < 0>I2 = 77%, random-effect modelling] (Figure 2B).
Duration Of Hospitalization (In Days)
In overall three studies (n = 126) reported on the duration of hospitalization outcome, our pooled analysis showed that the use of nitazoxanide was associated with shorter duration of hospitalization when compared with standard of care/placebo in patients with viral gastroenteritis [Mean Difference -0.82 days (95% CI -1.10, -0.54), p < 0>I2 = 0%, random-effect modelling] (Figure 3).There was only one study sub-group in adult population (n = 26) reported on the duration of hospitalization outcome, so the outcome cannot be interpreted. (Figure 3A) Two studies (n = 100) in child population reported on the duration of hospitalization outcome. Our pooled analysis showed that the use of nitazoxanide was associated with shorter duration of hospitalization when compared with standard of care/placebo in patients with viral gastroenteritis [Mean Difference -0.82 days (95% CI -1.10, -0.54), p < 0>I2 = 0%, random-effect modelling] (Figure 3B)
Publication Bias
Because the number of included studies in each outcome is fewer than 10 studies, the funnel plots and statistical tests for detecting publication bias are not reliable when compared with whenever there are more than 10 included studies in each outcome.28,29 Therefore, the test for publication bias was not performed in this study.
Discussion
According to our overall pooled analysis, it was discovered that nitazoxanide was associated with reduction of duration of diarrhea and duration of hospitalization, the same outcome was seen in our sub-group pooled analysis, adult and child population. The use of nitazoxanide in treating viral gastroenteritis is still controversional, because viral gastroenteritis is a self-limiting gastrointestinal infection.30,31,32 There are many clinical practices guidelines (CPG) available for the treatment of AGE, including WHO recommendation.33,34,35 The main goal for treating acute gastroenteritis is to prevent dehydration, and the first-line therapy recommended in all of the CPG for this is oral rehydration solution (ORS). The only active treatment recommended by WHO for AGE is zinc.33,35,36 Meanwhile, the use of other pharmaceutical agents is still controversial and still has a high variability in practice.36 As already known, Nitazoxanide (2-(acetolyoxy)-N-(5-nitro-2-thiazolyl)benzamide) is a broad-spectrum parasiticidal agent. The use of Nitazoxanide has already been approved by the US Food and Drug Administration (FDA) and other health agencies worldwide as the first-line treatment for Cryptosporidium parvum or Giardia lamblia infection in healthy individual, therefore, Nitazoxanide is commonly know as antiprotozoal. Other common indication for the use of Nitazoxanide is helminth infection.4,37 Nitazoxanide has been used in millions of children and adults with mild adverse effects.16 Nitazoxanide has 2 major active metabolites, which are tizoxanide and tizoxanide glucuronide.37 Nitazoxanide and its known metabolite, tizoxanide have been reported to have a role as a broad-spectrum antiviral agent, against many kind of viruses in the recent years.38,39 Previous studies regarding the antiviral effect of Nitazoxanide have been reported, including reduced duration of symptoms in individu with acute uncomplicated influenza40, hepatitis B and C41,42, Japanese encephalitis43, and coronavirus39,44.Norovirus and Rotavirus are the most common etiology of viral gastroenteritis. Other less common etiology of viral gastroenteritis are Astrovirus and Adenovirus.1,10,11 Acute gastroenteritis, however, accounts for a burden in public health, especially in low-income and middle-income countries, and still have a high rates of morbidity and mortality, especially in children and infants.8,9 Its burden in public health includes, higher total cost because of hospitalization rates, missing productive days, and care seeking rates.45Many studies have also reported that Nitazoxanide has an antiviral activity for the etiology of viral gastroenteritis, which is rotavirus and norovirus.32 Based on our population in this study, the cause of viral gastroenteritis in adult population was Norovirus, Rotavirus, and Adenovirus, and Norovirus accounts for the highest number in two of the studies. Meanwhile, the cause of viral gastroenteritis in child population was Rotavirus. Norovirus (NoV) infection is characterized by a non-febrile, non-bloody, and watery gastroenteritis often accompanied with vomiting, abdominal cramps. Norovirus (NoV) infection usually lasting for 12–60 hours. In infant aged less than 1 year, the symptoms can last until 6 days, and in individu ages more than 85 years, the symptoms can last until 4 days.46,47 Norovirus (NoV) is a non-enveloped single-stranded RNA virus belongs to Caliciviridae family. The genome has 3 open reading frames (ORF), which are: ORF-1 (codes non-structural protein); ORF-2 (codes mayor capsid protein VP1); and ORF-3 (codes minor capsid protein VP2). NoV has been divided into 10 genogroup (GI-GX), but only GI, GII, and GIV could cause acute gastroenteritis in human.48,49Rotavirus is a most common etiology of acute watery diarrhea, especially in children younger than 5 years old. The symptoms can last until 5 days on previous studies, and was associated with dehydration.50,51 Rotavirus (RV) is a non-enveloped double-stranded RNA genome belongs to Reoviridae family. Rotavirus consists of 11 RNA gene segments, which encodes viral protein with multilayered protein capsid. In the 11 gene segments, there are 6 structural proteins, which are VP1, VP2, VP3, VP4, VP6, and VP7, and the rest 5 are non-structural protein (NSP). RV has two surface proteins in its virion, VP7 and VP4. These surface proteins will stimulated the production of G type and P type, which are the neutralizing antibodies when infection occurs.50,52,53Up to this date, the use of Nitazoxanide in million of adults and children is proven safe and is already been marketed globally, for many purposes.15 The use of Nitazoxanide in viral gastroenteritis is based on its antiviral effect on the virus, which is Norovirus and Rotavirus.22-27 There are several mechanism regarding antiviral effect of Nitazoxanide. Based on the previous studies, Nitazoxanide has no effect on virus infectivity and binding or entry into target cells. Nitazoxanide also do not inhibit protein expression. The antiviral action of Nitazoxanide is targeted in reducing the size of viroplasms and altered the virus’ cytoplasmic structures, where the replication of the virus genome takes place, and later will disturb the virus’ replication process.16,54There are numerous non-structural and structural proteins in viroplasm, such as NSP5 and NSP2, and VP1, VP2, VP3 and VP6, respectively. Meanwhile, interaction between NSP5 and NSP2 oligomers plays a major role in rotavirus viroplasm formation. However, the detailed mechanism for the impaired NSP2/NSP5 interaction caused by Nitazoxanide is still unknown.16,55,56In previous study showed that Nitazoxanide inhibit virus replication by activating host cellular antiviral response, and inducing the expression of interferon-stimulated genes (ISGs). Interferon is still one of the important component of the innate immunity in response to virus infection. Interferon will then activated the JAK-STAT pathway, the principal cascade for IFN signaling. The ISG activated includes interferon regulatory factor 1 (IRF-1), IRF-9, RIG-I, IFI27, PKR, ISG15, Mx1, and MDA5, and some of this has activity against many viruses.57,58,59 Some of the previous data regarding ISG antiviral activity includes: ISG15, which mitigates MNV-1 replication in vitro and in vivo in the early phase of the viral life cycle60; MDA5, a cellular sensor, which recognized MNV-1 and then triggered a host immune respons61; and PKR mediated type II IFN, which will inhibit MNV-1 translation62. Another mechanism based on previous data showed that nitazoxanide also played a role in the host antiviral pathway. Nitazoxanide can activated the protein kinase by double stranded RNA (PKR). PKR is a serine/threonine kinase that is expressed in all differentiated cells within low level. PKR is activated by dsRNA. Binding of dsRNA to PKR will promote dimerization and autophosphorylation. Later, the activated PKR will phosphorylate the translational eukaryotic initiation factor 2 alpha (eIF2α), which is a halting viral protein synthesis. PKR is also known as an interferon induced effector of cellular immunity.46,54However, the exact antiviral mechanism of nitazoxanide is still unclear and not well known until now. And up to date, there is still no consensus or guideline regarding the antiviral mechanism of nitazoxanide. All of the previous studies showed that the antiviral mechanism depend on the virus and host cells.57This study still has several limitations. There are currently small number of studies that specifically asses the use of Nitazoxanide in improving the outcome of viral gastroenteritis, and this study still lacks the sub-group population data, especially in adult population. Most of the included studies in these systematic review and meta-analysis also only have a small number of samples. More studies with larger sample sizes and good methodological design might still be needed to confirm the results of our study.
Conclusion
Our systematic review and meta-analysis indicated that the use of Nitazoxanide in viral gastroenteritis was associated with shorter duration of diarrhea and shorter duration of hospitalization when compared with standard of care/placebo in adult and child population. However, further randomized clinical trials are still needed to confirm the results of our study.
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