Oral Ribavirin Research Articles

HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV).

Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, LG/LG, and S/LG) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.

Ribavirin for Treatment of Subjects with Respiratory Syncytial Virus-Related Infection: A Systematic Review and Meta-Analysis.

Respiratory syncytial virus (RSV)-associated diseases have caused an estimated 1.8 million hospital admissions and 40,000 deaths among children. RSV can cause lower respiratory tract infections (LRTIs) in all age groups, adults with comorbidities, and immunocompromised patients. The aim was to summarize the evidence concerning efficacy and safety of ribavirin in subjects diagnosed with RSV associated with LRTI. A systematic review and meta-analysis were performed. Eligible studies were observational (> 10 subjects) and randomized-controlled trials of subjects with aerosol/oral ribavirin for RSV-LRTI. Comparator was supportive care or placebo. Systematic search on PubMed, Cochrane Library, and Web of Science databases was conducted between January 2001 and January 2022. PROSPERO register number: CRD42022308147. After retrieving 907 studies, 10 observational studies and 1 randomized controlled trial were included (4/11 high quality of evidence). Seven studies included subjects with haematological malignancy/stem cell transplant, two lung transplants, and two healthy individuals. A total of 788 subjects diagnosed with RSV infection were included; 14.3% of them presented with only LRTI. Among 445 subjects treated with ribavirin, 195 (43.8%) received an aerosolized formulation. Pooled meta-analysis showed no differences in mortality [risk ratio (RR): 0.63; 95% confidence interval (CI): 0.28-1.42] in all subjects treated with aerosol/oral ribavirin compared to supportive care. In subgroup analysis, mortality was significantly lower in haematological subjects (RR: 0.32; 95% CI: 0.14-0.71), but did not differ significantly in lung transplant recipients (RR: 0.89; 95% CI 0.31-2.56). Oral ribavirin (vs. supportive care) was associated with increased viral clearance (RR: 2.60; 95% CI: 1.35-4.99). Seventeen adverse events were reported among 119 subjects, but none were severe. Ribavirin should be considered for treatment of RSV-LRTI in haematological subjects. There is a lack of evidence to support its use in lung transplant recipients. Oral formulation appears to be an easier, safe, and cost-effective alternative to aerosolized ribavirin. Further advances needs to focus on newer antivirals.

Ribavirin Use in Hospitalized Children.

We describe ribavirin administration in hospitalized children over an 11-year period. Most patients were immunocompromised; there was variability in ribavirin use across hospitals. There was a clear shift toward the use of oral ribavirin despite a lack of evidence for its use.

Thyroid Dysfunction During Combined Pegylated Interferon Alpha and Ribavirin Therapy in Patients of Chronic Hepatitis C-Virus Infection

Objective: To determine frequency of thyroid dysfunction among patients of chronic hepatitis C receiving combined pegylated interferon alpha and ribavirin therapy.
 Study Design: Cross sectional study.
 Place and Duration of Study: Department of Medicine, Military Hospital Rawalpindi, from Jan to Jul 2017.
 Methodology: One hundred and twenty patients, aged 18–60 years from both genders, with established hepatitis C were included; while the patients with decompensated liver disease, previous antiviral treatment, pre-existing thyroid, autoimmune or severe cardiopulmonary disease and on immuno-suppressants or steroids were excluded. After formal informed consent, they were prescribed 24 weeks pegylated interferon alpha-2 (3 million units subcutaneously thrice weekly) and oral ribavirin (1000–1200 mg daily) therapy. After 12 weeks, serum thyroid stimulating hormone, free thyroxine and triiodothyronine levels were determined by chemiluminescence technique.
 Results: Out of 120 patients, 100 (83.33%) were males and 20 (16.67%) were females with male to female ratio of 5:1. Mean thyroid stimulating hormone levels at baseline and 12 weeks were 2.86 ± 1.03uiu/ml and 2.16 ± 0.79 uiu/ml respectively. Mean triiodothyronine levels at baseline and 12 weeks were 3.27 ± 1.31pg/ml and 2.69 ± 1.01 pg/ml respectively. Mean thyroxine levels at baseline and 12 weeks were 1.26 ± 0.38 pg/ml and 1.07 ± 0.53 pg/ml respectively. Frequency of thyroid dysfunction was found in 40 (33.33%) patients.
 Conclusion: Frequency of thyroid dysfunction among hepatitis C patients receiving combined pegylated interferon alpha and ribavirin therapy is quite high.

Risk Factors for Treatment Failure with Oral Antivirals in HCV

Introduction: Chronic hepatitis C virus (HCV) infection is one of the major cause of cirrhosis of liver and leads to significant morbidity and mortality. In past, HCV therapy was limited to subcutaneous peg interferon plus oral ribavirin, a regimen that was generally poorly tolerated and provided low efficacy, with cure rates below 40% for HCV genotypes 1 and 4, and below 75% for HCV genotypes 2 or 3. The availability of oral direct-acting antiviral (DAA) as treatment for chronic hepatitis C has revolutionized the field. Although current HCV therapies rarely fail to achieve viral eradication, a subset of patients experience treatment failure. Aim: To study the risk factors associated with treatment failure with oral antiviral drugs in patients of Chronic hepatitis C. Materials & Methods: It was a retrorospective study done at Medical Gastroenterology Department, PGIMS, Rohtak in which six years data i.e.from 01.01.2015 to 31.12.2020, pertainining to Eighty Six (86) chronic hepatitis C patients who had treatment failure i.e. SVR failure on oral antiviral drugs was analyzed. Observations: Out of the total 86 patients, there was clear cut male predominance i.e. 54 (62.79 %) with rural background (villages) i.e.73 (84.88%). The age distribution in these 86 patients varied between 10-80 yrs of age and characterstically peak was seen in 31-40 yrs age group i.e.25 patients (29.06 %). The majority of patients had high baseline HCV viral load (> 4 lakhs I.U. /ml) i.e. 52 patients (60.46%). Out of total 86 patients, , 50 patients (58.13%) were cirrhotic, 34 patients (39.53 %) were smokers, 33 patients (38.37%) were alcoholic, 26 patients (30.23 %) had past history of surgical intervention, 9 patients (10.46 %) were diabetic, 9 patients (10.46 %) had got tattoo, 8 patients (9.30%) had history of previous blood transfusion and 13 patients (15.11%) gave history of use of alternative medications. Results: The direct risk factors associated with development of failed SVR in HCV patients are high baseline HCV RNA viral load, cirrhosis, rural background and indirect risk factors are smoking, alcohol and Diabetes Mellitus but large scale studies in future are required to confirm the same.

Vaginal bleeding as a sign of Crimean\u2013Congo hemorrhagic fever infection: a case report

BackgroundCrimean–Congo hemorrhagic fever is a severe vector-borne viral hemorrhagic fever with considerable mortality in humans. This disease is endemic in Afghanistan, and its incidence rate has rapidly increased in recent years. This infection can cause a broad range of hemorrhage manifestations including epistaxis, petechial or purpuric rashes, hematemesis, and melena; however, vaginal bleeding is also reported as a rare manifestation.Case presentationWe report the case of a previously healthy 30-year-old Afghan female of shepherding occupation, with a sudden onset of fever, generalized body pain, epistaxis, and vaginal bleeding. She was admitted to the hospital after 7 days of symptom manifestation, with predominant signs being high fever, vaginal bleeding, and elevated liver enzymes. The serological test result for Crimean–Congo hemorrhagic fever was positive. She was treated with oral ribavirin and discharged with normal parameters.ConclusionsPeople in high-risk professions in endemic areas should be informed that vaginal bleeding is a serious symptom and requires immediate action and, therefore, might be attributed to nongynecologic disorders.

Respiratory syncytial virus-associated acute respiratory illness in adult non-immunocompromised patients: Outcomes, determinants of outcomes, and the effect of oral ribavirin treatment.

BackgroundRespiratory syncytial virus (RSV) is an increasingly common cause of respiratory illness in adult non‐immunocompromised patients. Oral ribavirin was reported to improve outcomes of RSV infection in immunocompromised patients. This study aimed to determine the outcomes of non‐immunocompromised patients hospitalized with RSV‐associated acute respiratory illnesses (RSV‐ARI), the factors independently associated with the outcomes and the effect of oral ribavirin treatment.MethodsThis retrospective, observational cohort study included 175 adults admitted to the hospital with virologically confirmed RSV‐ARI during 2014–2019. Severe ARI was identified using Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria for severe community‐acquired pneumonia. The primary outcome was all‐cause mortality within 30 days after enrollment. A multivariable Cox model was performed to identify significant predictors of mortality.ResultsMean age was 76 ± 12.7 years. Seventy‐eight (44.6%) patients met the diagnostic criteria for severe ARI. Thirty‐six (20.6%) patients required invasive mechanical ventilation, and 11 (6.3%) required vasopressor. Ninety‐nine (56.6%) patients received oral ribavirin treatment, and 52 (29.7%) received systemic corticosteroids. Forty‐one (23.4%) patients had evidence of bacterial infection. Overall mortality was 7.4%. Mortality among patients with non‐severe ARI and severe ARI was 1.04% and 15.4%, respectively. Estimated glomerular filtration rate <50 ml/min/1.73 m2, severe ARI, systemic corticosteroids, and bacterial infection were independently associated with higher risk of mortality. Treatment with oral ribavirin was the only factor associated with reduced mortality (adjusted HR: 0.19, 95% CI: 0.04–0.9, P = 0.03).ConclusionRSV‐ARI may result in significant mortality and health care utilization. Treatment with oral ribavirin may improve survival in these patients.

Hepatitis E Virus Species C Infection in Humans, Hong Kong.

Hepatitis E virus (HEV) variants belonging to Orthohepevirus species A (HEV-A) are the primary cause of human hepatitis E. However, we previously reported that Orthohepevirus species C genotype 1 (HEV-C1), a divergent HEV variant commonly found in rats, also causes hepatitis in humans. Here, we present a clinical-epidemiological investigation of human HEV-C1 infections detected in Hong Kong, with an emphasis on outcomes in immunocompromised individuals. A surveillance system for detecting human HEV-C1 infections was established in Hong Kong. Epidemiological and clinical characteristics of HEV-C1 cases identified via this system between 1 August 2019 and 31 December 2020 were retrieved. Phylogenetic analysis of HEV-C1 strain sequences was performed. Infection outcomes of immunocompromised individuals with HEV-A and HEV-C1 infections were analyzed. HEV-C1 accounted for 8 of 53 (15.1%) reverse-transcription polymerase chain reaction (RT-PCR)-confirmed HEV infections in Hong Kong during the study period, raising the total number of HEV-C1 infections detected in the city to 16. Two distinct HEV-C1 strain groups caused human infections. Patients were elderly and/or immunocompromised; half tested negative for HEV immunoglobulin M. Cumulatively, HEV-C1 accounted for 9 of 21 (42.9%) cases of hepatitis E recorded in immunocompromised patients in Hong Kong. Immunocompromised HEV-C1 patients progressed to persistent hepatitis at similar rates (7/9 [77.8%]) as HEV-A patients (10/12 [75%]). HEV-C1 patients responded to oral ribavirin, although response to first course was sometimes poor or delayed. Dedicated RT-PCR-based surveillance detected human HEV-C1 cases that evade conventional hepatitis E diagnostic testing. Immunosuppressed HEV-C1-infected patients frequently progress to persistent HEV-C1 infection, for which ribavirin is a suitable treatment option.

Oral Ribavirin for Treatment of Respiratory Syncytial Virus in Lung Transplantation Recipients

Respiratory syncytial virus (RSV) can cause severe respiratory infection and is a risk factor for development of bronchiolitis obliterans syndrome (BOS) in patients who have undergone lung transplantation (LT). The treatment options are limited in this population. We assessed the efficacy of oral administration for the treatment of RSV infection after LT. A retrospective case-control was conducted in LT patients who documented RSV infection. Demographic, clinical, and efficacy variables (resolution infection, recovery of lung function, incidence of BOS, mortality) was compared between the oral ribavirin (RBV) group and the control group. Thirty-six LT patients were included (19 RBV group, 17 control group). Significant differences were found for age, sex and coinfections. However, no differences of immunosuppressive level and baseline forced expiratory volume in the first second of expiration (FEV1) were found. RSV clearance was evident in 5 patients (26.3%) of the RBV group vs 2 patients (11.8%) in the control group (odds ratio [OR], 0.37; P=.282). At 3 months, FEV1 remained stable in 12 patients (80%) of the RBV group vs 13 patients (81.3%) of the control group (OR, 0.92; P=.321). At 6 months, FEV1 remained stable in 11 patients (73.3%) of the RBV group and 12 patients (75%) of the control group (OR, 1.25; P=.779), and BOS appeared in 6 patients (31.6%) vs 4 patients (23.5%) of the control group (OR, 1.50; P=.591). Mortality rates were 26% (5 patients) in the RBV group vs 29.4% (5 patients) in the control group (OR, 1.40; P=.637). No significant differences in efficacy parameters were found between groups; however, stabilization without worsening of respiratory function was observed at 3 and 6 months. Because of the variability in the treatment regimen and the heterogeneity of groups, a protocol was developed to standardize and evaluate the use of oral RBV as treatment for RSV in LT.

Management of Lassa Fever: A Current Update

Lassa fever (LF) is on the top-priority infections list of both the Food and Drug Administration (FDA) and World Health Organization (WHO). This review explores the different treatment approaches found in the literature within the last 20 years. Even though ribavirin stands out among medication options, only one clinical trial was done to assess its efficacy in humans, which necessitated that we look in-depth about the latest updates in managing LF infection. For that matter, we used a Medical Subject Headings (MeSH) search on PubMed. Inclusion criteria included papers written in the English language and human subjects. Intravenous (IV) ribavirin is the most effective treatment for an acute infection. Post-exposure prophylaxis with oral ribavirin is recommended. There is not sufficient evidence to recommended convalescent plasma for the treatment of Lassa fever. LF continues to be left in the shade from global and scientific attention despite experts expecting a rise in current and future infections due to the Lassa fever virus (LFV).

Prevalence of Thyroid Dysfunction in Chronic Hepatitis C Patients on Interferon Therapy

Objective: to record the prevalence of thyroid dysfunction in chronic HCV cases receiving interferon therapy Methodology: A total of 100 patients with a diagnosis of chronic Hepatitis C between 35-70 years of either sex with normal Thyroid function test at the time of commencement of therapy were included. This trial was conducted during the period 2021-22 at Services Hospital Lahore. Interferon alfa 3 million units were administered to patients three times per week, along with oral ribavirin 1000 mg or 1200 mg every day (depending on their weight) for 24 weeks. During therapy, these individuals had clinical evaluations every 2, 4, and 6 months. The presence and severity of adverse events were evaluated at each visit, along with standard laboratory tests. TSH levels were used to assess patients for thyroid illness every 2, 4, and 6 months. Results: Mean age was calculated as 48.57+11.35 years, 52(52%) were male and 48(48%) were females, frequency of thyroid dysfunction in Chronic HCV cases receiving interferon therapy was recorded in 19(19%) of the cases. Conclusion: The incidence of thyroid dysfunction in individuals taking interferon treatment for chronic hepatitis C infection is not very high. However, we recommend that those who are currently receiving treatment for chronic hepatitis C should be evaluated for thyroid dysfunction. Keywords: Chronic Hepatitis C infection, Interferon therapy, Thyroid Dysfunction,

Evaluation of Efficacy of Ribavirin on Laboratory Test and Severity Score in Crimean-Congo Hemorrhagic Fever in Children

Crimean-Congo hemorrhagic fever (CCHF) is endemic in Tokat province. It is observed in all age groups. The case fatality rate varies 20-30% in hospitalized patients and 0-5% among children. Ribavirin use and supportive measures are the main treatment modalities, but the effects of ribavirin in CCHF are controversial. Most of the studies investigating the effectiveness of ribavirin are done by comparing the initial and the final laboratory values. The purpose of this study was to evaluate the effects of oral ribavirin use in children with CCHF by using all the clinical and laboratory findings and to investigate the presence of unnoticed results. In the study, the data of 67 patients under 19 years old who were hospitalized and followed up with a diagnosis of CCHF during 2012-2020 epidemic period were retrospectively analyzed. Epidemiological and demographic characteristics, clinical and laboratory data were retrieved from the patient files. We implemented a linear mixed-effects model to assess the effects of the ribavirin, taking into account the repeated measures of the data. Ribavirin was given to 33 (49.2%) of the patients. 54 (80.6%) of the patients were male, 13 (19.4%) were female, 52 (77.6%) of the patients were living in rural areas and 15 (22.4%) were living in urban areas. The mean age was 15.1 (median= 15.5, range= 8-18) years in patients who did not receive ribavirin, and 15.2 (median= 15, range= 11-18) years in ribavirin administered patients. At the time of admission 63 (94%) of the patients had fever, 60 (89.6%) had fatigue, 38 (56.7%) had rash, 48 (71.6%) had myalgia, 30 (44.8%) had headache, 25 (37.3%) had abdominal pain, 30 (44.8%) had vomiting, 21 (31.8%) had diarrhea, 29 (43.3%) had drowsiness, 29 (43.3%) had bleeding in the mucosa and 27 (40.3%) had petechiae. Drowsiness and mucosal bleeding rates were significantly higher in patients who received ribavirin (p<0.05). The time from tick bite to hospital admission was 4.85 (median= 4.5, range= 2-9) days in patients who did not receive ribavirin, and 4.64 (median= 5, range= 2-9) days in ribavirin administered patients. The mean length of the hospital stay in patients who did not receive ribavirin was 6.68 (median= 7, range= 4-10) days, while it was 7.45 (median= 8, range= 3-13) days in those treated with ribavirin. Linear-mixed effect test results showed that ribavirin decreased hemoglobin (Hb) (95% GA= -0.12/-0.02), suppressed white blood cell count (WBC) (95% GA= -0.15/-0.02) and absolute lymphocyte count (ALC) (95% GA= -0.12/0.05), and decreased alanine aminotransferase (ALT) (95% GA= -9.32/-1.49), lactate dehydrogenase (LDH) (95% GA= -25.06/-2.36) and severity score index (95% GA= -0.28/-0.004). As a result, ribavirin suppressed Hb, WBC and ALC levels in children with CCHF, but decreased liver enzymes and severity score much faster in the elapsed time.

Clinical outcomes of different therapeutic options for COVID-19 in two Chinese case cohorts: A propensity-score analysis.

BackgroundThe timing of administration of agents and use of combination treatments in COVID-19 remain unclear. We assessed the effectiveness of therapeutics in cohorts in Hong Kong SAR and Anhui, China.MethodsWe conducted propensity-score analysis of 4771 symptomatic patients from Hong Kong between 21st January and 6th December 2020, and 648 symptomatic patients from Anhui between 1st January and 27th February 2020. We censored all observations as at 13st December 2020. Time from hospital admission to discharge, and composite outcome of death, invasive mechanical ventilation or intensive care unit admission across 1) all therapeutic options including lopinavir-ritonavir, ribavirin, umifenovir, interferon-alpha-2b, interferon-beta-1b, corticosteroids, antibiotics, and Chinese medicines, and 2) four interferon-beta-1b combination treatment groups were investigated.FindingsInterferon-beta-1b was associated with an improved composite outcome (OR=0.55, 95%CI 0.38, 0.80) and earlier discharge (−8.8 days, 95%CI −9.7, −7.9) compared to those not administered interferon-beta-1b. Oral ribavirin initiated within 7 days from onset was associated with lower risk of the composite outcome in Hong Kong (OR=0.51, 95%CI 0.29, 0.90). Lopinavir-ritonavir, intravenous ribavirin, umifenovir, corticosteroids, interferon-alpha-2b, antibiotics or Chinese medicines failed to show consistent clinical benefit. Interferon-beta-1b co-administered with ribavirin was associated with improved composite outcome (OR=0.50, 95%CI 0.32, 0.78) and earlier discharge (−2.35 days, 95%CI −3.65, −1.06) compared to interferon-beta-1b monotherapy.InterpretationOur findings support the early administration of interferon-beta-1b alone or in combination with oral ribavirin for COVID-19 patients.FundingHong Kong Health and Medical Research Fund; Hong Kong Innovation and Technology Commission; Chinese Fundamental Research Funds for the Central Universities.

449 - Efficacy of Oral Ribavirin in Respiratory Syncytial Virus Infection in Hematopoietic Stem Cell Transplant Patients: A Single-Centre Experience

Background: Respiratory syncytial virus (RSV) is one of the most commonly encountered respiratory viruses among patients who have been diagnosed with a hematological malignancy or a hematopoietic stem cell transplantation (HSCT). In immunocompromised patients including HSCT recipients, RSV can progress to a more severe lower respiratory infection (LRI), often complicated by respiratory failure leading to increased morbidity and mortality. Little is known about the best management strategy in this immunocompromised group and strategies to manage RSV is challenging. Data on aerosolized ribavirin to treat RSV infections in HSCT recipients come from small, retrospective studies with heterogeneous treatment combinations but nevertheless, have shown to prevent poor outcomes. There is very little data on oral ribavirin treatment but the retrospective data so far has been promising. Aim: To evaluate the effectiveness of oral ribavirin in HSCT patients with RSV infection at our centre in London, Ontario. Methods: Eighteen HSCT patients with RSV were analyzed retrospectively. In 2012, there were 5 patients treated with supportive care alone. After 2012, there were 13 patients treated with oral ribavirin. RSV diagnosis was established by polymerase chain reaction assay via nasopharyngeal swabs. Oral ribavirin was initiated at 15 mg/kg/day in three divided doses for 7-10 days with possibility of extension in persistently symptomatic patients. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. Findings: An outbreak of RSV occurred in our oncology unit in early 2012 where 5 HSCT patients ((3 autologous HSCT and 2 allogeneic HSCT patients) contracted RSV infection as well. No definitive treatment options were available during this period and patients were managed with supportive care alone. 4/5 HSCT patients died of RSV infection leading into an 80% mortality rate. This experience led to the development of a protocol for the HSCT patients focusing on prevention of nosocomial transmission, early PCR testing and treatment with oral ribavirin for those confirmed with RSV infection and signs of pneumonia or LRI. Since 2012, 13 HSCT patients (4 autologous HSCT patients and 9 allogeneic HSCT patients) were diagnosed with RSV infection and promptly treated with oral ribavirin. The median treatment duration was 10 days (range: 7-12). All patients treated with oral ribavirin survived the infection. Oral ribavirin was well tolerated with minor adverse effects. Conclusion: We found that HSCT patients with lower respiratory RSV infections can be successfully managed by use of prevention strategies and oral ribavirin. Although, our experience reflects a small sample size, the protocol was associated with decreased mortality compared to patients who received supportive care alone. Our experience supports the use of oral ribavirin for the early treatment of HSCT patients with RSV associated LRI and may be an alternative to aerosolized RBV. But ongoing review of our experience with this protocol is necessary and large prospective studies are needed to determine the optimal therapy in this patient group. Disclosures No relevant conflicts of interest to declare.

The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin

BackgroundTryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-α on the activity of serotonergic receptors 5-HT1A and 5-HT2A, and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain.MethodsThe study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-α2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery–Åsberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement.ResultsOf the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease (β = −0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery–Åsberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively).LimitationsThis study had an open-label design in a population receiving naturalistic treatment.ConclusionThe present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a.

Clinical Outcomes of Japanese Encephalitis after Combination Treatment of Immunoglobulin, Ribavirin, and Interferon-α2b.

Background and PurposeJapanese encephalitis (JE) is caused by the JE virus of the Flaviviridae family and is spread by mosquito bites, and no specific antiviral treatment for it exists. Here we describe the clinical presentations, laboratory findings, clinical outcomes, and adverse events after combination treatment of immunoglobulin, ribavirin, and interferon-α2b administered to patients with JE.MethodsData were collected and reviewed from a prospective cohort of encephalitis patients admitted to Seoul National University Hospital between August 1, 2010 and October 31, 2019. We reviewed the medical records of the patients diagnosed with JE and treated either with supportive care only or with combination treatment of intravenous immunoglobulin, oral ribavirin, and subcutaneous interferon-α2b.ResultsEleven patients were diagnosed with laboratory-confirmed JE based on the diagnosis criteria of JE. The median age was 61 years, and five patients were male. Eight patients were treated with the combination therapy, while three patients received supportive management only. Four of the eight patients (50%) treated with the combination therapy showed partial recovery, while one patient (12.5%) showed complete recovery. Two patients experienced hemolytic anemia related to ribavirin and febrile reaction to immunoglobulin, respectively. Among the three patients who received supportive management only, one (33.3%) showed partial recovery and the other two (67.7%) did not show improvement.ConclusionsCombination treatment of immunoglobulin, ribavirin, and interferon-α2b was found to be tolerable in JE in this study. Further studies of appropriate designs and involving larger numbers of patients are warranted to explore the efficacy of this combination therapy.

Современные возможности противовирусной терапии клещевого энцефалита у детей при остром и хроническом течении

Objective. To evaluate the efficacy of antiviral therapy and serotherapy for focal tick-borne encephalitis (TBE) in children with acute and chronic infection by assessing clinical and laboratory parameters, as well as MRI findings. Patients and methods. We followed-up 130 children aged 8 to 17 years with focal TBE affecting the central nervous system (CNS). Patients in groups 1 (n = 84) and 2 (n = 20) received therapy in the acute period of infection (on average 3.5 ± 1.3 days following disease onset). Patients in groups 3 (n = 15) and 4 (n = 11) received therapy for chronic TBE infection. Children from group 1 and 3 received antiviral therapy, including oral ribavirin, recombinant interferon-α2 (IFN-α2) (intramuscular injections or suppositories with antioxidants; Viferon®), and oral processed anti-IFN-γ antibodies (Anaferon for children). Children from groups 2 and 4 received serotherapy (anti-TBE immunoglobulin) and ribonuclease (intramuscular injections). Treatment duration depended on the disease phenotype; patients were followed-up for one year. Etiological diag-nostics included measurement of anti-TBE IgM and IgG and TBE antigen using enzyme-linked immunosorbent assays (ELISA), as well as detection of viral RNA in serum and cerebrospinal fluid (CSF) using polymerase chain reaction. All patients have undergone MRI of the brain and cervical spinal cord. Children were examined before treatment and then at several time-points during therapy. Results. In patients from group 1, the period of symptom increase was 4 days shorter than that in patients from group 2. In addition to that, their period of impaired consciousness and CSF pleocytosis was 5 days shorter than in group 2; they had more rapid viral clearance from CSF. Seventy patients from group 1 (83.3%) recovered without any deficit; none of them demonstrated progression of TBE infection. Six children from group 2 (30%) developed chronic TBE infection, whereas 11 patients (55%) had neurological deficit without progression as an outcome. The majority of patients from group 3 (86.7%) demonstrated improvement with one child who had complete regression of symptoms. In all participants from this group, virus replication was stopped. More than two-thirds of children from group 4 (72.7%) had aggravation of symptoms, persistent viral replication, and progression of atrophic CNS changes (according to MRI findings). Conclusion. Antiviral therapy (ribavirin, IFN-a2, and anti-IFN-γ antibodies) are most effective during the first 5 days of the disease; however, it was also effective in children with chronic TBE infection and ensured improvement with partial regression of symptoms. Anti-TBE immunoglobulin and ribonuclease were ineffective in children with focal TBE. Key words: viferon, children, tick-borne encephalitis, acute and chronic course, antiviral therapy, serotherapy

1356. Ribavirin Use in Hospitalized Children

BackgroundRespiratory syncytial virus (RSV) infection is a significant cause of morbidity and mortality in immunocompromised children. Aerosolized ribavirin is approved for treatment of RSV lower respiratory tract infections. However, due to high cost, challenges to administration and uncertainty about benefit, use is limited. Recent studies in adult patients have reported similar outcomes between patients treated with aerosolized and oral ribavirin. We sought to characterize trends in use of ribavirin for hospitalized children.MethodsWe used the Pediatric Health Information System (PHIS), an administrative database which contains resource utilization data from 52 children’s hospitals, to perform a retrospective analysis of children hospitalized between January 1, 2010 through December 31, 2019 who were billed for ribavirin treatment. Data related to ribavirin use (number of courses, route of administration) and clinical characteristics were abstracted. International Classification of Diseases, 9th Revision (ICD-9) or 10th Revision (ICD-10) codes and All Patients Refined Diagnosis Related Groups (APR DRG) classifications were used to define underlying clinical conditions and illness severity. Summary statistics were used to describe patient characteristics and the use of ribavirin.ResultsThirty-eight hospitals reported ribavirin use; 1 hospital was excluded due to inaccuracies in charge coding. We identified 837 children who received 937 courses of ribavirin (Table 1). The overall frequency of ribavirin use was unchanged over the study period, and the number of ribavirin treatment courses per hospital ranged from 1 to 228 (Figure 1). The most frequent routes of administration were inhalation (603/937, 64%) and oral (322/937, 34%). There was a decrease in the use of aerosolized ribavirin over time, with a corresponding increase in the use of oral ribavirin (Figure 2).Table 1: Patient demographics (N=837) Figure 1: Total ribavirin treatment courses over the study period (a) by year and (b) by treating hospital Figure 2: (a) Route of administration (inhalation versus oral), by year during the study period and (b) use of oral ribavirin over time during the study period ConclusionAlthough overall prescribing rates of ribavirin in hospitalized children have remained stable, use varies widely across centers and the proportion of oral ribavirin use has increased over time. Comparative effectiveness studies are needed in the pediatric population to evaluate outcomes of children treated with aerosolized vs. oral ribavirin.Disclosures All Authors: No reported disclosures

Successful Treatment of Severe Parainfluenza Pneumonia in a Liver Transplant Recipient with Oral Ribavirin and Intravenous Immunoglobulin

: The most common viruses affecting immunocompromised hosts include cytomegalovirus, herpes simplex virus, varicella-zoster virus, influenza virus, measles virus, and adenovirus. Parainfluenza virus infection is common among human populations. It causes non-specific symptoms in immune-competent hosts; therefore, it may go undiagnosed. However, it is particularly dangerous for immunocompromised patients by presenting a high risk of morbidity and sometimes mortality among them. Patients who have bone marrow or solid organ transplantation need to follow an intense immunosuppressing routine, which leaves them extremely vulnerable to opportunistic agents such as parainfluenza viruses. Several factors determine the severity of parainfluenza virus infections, such as the type of the virus, the level of immunosuppression, and co-infection with other agents. Co-infection is especially important because it makes a correct differential diagnosis difficult. While almost all bodies of influenza infection information in immunocompromised patients are from studies of bone marrow transplant recipients, there are very limited data available on influenza infections in liver transplant patients. We present a liver transplant patient with severe parainfluenza pneumonia that was improved significantly with oral ribavirin and intravenous immunoglobulin. A 23-year-old female patient with a history of liver transplantation from 18 months ago presented with a one-week cough and tachypnea. Chest computed tomography demonstrated ground-glass opacities and diffuse infiltrates throughout both lungs. A multiplex polymerase chain reaction for the detection of respiratory viruses in the nasopharynx was positive for parainfluenza virus type 3 and she was successfully treated with oral ribavirin and intravenous immunoglobulin. Respiratory infection with the parainfluenza virus in immunocompromised adults, including transplant patients, is associated with significant morbidity and mortality, and early treatment with ribavirin and intravenous immunoglobulin may markedly improve their outcomes. To the best of our knowledge, this is the first case report of the successful treatment of parainfluenza infection with ribavirin and intravenous immunoglobulin in a patient with liver transplantation.

Efficacy of Oral Ribavirin in Respiratory Syncytial Virus Infection in Hematopoietic Stem Cell Transplant Patients: A Single-Centre Experience

Background: Respiratory syncytial virus (RSV) is one of the most commonly encountered respiratory viruses among patients who have been diagnosed with a hematological malignancy or a hematopoietic stem cell transplantation (HSCT). In immunocompromised patients including HSCT recipients, RSV can progress to a more severe lower respiratory infection (LRI), often complicated by respiratory failure leading to increased morbidity and mortality. Little is known about the best management strategy in this immunocompromised group and strategies to manage RSV is challenging. Data on aerosolized ribavirin to treat RSV infections in HSCT recipients come from small, retrospective studies with heterogeneous treatment combinations but nevertheless, have shown to prevent poor outcomes. There is very little data on oral ribavirin treatment but the retrospective data so far has been promising. Aim: To evaluate the effectiveness of oral ribavirin in HSCT patients with RSV infection at our centre in London, Ontario. Methods: Eighteen HSCT patients with RSV were analyzed retrospectively. In 2012, there were 5 patients treated with supportive care alone. After 2012, there were 13 patients treated with oral ribavirin. RSV diagnosis was established by polymerase chain reaction assay via nasopharyngeal swabs. Oral ribavirin was initiated at 15 mg/kg/day in three divided doses for 7-10 days with possibility of extension in persistently symptomatic patients. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. Findings: An outbreak of RSV occurred in our oncology unit in early 2012 where 5 HSCT patients ((3 autologous HSCT and 2 allogeneic HSCT patients) contracted RSV infection as well. No definitive treatment options were available during this period and patients were managed with supportive care alone. 4/5 HSCT patients died of RSV infection leading into an 80% mortality rate. This experience led to the development of a protocol for the HSCT patients focusing on prevention of nosocomial transmission, early PCR testing and treatment with oral ribavirin for those confirmed with RSV infection and signs of pneumonia or LRI. Since 2012, 13 HSCT patients (4 autologous HSCT patients and 9 allogeneic HSCT patients) were diagnosed with RSV infection and promptly treated with oral ribavirin. The median treatment duration was 10 days (range: 7-12). All patients treated with oral ribavirin survived the infection. Oral ribavirin was well tolerated with minor adverse effects. Conclusion: We found that HSCT patients with lower respiratory RSV infections can be successfully managed by use of prevention strategies and oral ribavirin. Although, our experience reflects a small sample size, the protocol was associated with decreased mortality compared to patients who received supportive care alone. Our experience supports the use of oral ribavirin for the early treatment of HSCT patients with RSV associated LRI and may be an alternative to aerosolized RBV. But ongoing review of our experience with this protocol is necessary and large prospective studies are needed to determine the optimal therapy in this patient group. Disclosures No relevant conflicts of interest to declare.