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Chapter 1 - RB

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Ribavirin

Ribavirin has activity against RNA and DNA viruses and until the newer hepatitis C therapies, was used most commonly for hepatitis C, as well as hemorrhagic fevers and RSV.

From: Stiehm's Immune Deficiencies (Second Edition), 2020

Related terms:

Pegylated Interferon

Interferon Type I

Telaprevir

Interferon Alfa

Sofosbuvir

Hepatitis C

Genotype

Hepatitis C Virus

Peginterferon Alpha

Human Immunodeficiency Virus

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Ribavirin

Debasis Mondal, in xPharm: The Comprehensive Pharmacology Reference, 2007

Introduction

Ribavirin is a synthetic nucleoside with antiviral activity. When used as an aerosol (Virazole), ribavirin is active against respiratory syncitial virus (RSV). Oral ribavirin (Rebetol) in combination with interferon alpha is used for the treatment of hepatitis C virus (HCV). The combination treatment of HCV with interferon alfa and oral ribavirin produces a higher sustained response rate than interferon or ribavirin alone Abramowicz (2002). The mechanism of action of ribavirin in the treatment of RSV or HCV is unknown. Intravenous administration of ribavirin appears to decrease mortality in Lassa fever with renal syndrome caused by hantavirus Drug Facts and Comparisons (2001).

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Ribavirin

In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016

Teratogenicity

Ribavirin is teratogenic and embryotoxic in laboratory animals and should not be given to pregnant women. Concern has been expressed about the safety of people in the same room as patients being treated with ribavirin by aerosol, particularly women of child-bearing age. However, no ribavirin was detected in the urine, plasma, or erythrocytes of 19 nurses exposed to ribavirin administered via ventilator, oxygen tent, or oxygen hood over 3 days [122].

The voluntary Ribavirin Pregnancy Registry was established in 2003 to monitor pregnancy exposures to ribavirin and to evaluate the potential human teratogenicity of prenatal exposure [123]. It documents pregnant women who have been exposed to ribavirin during pregnancy or during the 6 months before conception either directly (by taking ribavirin) or indirectly (through sexual contact with a man taking ribavirin). After more than five years, 49 live births after direct exposure and 69 live births after indirect exposure have been documented, including six cases of birth defects (three direct exposures and three indirect), all among live-born infants: two cases of torticollis and one each of hypospadias; polydactyly and a neonatal tooth; glucose-6-phosphate dehydrogenase deficiency; ventricular septal defect and cyst of the fourth ventricle of the brain.

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ANTIVIRAL AGENTS

M.A. Parniak, ... M.E. Abram, in Encyclopedia of Respiratory Medicine, 2006

Drug for the Treatment of Respiratory Syncytial Virus Infection

Ribavirin

The synthetic nucleoside ribavirin (1-(3,4-dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H-[1,2,4]-triazole-3-carboxylic acid amide) is a guanosine analog that is approved for the treatment of pediatric respiratory syncytial virus (RSV) infection (Figure 5). RSV is the most common cause of severe lower respiratory tract disease in infants, causing up to 90% of bronchiolitis and 40% of bronchopneumonia cases. Disease symptoms are much milder in older children and adults. Although orally administered ribavirin is rapidly absorbed with good bioavailability (approximately 45%), treatment of pediatric RSV infection requires the drug to be administered by continuous aerosol (nebulizer) for 12–18 h daily for 3–6 days. This therapy is expensive and requires specialized equipment and monitoring. Its use is therefore generally reserved for treatment of RSV infection in high-risk infants (e.g., premature infants, immunocompromised children, or infants with congenital heart disease).

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Figure 5. Structure of ribavirin, which is used for the treatment of high-risk pediatric respiratory syncytial virus infection.

Mechanism of action

Ribavirin is in fact a broad-spectrum antiviral agent that inhibits a wide range of RNA and DNA viruses. The mechanism for the antiviral activity of ribavirin is unclear and may differ for different types of viruses. However, it is generally thought that ribavirin therapy alters cellular nucleotide pools, thereby affecting viral mRNA synthesis. It is likely that ribavirin must be phosphorylated by cellular kinases to provide antiviral activity. Ribavirin-5′-monophosphate inhibits the cellular enzyme inosine-5′-phosphate dehydrogenase, blocking the conversion of inosine-5′-monophosphate to xanthosine-5′-monophosphate. This decreases levels of guanosine triphosphate (GTP), which impacts on both RNA and DNA metabolism. Ribavirin-5′-triphosphate may also be a competitive inhibitor of GTP-dependent 5′-capping of viral mRNA.

Contraindications

Aerosolized ribavirin may cause bronchospasm or conjunctival irritation. It requires close supervision, especially with mechanical ventilation, because precipitation of the drug may occur. Healthcare workers involved in the administration and monitoring of aerosol ribavirin treatment may occasionally experience irritation of the eyes and respiratory tract. Ribavirin is mutagenic, teratogenic, and embryotoxic; thus, aerosolized ribavirin is a risk to pregnant healthcare workers.

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Antiviral Agents☆

E. Paintsil, Y.-C. Cheng, in Encyclopedia of Microbiology (Fourth Edition), 2019

Clinical indications

Respiratory syncytial virus

Ribavirin is licensed for the treatment of carefully selected, hospitalized infants and young children with severe lower respiratory tract infections caused by RSV. Use of aerosolized ribavirin in adults and children with RSV infections reduced the severity of illness and virus shedding. However, placebo controlled trials have failed to demonstrate a consistent decrease in need for mechanical ventilation, duration of stay in intensive care unit, or duration of hospitalization among ribavirin recipients. The use of ribavirin for the treatment of RSV infections is controversial and remains discretionary. The most common adverse events following aerosol administration of ribavirin include bronchospasm and malfunction of ventilator delivery systems. The usual dosage of aerosolized ribavirin is 20 mg ml− 1 of drug instilled in a small-particle aerosol generator (SPAG) and administered for 12–22 h day− 1 for 3–6 days. To avoid potential exposure of health care workers to ribavirin, special containment delivery system in an isolation room with negative pressure is used.

Hepatitis C

Oral ribavirin in combination with interferon-α (IFN-α) and a direct-acting antiviral agent (DAA) is recommended for hepatitis C infection.

Lassa fever and hemorrhagic fever

Systemic ribavirin has demonstrated efficacy in the management of life-threatening infections caused by Lassa fever and hemorrhagic fever with renal syndrome. Oral ribavirin is recommended for prophylaxis against Lassa fever in exposed contacts.

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Ribavirin☆

D. Mondal, in Reference Module in Biomedical Sciences, 2017

Abstract

Ribavirin is a synthetic nucleoside with antiviral activity. When used as an aerosol (Virazole), ribavirin is active against respiratory syncitial virus (RSV). Ribavirin, in combination with pegylated interferon alfa, is also used primarily to treat hepatitis C virus. In this indication the oral (capsule or tablet) form is used. It can also be used in people coinfected with hepatitis B, HIV and in the pediatric population. The combination treatment of HCV with interferon alfa and oral ribavirin produces a higher sustained response rate than interferon or ribavirin alone. It has also been used to treat viral hemorrhagic fevers (orphan indication).

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Hepatitis C

Stuart C. Ray, David L. Thomas, in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015

Ribavirin

Ribavirin is a guanosine analogue with high oral bioavailability and exceptionally broad, although not particularly potent, antiviral activity. At least four different mechanisms of action have been proposed to explain its efficacy in the treatment of HCV infection. First, ribavirin is a potent inhibitor of cellular inosine monophosphate dehydrogenase and thus may influence intracellular nucleoside pools; second, it has been suggested that it may weakly inhibit the NS5B-encoded RNA-dependent RNA polymerase; third, it has been shown to promote the mutagenicity of RNA viruses; and, fourth, ribavirin may possibly modulate the Th1/Th2 balance in the host immune response.569-572 When administered alone, ribavirin therapy appears to reduce liver enzyme levels in 21% to 43% of patients.573-575 However, HCV RNA levels were significantly reduced in only a few percent of patients receiving ribavirin monotherapy. Ribavirin has a multiple dose half-life of 12 days and can be administered once or twice daily. Interestingly, the clinical importance of ribavirin appears to be in preventing relapse.

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Antiviral Agents

David W. Kimberlin, in Principles and Practice of Pediatric Infectious Diseases (Fifth Edition), 2018

Chemistry, Mechanism of Action, Spectrum, and Resistance.

Ribavirin (Virazole, Rebetron combination therapy) is a synthetic nucleoside analogue developed in 1972 that most closely resembles guanosine in structure.226 Ribavirin is absorbed rapidly across cell membranes and is enzymatically converted by host cell enzymes into its 5′-phosphate derivatives and the deribosylated base.227 These metabolites interfere with the capping and elongation of messenger RNA. Ribavirin also appears to reduce guanine nucleosides by feedback inhibition.228

Although more potent against RNA viruses, ribavirin is active in vitro against a wide range of RNA and DNA viruses, including myxoviruses, paramyxoviruses, arenaviruses, bunyaviruses, herpesviruses, adenoviruses, poxviruses, and retroviruses.229,230 It is approved in the United States for the treatment of RSV infections and, in combination with interferon, for hepatitis C virus infections. Resistance to ribavirin has not been observed, although Sindbis virus mutants with diminished susceptibility to ribavirin have been reported.231

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Neurologic Aspects of Systemic Disease Part II

Christine L. Ahrens, Edward M. Manno, in Handbook of Clinical Neurology, 2014

Ribavirin

Ribavirin is indicated for the treatment of chronic hepatitis C in combination with interferon α-2B (pegylated and nonpegylated) in patients with compensated liver disease. (Rebetol®, 2013) (ribavirin) monotherapy is not effective for the treatment of hepatitis C (37).

Mechanism of action

Ribavirin is a neucleoside analog and has antiviral activity against multiple RNA viruses. However, its mechanism in the treatment of hepatitis C has not been fully elucidated. It is proposed that ribavirin has effects on the host immune response (Lau et al., 2002).

Neurotoxicity

The most concerning adverse effect associated with ribavirin use is hemolytic anemia. Other adverse effects include fatigue, leukopenia, pruritis, rash, and gout. Ribavirin is a well known teratogenic drug and is US Food and Drug Administration (FDA) pregnancy category X. Clear recommendations on use in women of childbearing age are outlined within the prescribing information (Epivir-HBV, 2011).

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