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DRUG RECORD

 

RIBAVIRIN

OVERVIEW
Ribavirin

 

Introduction

Ribavirin is a nucleoside analogue and antiviral agent used in therapy of chronic hepatitis C and other flavivirus infections.  Ribavirin has not been associated with clinically apparent liver injury.

 

Background

Ribavirin (rye" ba vye' rin) is a guanosine nucleoside analogue which has antiviral activity against many RNA and DNA viruses in vitro, but has been found to have clinical effects in humans mostly against flaviviruses, including the hepatitis C virus (HCV), respiratory syncytial virus (RSV), and perhaps the Ebola and Hanta viruses.  The in vitro antiviral activity of ribavirin appears to be mediated by depletion of intracellular guanosine through inhibition of inosine monophosphate dehydrogenase (a necessary enzyme in purine nucleoside synthesis).  Ribavirin may also have indirect effects on viral replication caused by increasing interferon induced gene expression and modulating immune responses.  Ribavirin is indicated as adjunctive therapy with alpha interferon or peginterferon in combination with an HCV specific protease inhibitor (boceprevir or telaprevir) in chronic hepatitis C.  Ribavirin is also used by inhalation for acute RSV infection.  Ribavirin has been used experimentally to treat chronic hepatitis E, and is currently under evaluation in interferon-free regimens for hepatitis C in combination with other oral direct acting antivirals.  Ribavirin was approved for use in hepatitis C in 1998 and is widely used for that indication.  Ribavirin is available as capsules of 200 mg in generic forms and under the brand names of Copegus and Rebetol.  The recommended dose of ribavirin in adults is 800 to 1200 mg daily in two divided doses for 24 to 48 weeks in combination with peginterferon, with or without boceprevir or telaprevir.  Side effects include hemolytic anemia, pruritus and nasal stuffiness.

 

Hepatotoxicity

Oral therapy with ribavirin alone is rarely used and has not been associated with serum aminotransferase elevations.  Because ribavirin is usually used in patients with underlying liver disease (hepatitis C), it is difficult to interpret increases in serum ALT levels during therapy, and typically ribavirin decreases serum ALT levels in patients with hepatitis C.  Ribavirin does cause a dose dependent red cell hemolysis which can be severe.  The onset of hemolysis is usually after 2 to 3 weeks of therapy and can present with symptoms of anemia and sudden decreases in hematocrit levels by 5% to 10%.  The hemolysis is accompanied by a mild increase in indirect bilirubin, which may result in total bilirubin concentrations of 1.5 to 2.5 mg/dL.  This indirect hyperbilirubinemia is generally benign and resolves rapidly once therapy is stopped.  Patients with underlying Gilbert syndrome or with advanced liver disease may become visibly jaundiced.  Patients with deficiencies in inosine triphosphatase activity (ITPA variants) are relatively protected against the hemolysis of ribavirin, probably because the increased levels of intracellular ITP provide an alternate source for intracellular guanosine and adenosine triphosphate which are depleted in red cells by ribavirin-triphosphate.

 

Rare instances of fatty liver with lactic acidosis and hepatic dysfunction have been reported in patients with HIV infection receiving antiretroviral therapy as well as ribavirin (in combination with interferon as therapy of coinfection with hepatitis C).  This complication has not been reported with use of ribavirin alone and drug-drug interactions are likely the cause, ribavirin increasing the risk of lactic acidosis from other nucleoside analogues used in the treatment of HIV infection (particularly stavudine, didanosine and zidovudine).

 

Mechanism of Injury

Ribavirin is metabolized minimally by the liver and is excreted largely unchanged by the kidneys, perhaps accounting for the absence or rarity of hepatic injury.  The hyperbilirubinemia associated with ribavirin use is due to red cell hemolysis and excess production of bilirubin.

Agents active against hepatitis C include alpha interferon, peginterferon, boceprevir, ribavirin, simeprevir, sofosbuvir, telaprevir.

 

Drug Class:  Antiviral Agents, Nucleoside Analogues, Hepatitis C Agents

 

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CASE REPORT
Ribavirin

 

Case 1.  Hyperbilirubinemia during ribavirin therapy in a patient with Gilbert syndrome.
[NIH Case #R52]


A 53 year old man with chronic hepatitis C developed mild jaundice during experimental therapy with ribavirin.  He was known to have had chronic hepatitis C for 10 years, acquired because of a blood transfusion.  He was otherwise well, but had a previous history of hepatitis B from which he had recovered.  He denied all symptoms of liver disease except for mild and intermittent fatigue.  He had elevations of serum aminotransferase levels (ALT 123 U/L, AST 91 U/L), but normal serum bilirubin 0.9 mg/dL and albumin 4.2 g/dL.  He was positive for anti-HCV, and HCV RNA was present at levels of 3 to 6 million IU/mL, genotype 1b.  HBsAg and anti-HAV were negative and autoantibodies were not detected.  A liver biopsy showed marked disease activity (histology activity index score of 12 of a total possible of 18) and bridging hepatic fibrosis (Ishak fibrosis score of 3 of a possible 6).  He was enrolled in an experimental study of ribavirin monotherapy and received 1200 mg daily for 12 months.  Serum enzymes improved during treatment, but serum bilirubin levels were intermittently elevated with a peak total bilirubin of 3.1, direct 0.5 mg/dL.  A concurrent reticulocyte count had risen from 2.4 to 9.3% and hematocrit had fallen from 49.2% to 39.7% (Table).  He denied worsening of fatigue or itching.  Upon stopping ribavirin, the hemolysis resolved and bilirubin levels and reticulocyte counts fell while serum aminotransferase levels and hematocrit rose to baseline levels.  There was no sustained improvement in the liver disease.


Key Points

Medication:Ribavirin (1200 mg daily)
Pattern: Not applicable
Severity:None; hyperbilirubinemia without liver injury
Latency: 2-4 weeks
Recovery: 2-4 weeks
Other medications:None

Laboratory Values

Months After Starting

ALT

(U/L)

Total Bilirubin (mg/dL) Retics (%)

Hct

(%)

HCV RNA

(million IU/mL)

Pre 123 0.9 1.0 50.3 6.5
0 148 1.5 2.4 49.2 3.4
Ribavirin (1200 mg daily) started
1 85 1.7 8.8 41.0 2.6
2 65 2.0 9.3 39.7 2.5
4 35 2.1 10.4 36.4 2.5
6 47 1.5 11.7 38.8 1.9
8 54 3.1 9.3 39.7 1.8
12 43 1.9 9.9 37.9 1.8
Ribavirin stopped and patient followed on no therapy
+1 72 0.6 2.4 48.0
+2 212 0.8 1.3 48.6 3.0
+6 157 1.4 1.3 49.0
Normal Values <42 <1.2 <1.0 >38 None

Abbreviations: Retics, reticulocytes; Hct, hematocrit; HCV, hepatitis C virus.

Comment

A patient with chronic hepatitis C and probable Gilbert syndrome (constitutional indirect hyperbilirubinemia) developed visible jaundice during an experimental study of monotherapy with ribavirin.  At the same time that serum bilirubin levels increased, serum ALT levels had fallen in response to the ribavirin therapy.  There was a concomitant minor decrease in HCV RNA levels.  The increase in indirect hyperbilirubinemia with reticulocytosis and decrease in hematocrit indicated that the jaundice was due to hemolysis in a patient with impaired ability to conjugate bilirubin, rather than hepatic injury or cholestasis.  There was a rapid reversal of the hyperbilirubinemia with stopping therapy.  Both before and after therapy, total serum bilirubin levels were occasionally slightly above normal (1.5-1.8 mg/dL), probably based upon how long he had been fasting at the time of the blood draw.

 

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PRODUCT INFORMATION
Ribavirin

 

REPRESENTATIVE TRADE NAMES
Ribavirin – Generic, Copegus®, Rebetol®

 

DRUG CLASS
Antiviral Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Ribavirin 36791-04-5 C8-H12-N4-O5 Ribavirin Chemical Structure

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REFERENCES
Ribavirin

 

References updated: 10 January 2014

  1. Zimmerman HJ. Antiviral agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 621-3.  (Expert review of antiviral agents and liver injury published in 1999; mentions that ribavirin can cause hemolysis and hyperbilirubinemia, but "no other evidence of hepatic injury").

  2. Spengler U. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 567-91.  (Review of hepatotoxicity of antiviral agents published in 2007).

  3. Hayden. Antiviral agents(nonretroviral). In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 1243-72.  (Textbook of pharmacology and therapeutics).

  4. Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, Yurdaydin C, Swain M, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 897-903. PubMed Citation  (Controlled trial of 12 month course of ribavirin vs placebo in 29 patients with chronic hepatitis C; serum aminotransferase levels decreased in all but one ribavirin treated patient; none developed worsening of liver disease: Case 1).

  5. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36(5 Suppl 1): S237-44. PubMed Citation  (Review of side effects of interferon and ribavirin).

  6. Soriano V, Miralles C, Berdú, Berdun MA, Losada E, Aguirrebenjoa K, Ocampo A, et al.; PRESCO Study Group. Premature treatment discontinuation in HIV/HCV-coinfected patients receiving pegylated interferon plus weight-based ribavirin. Antivir Ther 2007; 12: 469-76. PubMed Citation  (Among 389 patients with HIV-HCV coinfection treated with peginterferon and ribavirin in Spain, 45% stopped therapy early, 2 developed mitochondrial injury with pancreatitis and lactic acidosis [despite not using didanosine], resolving with stopping therapy).

  7. Drugs for non-HIV viral infections. Treat Guidel Med Lett 2007; 5: 59-70. PubMed Citation  (Review of status of non-antiretroviral antiviral agents for prevention and treatment of herpes, varicella-zoster, cytomegalovirus, influenza A and B, and hepatitis B and C; no mention of liver related side effects for ribavirin).

  8. Jain MK, Zoellner C. Role of ribavirin in HCV treatment response: now and in the future. Expert Opin Pharmacother 2010; 11: 673-83. PubMed Citation  (Review of the chemistry, mechanism of action, pharmacokinetics, clinical efficacy and side effects of ribavirin in chronic hepatitis C; ribavirin is used only in combination with interferon or peginterferon; major side effect is hemolysis; ribavirin and peginterferon may predispose patients with HIV infection also receiving antiretroviral nucleoside analogues such as stavudine to develop lactic acidosis).

  9. Kamar N, Rostaing L, Abravanel F, Garrouste C, Lhomme S, Esposito L, Basse G, et al. Ribavirin therapy inhibits viral replication on patients with chronic hepatitis E virus infection. Gastroenterology 2010; 139: 1612-8. PubMed Citation  (Among six patients with chronic hepatitis E treated with ribavirin [400-800 mg daily], all became HEV RNA negative during therapy and 4 remained negative afterwards; side effects included hemolysis and anemia, but serum ALT levels improved in all patients).

  10. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, Little LD, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 2010; 464: 405-8. PubMed Citation  (Genome wide association study in 1602 patients with chronic hepatitis C treated with peginterferon and ribavirin found that variants leading to inosine triphosphatase deficiency were associated with protection against ribavirin associated hemolysis).

  11. Hitomi Y, Cirulli ET, Fellay J, McHutchison JG, Thompson AJ, Gumbs CE, Shianna KV, et al. Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function. Gastroenterology 2011; 140: 1314-21. PubMed Citation  (Analysis of role of inosine triphosphate [ITP] in protecting against hemolysis caused by ribavirin, suggesting that ITP provides an alternate source for guanosine and adenosine triphosphate, which are depleted by build up of ribavirin triphosphate in red cells).

  12. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, et al.; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195-206. PubMed Citation  (Among 734 patients with chronic hepatitis C, genotype 1, treated with boceprevir, peginterferon and ribavirin for 28-48 weeks, sustained reponse rates were 63-66%; adverse events included hemolysis and anemia, but no worsening liver enzyme levels or flares of hepatitis mentioned).

  13. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, et al.; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405-16. PubMed Citation  (Among 727 patients with chronic hepatitis C, genotype 1, treated with the combination of telaprevir, peginterferon and ribavirin, sustained response rates were 69-75%; adverse events included hemolysis and anemia, but no worsening of liver enzyme levels or flares of hepatitis mentioned).

  14. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368: 34-44. PubMed Citation  (Among 85 patients with chronic hepatitis C treated with sofosbuvir and ribavirin with or without peginterferon for 8-12 weeks, serum enzymes became or remained normal and HCV RNA became undetectable in all patients during therapy; adverse events included anemia and hemolysis, but there were no instances of worsening of liver enzymes or flares of hepatitis).

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OTHER REFERENCE LINKS
Ribavirin
  1. PubMed logoRecent References on Ribavirin

  2. Clinical Trials logoTrials on Ribavirin

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