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.
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 was initially widely used for that indication. With the development of potent, all oral, direct acting antiviral agents for hepatitis C, ribavirin has been used far less frequently although it is occasionallystill used in patients who relapse or fail to respond to optimal direct acting agents for hepatitis C. 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.
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 or oral direct acting antiviral agents against 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).
Treatment of patients with advanced cirrhosis with chronic hepatitis C using potent direct acting antiviral agents has resulted in several instances of acute hepatic decompensation, typically arising during the first few weeks of treatment. Many of these patients were also receiving ribavirin, but sudden decompensation has also been described in non-ribavirin containing regimens and no single antiviral agent appears to be responsible. Because ribavirin is generally used in combination with other antiviral agents its contribution to adverse events and particularly liver-associated adverse events is difficult to assess. If ribavirin is capable of causing significant liver injury, this must be quite rare.
Likelihood score: E* (unproven although suspected rare cause of clinically apparent liver injury).
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.
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.
|Medication:||Ribavirin (1200 mg daily)|
|Pattern:|| Not applicable|
|Severity:||None; hyperbilirubinemia without liver injury|
|Months After Starting
|Total Bilirubin (mg/dL)
|Ribavirin (1200 mg daily) started
| Ribavirin stopped and patient followed on no therapy
Abbreviations: Retics, reticulocytes; Hct, hematocrit; HCV, hepatitis C virus.
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.
REPRESENTATIVE TRADE NAMES
Ribavirin – Generic, Copegus®, Rebetol®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 10 June 2018
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Sperl J, Horvath G, Halota W, Ruiz-Tapiador JA, Streinu-Cercel A, Jancoriene L, Werling K, et al. Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial. J Hepatol 2016; 65: 1112-1119. PubMed Citation. (Among 257 patients with chronic hepatitis C, genotypes 1 and 4, SVR rates were 99% with 12 weeks of elbasvir and grazoprevir and 90.5% with 12 weeks of sofosbuvir, peginterferon and ribavirin; adverse events were more frequent in the interferon treated subjects but there were no deaths and no liver-related serious adverse events or late ALT elevations).
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