AUTHOR INFORMATION

Section 1 of 11

Authored by Nicholas John Bennett, MBBCh, PhD, Staff Physician, Department of Pediatrics, State University of New York Upstate Medical University

Coauthored by Joseph Domachowske, MD, Associate Professor, Department of Pediatrics, Division of Infectious Diseases, State University of New York-Upstate Medical University; Donald K Strickland, MD, National Liaison, Avastin, Genentech BioOncology

Nicholas John Bennett, MBBCh, PhD, is a member of the following medical societies: American Academy of Pediatrics

Edited by Leonard R Krilov, MD, Chief of Pediatric Infectious Diseases, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine; Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Author's Email:	Nicholas John Bennett, MBBCh, PhD
Editor's Email:	Leonard R Krilov, MD

eMedicine Journal, May 23 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

Background: Hepatitis C virus (HCV) is 1 of 6 (along with A, B, D, E, and G) that cause viral hepatitis. Prior to identification of the virus, it was known as non-A/non-B hepatitis, to distinguish it from the viral causes of nonalcoholic hepatitis that were known at the time.

Unfortunately, most patients who are infected have chronic infection and are at risk for progressive liver disease. Furthermore, diagnosis primarily relies on identifying the risk factors of transmission because patients typically have few, if any, symptoms. Once diagnosed, present treatment options for eradication are limited and often result in significant adverse effects.

Although HCV infection is uncommon among pediatric patients, the caregiver should be familiar with the basic concepts. For example, patients transfused as recently as July 1992 may have been exposed to the virus. Furthermore, vertical transmission of HCV is possible. Most studies performed to further delineate the natural history have involved adult cohorts; therefore, further research on the ultimate outcome of infection during childhood is clearly needed.

Pathophysiology: HCV is a member of the Flaviviridae family of RNA-containing viruses; thus, it is not integrated into the host genome. Although the liver is the primary target of infection, studies to better define the steps of HCV infection are greatly hampered by the lack of a suitable animal model for such studies. A tissue-culture system using recombinant DNA technology was only recently developed and will likely advance the scientific knowledge base considerably.

The primary immune response to HCV is mounted by cytotoxic T lymphocytes. Unfortunately, this process fails to eradicate infection in most people; in fact, it may contribute to liver inflammation and, ultimately, tissue necrosis. The ability of HCV to escape immune surveillance is the subject of much speculation. One likely means of viral persistence relies on the presence of closely related but heterogeneous populations of viral genomes. Further studies of these quasi-species enable classification of several genotypes and subtypes, which may have clinical implications.

Frequency:

• In the US: An estimated 30,000 new infections occur annually, although only 25-30% are diagnosed. Since the 1980s, acute infections have declined by more than 80%. Nearly 4 million Americans, or about 2% of the population in the United States, are infected with HCV.

• Internationally: Although the worldwide prevalence varies considerably by geographic region, more than 3% of the global population is infected.

Mortality/Morbidity:

• Acute fulminate infection is rare. More than 80% of acutely infected patients have chronic HCV. Annually, it accounts for 8,000-10,000 deaths in the United States.

• In more than 20% of chronically infected adults, progression to cirrhosis occurs an average of 20 years after initial infection. Patients with this condition have a secondary risk of portal hypertension, liver failure, and other complications. Hepatitis C is now one of the leading reasons for liver transplantation in the United States, accounting for up to 40% of transplant cases.

• In 1-5% of patients, most of whom have underlying cirrhosis, hepatocellular carcinoma (HCC) is diagnosed an average of 30 years after initial HCV infection.

Race:

• With respect to the frequency of infection worldwide, significant racial differences exist.

• In the United States, infection is more common among members of minority populations than in other groups.

• The effect of ethnic background on the risk of significant liver disease is undefined.

Sex:

• HCV infection is more common among males than females.

Age:

• In the United States, the highest incidence is among those aged 20-39 years, and the highest prevalence is among those aged 30-49 years.

• The age at time of initial infection likely has important implications on the natural history of infection because individuals who are infected at a younger age tend to have a decreased risk of progression to cirrhosis and HCC.

CLINICAL

Section 3 of 11

History:

• The incubation period varies widely, with a mean of 7-10 weeks and a range of 2-20 weeks.



• Infections are often inapparent or subclinical. Only 25-35% of patients have nonspecific symptoms such as weakness, malaise, and anorexia; likewise, patients with chronic hepatitis C virus (HCV) often have few, if any, symptoms. Fatigue is reported most often.

Physical:

• Approximately 25% of acutely infected patients have jaundice, whereas less than one third have hepatomegaly.



• Some patients with chronic infection have findings consistent with chronic liver disease; these include hepatomegaly, ascites, splenomegaly, and spider nevi.

Causes:

• Direct percutaneous exposure is the primary means of transmission.



• Blood transfusions are another means of transmission.


• • Historically, most HCV infections result from blood transfusions.
  
  
  
  • The risk of transfusion-borne HCV began to decline in 1986, when surrogate-marker screening of blood donors started.
  
  
  
  • Further declines were noted after the introduction of HCV-directed antibody screening in 1990 (first generation) and 1992 (second generation).
  
  
  
  • The current risk of transfusion-derived HCV is estimated to be 1 case in every 100,000 units transfused.
  
  
  
• Currently, the use of injected drugs is the most important epidemiologic risk factor, probably accounting for around 50% of both acute and chronic infections.



• Other parenteral routes may be involved.


• • Hemodialysis is a possible cause of HCV infection.
  
  
  
  • Patients who are healthcare employees may have an accidental exposure.
  
  
  
  • Tattooing, body piercing, and acupuncture with unsterile equipment are possible ways of infection.
  
  
  
• With sexual transmission, the risk appears to be low, even among individuals with multiple sex partners; however, the presence of coexisting, sexually transmitted diseases (eg, infection with human immunodeficiency virus [HIV]) appears to increase the risk.



• Vertical transmission may occur.


• • Perinatal transmission is possible and affects an estimated 5% of babies born to HCV-infected mothers.
  
  
  
  • The risk is higher for babies born to mothers who are coinfected with HCV and HIV.
  
  
  
  • Breastfeeding is not contraindicated for HCV-seropositive mothers.
  
  
  
• Perhaps 10% of HCV-infected adults have no identified risk factor for HCV infection; this frequency is probably higher among pediatric patients.

DIFFERENTIALS

Section 4 of 11

Hepatitis A
Hepatitis B

Other Problems to be Considered:

Alcoholic liver disease
Drug toxicities

WORKUP

Section 5 of 11

Lab Studies:

• Both acute and chronic hepatitis C virus (HCV) infections are often asymptomatic; therefore, the diagnosis often relies on the identification of a potential risk factor and on subsequent screening for HCV-directed antibodies.



• Serum alanine aminotransferase (ALT) levels may be helpful.


• • Acute infections: The peak serum ALT level is less than 2000 IU/mL for most patients with acute HCV infection, and 50% have a peak serum ALT level less than 800 IU. Overall, this peak is generally less than that of hepatitis A or hepatitis B infections.
  
  
  
  • Chronic infections: Many patients have normal serum ALT levels, although these levels may fluctuate significantly over time.
  
  
  
• HCV-directed antibodies may be detected.


• • Acute infection: Antibodies are generally detectable approximately 6-8 weeks after exposure; however, as many as 5% of infected patients do not produce antibodies.
  
  
  
  • Chronic infection: Once present, antibodies generally persist.
  
  
  
  • Antibody screening by means of enzyme immunoassay (EIA) is inexpensive and reliable; generally, this is the screening test of choice for diagnosis. Recombinant immunoassay (RIBA) can then be used to confirm positive EIA results.
  
  
  
• HCV RNA may be detected with the polymerase chain reaction (PCR) test. Several US Food and Drug Administration (FDA)–approved test kits are currently available that can be used for blood product screening or diagnostic testing. (Kits are not usually approved for both uses.)


• • HCV RNA is usually detectable within 1-2 weeks of exposure.
  
  
  
  • Quantitative assays are available, but HCV viral load has not been definitively shown to be useful in predicting outcome (unlike HIV viral load).
  
  
  
  • PCR testing is useful to confirm positive EIA results in the setting of indeterminate RIBA test results and to distinguish between resolved and chronic HCV infection in patients with positive EIA and RIBA results.
  
  
  
• Other viral serologic tests may be useful in ruling out other causes of hepatitis, which can be present alone or in combination with HCV.


• • Hepatitis A (HAV) immunoglobulin M (IgM) and immunoglobulin G (IgG)
  
  
  
  • Hepatitis B (HBV) surface antigen and antibody, core antibody
  
  
  
  • Cytomegalovirus IgM and IgG (and/or cytomegalovirus [CMV] in urine cultures)
  
  
  
  • Epstein-Barr virus IgM and IgG
  
  
  
  • HIV IgG enzyme-linked immunoassay (ELISA)
  
  
  

Imaging Studies:

• These studies generally are not warranted to establish the etiology of hepatitis.



• However, ultrasonography is useful to monitor for HCV-related complications.

Procedures:

• Although liver biopsy is generally not used to diagnose HCV, it is the most accurate method of evaluating the extent of HCV-related liver disease.



• Liver biopsy is recommended for all patients before they start antiviral therapy.

TREATMENT

Section 6 of 11

Medical Care:

• Acute infection


• • Supportive care is the mainstay of treatment.
  
  
  
  • Early initiation of antiviral therapy is not defined.
  
  
  
• Chronic infection


• • The goal is to identify complications and suitable candidates for antiviral therapy.
  
  
  
  • The purpose is to ameliorate symptoms and reduce the risk of progressive liver disease.
  
  
  

Surgical Care:

• Consider liver transplantation in patients with advanced liver disease.



• Surgical intervention may be necessary for complications such as portal hypertension and HCC.

Consultations:

• Consultation with a gastroenterologist may be indicated.

Diet:

• No special diet is required; however, instruct the patient to avoid alcohol use.

Activity:

• No modifications are required.

MEDICATION

Section 7 of 11

Alpha interferon (IFN) results in a sustained response in fewer than 20% of patients, and adverse effects are often problematic. More recently, the addition of oral ribavirin to IFN therapy has improved the sustained response rate to 40-50%. However, adverse effects remain a problem, and the response rate is lower for individuals infected with genotype 1, the most common genotype causing infection.

Pegylated IFN (the addition of polyethylene glycol to the drug) results in significantly higher rates of response, especially with nongenotype 1 hepatitis C virus (HCV) infections.

Drug Category: Antiviral agents -- IFNs are synthetically derived from a class of proteins that is produced and released by cells after viral invasion. They stimulate the production of another protein that inhibits viral replication. The nucleoside analogue ribavirin has some antiviral activity against HCV, although improvements are not typically sustained after monotherapy is discontinued. However, the use of ribavirin in combination with IFN alpha is more effective than either drug alone and provides sustained responses.

Drug Name	Interferon alfa-2b (Intron A) -- Protein product manufactured with recombinant DNA technology. Mechanism of antiviral activity is not clearly understood. However, modulation of host immune responses enhances cytolytic T-cell activity; stimulates natural killer cell activity and amplifies HLA class I protein on infected cells. Direct antiviral activity activates viral ribonucleases, inhibits viral entry to cells, and inhibits viral replication. Direct antifibrotic effect has been postulated. Prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 4 mo, discontinue treatment. If a response occurs (as measured by clinical improvement, a reduction in HCV viral load or histologic improvement on liver biopsy), continue treatment until no further improvement is observed. Whether continued treatment after that time is beneficial remains unknown. Some studies have some salvage regimens with PEG-IFN (see below) to be of benefit.
Adult Dose	3 million IU SC 3 times/wk for 12 mo
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of anaphylactic sensitivity to mouse IgG, egg protein, or neomycin; autoimmune hepatitis
Interactions	Theophylline may increase IFN alpha toxicity by reducing its clearance; cimetidine may increase the antitumor effects of IFN alpha; zidovudine and vinblastine may increase IFN alpha toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Acute hypersensitivity reactions rare; may exacerbate psoriasis; do not use different brands in 1 treatment regimen; may exacerbate preexisting psychiatric conditions, particularly major depression; rare GI hemorrhage (may be severe); bone marrow suppression; before initiating therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor patient periodically (eg, monthly) during treatment to determine response to treatment

Drug Name	Ribavirin (Rebetol, Copegus) -- Inhibits viral replication by inhibiting DNA and RNA synthesis. Administer as combination therapy with IFN alpha-2b. Ribavirin may potentiate the effects of IFN alpha, improving sustained-response rates with HCV. Rebetron is a kit that contains ribavirin and IFN alpha-2b for the treatment of HCV.
Adult Dose	Copegus: (administer with peginterferon alfa-2a) Note: Dose based on genotype Genotype 1/4: <75 kg: 1000 mg/d PO divided bid with meals for 48 wk >75 kg: 1200 mg/d PO divided bid with meals for 48 wk Genotype 2/3: 800 mg/d PO divided bid with meals for 24 wk Rebetol: (administered with peginterferon alfa-2b) 400 mg PO bid with meals Rebetol: (administered with IFN alfa-2b) <75 kg: 400 mg PO every am and 600 mg PO every pm >75 kg: 600 mg PO bid
Pediatric Dose	Rebetol: (administer with IFN alfa-2b) <3 years: Not established >3 years: <26 kg: 15 mg/kg/d PO divided bid with meals >26 kg: Administer as in adults Treatment duration is 24 wk (genotype 2/3 virus) or 48 wk (genotype 1 virus)
Contraindications	Documented hypersensitivity; significant or unstable cardiac disease
Interactions	Inhibits zidovudine phosphorylation, thereby decreasing effect
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in preexisting anemia, bone marrow suppression, renal failure, ischemic heart disease, cerebral vascular disease; decrease dose with hemoglobin <10 g/dL or decrease of 2 g/dL within 4 wk; discontinue with hemoglobin <8.5 g/dL

Drug Name	Peginterferon alfa-2a (Pegasys) and alfa-2b (PEG-Intron) -- Used in combination with ribavirin to treat patient with chronic HCV infection who have compensated liver disease and have not previously received IFN alfa. Consists of IFN alfa-2a attached to a 40-kD branched PEG molecule (alfa-2b has a smaller 12-kD PEG molecule and is made from IFN alpha-2b). Predominantly metabolized by the liver. Several recent small clinical trials have shown that PEG-IFN used in combination with ribavirin is superior to standard IFN therapy. Which populations these recommendations can be extended to (the trials involved mostly HIV/HCV co-infected individuals) and whether alfa-2a is better than alfa-2b or vice versa is not yet clear.
Adult Dose	Alfa-2a (Pegasys): 180 mcg SC qwk for monotherapy or combined with ribavirin Alfa-2b (PEG-Intron): Monotherapy: 1 mcg/kg/wk SC for 1 y Combined with oral ribavirin: 1.5 mcg/kg/wk SC for 1 y
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; autoimmune hepatitis; pancreatitis; colitis; ongoing or recent alcohol use; platelet count <70,000/mL
Interactions	Theophylline may increase toxicity by reducing clearance; cimetidine may increase the antitumor effects; zidovudine and vinblastine may increase toxicity; concurrent administration with interleukin-2 may increase nephrotoxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category X when combined with ribavirin Alfa-2a: Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis, aggressive behavior, hallucinations, violent behavior, suicidal ideation, suicide attempt, suicide, homicidal ideation [rare]), even without previous history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia; neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities Alfa-2b: Considered to have abortifacient potential; reduce starting dose by 50% or discontinue if serious adverse reactions develop during course of treatment (may reinitiate treatment if adverse reaction abates or decreases in severity); fatal and nonfatal pancreatitis or ulcerative and hemorrhagic colitis reported; life-threatening or fatal neuropsychiatric events may occur; severe suppression of bone marrow function may occur, which occasionally results in severe cytopenias; may cause headache and flulike symptoms and myelosuppressive, pulmonary, thyroid, cardiovascular, or infectious disorders

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Usually, inpatient care is necessary only if complications of chronic hepatitis C virus (HCV) infection, such as portal hypertension and HCC, are present.

Further Outpatient Care:

• Perform ongoing studies to monitor the status of HCV infection.


• • The serum ALT level has no consistent relationship to liver histologic findings.
  
  
  
  • Longitudinal assessment of HCV RNA provides a strong correlation with liver histologic results but is a weaker predictor of rate of progression.
  
  
  
  • The prothrombin time is useful for assessing liver function.
  
  
  
  • The serum alpha-fetoprotein assay is a potential screening test for HCC.
  
  
  
  • Ultrasonography is potentially useful to monitor for HCV-related complications such as portal hypertension and HCC.
  
  
  
• Identify suitable candidates for antiviral therapy, although all chronically infected patients are potential candidates.


• • Treatment is recommended for chronically infected patients who have a persistently elevated serum ALT level, portal or bridging fibrosis, and at least moderate inflammation and necrosis at liver biopsy.
  
  
  
  • Consider treatment for other patients on an individual basis. Do not treat patients with decompensated cirrhosis by using antiviral therapy.
  
  
  
• Perform immunization against hepatitis A virus (HAV) and hepatitis B virus (HBV).

Deterrence/Prevention:

• Discourage users of intravenous drugs from sharing needles.



• Adhere to universal precautions.



• Infected patients with multiple partners should use barrier protection during sex. No special precautions are needed for monogamous relationships.



• Instruct the patient not to share personal care articles such as toothbrushes or razors.



• Blood, organ, or sperm donation from HCV-infected patients is not permitted.

Complications:

• Fulminant hepatitis (rare)



• Cirrhosis, which may result in portal hypertension and liver failure



• Hepatocellular carcinoma



• Extrahepatic manifestations


• • Porphyria cutanea tarda
  
  
  
  • Sialadenitis resembling Sjögren syndrome
  
  
  
  • Mooren corneal ulcers, a form of chronic ulcerative keratitis
  
  
  
  • Type II cryoglobulinemia
  
  
  
  • Membranoproliferative glomerulonephritis
  
  
  
  • Non-Hodgkin lymphoma
  
  
  

Prognosis:

• Most patients chronically infected with HCV remain asymptomatic and do not have significant liver disease.



• The prognosis is guarded for those who have HCV-related complications such as HCC and liver failure.

Patient Education:

• Instruct the patient to avoid all alcohol use.



• Inform the infected patient about the health practices listed in Deterrence/Prevention.



• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education article, Hepatitis C.

MISCELLANEOUS

Section 9 of 11

Special Concerns:

• For individuals exposed to hepatitis C virus (HCV), passive immunization is not recommended.



• Screen patients for HCV infection if any of the following applies:


• • History of illegal injected drug use
  
  
  
  • Transfusion with clotting factor concentrates before 1987
  
  
  
  • Use of blood and/or blood components or organ transplants before July 1992
  
  
  
  • Use of HCV-contaminated blood from a donor
  
  
  
  • Individuals on long-term hemodialysis or those who have persistently abnormal serum ALT levels
  
  
  
  • Needle sticks, accidents with sharps, or mucosal exposures to HCV-positive blood
  
  
  
• Considering HCV testing in patients with HIV may be prudent, especially in those who acquired HIV through intravenous drug use. HCV is more easily transmitted than HIV, and the 2 viruses are often co-infections.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following increases the risk of cirrhosis in patients with chronic hepatitis C infection?

A: Younger age at the time of initial infection
B: Alcohol consumption
C: Infection with genotype 2A
D: Female sex
E: Persistently abnormal serum alanine aminotransferase (ALT) level

The correct answer is B: The risk of progressive liver disease among patients infected with HCV is higher in those who consume alcohol and in those who are older at the time of initial hepatitis C infection. Men have a higher risk than women. No consistent relationship between the risk of progressive liver disease with the infecting genotype and serum ALT values has been shown.

CME Question 2: Which of the following is currently the most important risk factor for exposure to the hepatitis C virus (HCV)?

A: Blood transfusions
B: Sexual transmission
C: Illegal injected drug use
D: Household contact with affected person
E: Hemodialysis

The correct answer is C: Illegal injection drug use probably accounts for about half of new and chronic HCV infections, and it is the most important risk factor. Screening of blood-product donors has dramatically reduced the risk of transfusion-acquired hepatitis C, and transmission by means of sexual or household contact or by means of hemodialysis is uncommon.

Pearl Question 1 (T/F): About 30-40% of individuals with acute hepatitis C infection have a chronic infection.

The correct answer is False: More than 80% of patients who are acutely infected with hepatitis C have a persistent infection. Unfortunately, most patients infected have chronic infection, and they are at risk for progressive liver disease.

Pearl Question 2 (T/F): The injection of illegal drugs is currently the most important risk factor for exposure to hepatitis C.

The correct answer is True: This risk factor probably accounts for 50% of both acute and chronic infections. Screening of blood-product donors has dramatically reduced the risk of transfusion-acquired hepatitis C, and transmission by means of sexual or household contact or by means of hemodialysis is uncommon.

Pearl Question 3 (T/F): Recombinant immunoassay should be used to confirm the presence of anti–hepatitis C antibodies detected with enzyme immunoassay.

The correct answer is True: Antibody screening by means of enzyme immunoassay is inexpensive and reliable; generally, this is the screening test of choice for diagnosis. Recombinant immunoassay can then be used to confirm positive enzyme immunoassay results. Polymerase chain reaction (PCR) tests are also available to test for and to monitor hepatitis C virus infection.

Pearl Question 4 (T/F): Liver biopsy is not helpful in the management of hepatitis C virus (HCV) infection.

The correct answer is False: Although liver biopsy is not helpful in the initial diagnosis of infection, it can be helpful prior to initiation of therapy with interferon and ribavirin to provide a baseline of the liver histology. Biopsy after several months of therapy can also identify response to therapy, even in the absence of a decline in the blood levels of HCV RNA.

BIBLIOGRAPHY

Section 11 of 11

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• Conry-Cantilena C, VanRaden M, Gibble J, et al: Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996 Jun 27; 334(26): 1691-6[Medline][Full Text].
• Donahue JG, Munoz A, Ness PM, et al: The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992 Aug 6; 327(6): 369-73[Medline].
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• Jacobson IM, Gonzalez SA, Ahmed F, et al: A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol 2005 Nov; 100(11): 2453-62[Medline][Full Text].
• Locasciulli A, Testa M, Pontisso P, et al: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997 Dec 1; 90(11): 4628-33[Medline].
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• McHutchison JG, Gordon SC, Schiff ER, et al: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C: Hepatitis Interventional Therapy Group. N Engl J Med 1998 Nov 19; 339(21): 1485-92[Medline][Full Text].
• NIH: Management of hepatitis C. NIH Consens Statement 1997 Mar 24-26; 15(3): 1-41[Medline].
• Paul IM, Sanders J, Ruggiero F, et al: Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood 1999 Jun 1; 93(11): 3672-7[Medline][Full Text].
• Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997 Mar 22; 349(9055): 825-32[Medline].
• Shepherd J, Brodin H, Cave C, et al: Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess 2004 Oct; 8(39): iii-iv, 1-125[Medline][Full Text].
• Villano SA, Vlahov D, Nelson KE, et al: Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999 Mar; 29(3): 908-14[Medline].
• Vogt M, Lang T, Frosner G, et al: Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999 Sep 16; 341(12): 866-70[Medline][Full Text].
• WHO: Hepatitis C: global prevalence. Wkly Epidemiol Rec 1997 Nov 14; 72(46): 341-4[Medline].

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