Hepatitis C

Synonyms and related keywords:

hepatitis C virus, HCV, non-A non-B hepatitis, acute hepatitis, hepatitis, virus infection, viral infection, virus, chronic liver disease, hepatocellular carcinoma, cirrhosis, liver transplant, liver transplantation, orthotopic liver transplantation, OLT, quasispecies, interferon, IFN

Author: Vinod K Dhawan, MD, Chief, Program Director, Division of Infectious Diseases, Professor, Department of Internal Medicine, King/Drew Medical Center, Charles R Drew University; Professor, Department of Clinical Medicine, UCLA

Vinod K Dhawan, MD, is a member of the following medical societies:

American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Royal College of Physicians and Surgeons of Canada

Editor(s):
George Y Wu, MD, PhD, Chief, Division of Gastroenterology-Hepatology, Herman Lopata Chair in Hepatitis Research; Professor, Department of Medicine, University of Connecticut Health Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Oscar S Brann, MD, Program Director of Gastroenterology Fellowship, Associate Clinical Professor UCSD School of Medicine, Department of Internal Medicine, Naval Medical Center San Diego; Alex J Mechaber, MD, FACP, Associate Director of Generalist Primary Care Clerkship, Assistant Professor, Department of Internal Medicine, Division of General Internal Medicine, University of Miami School of Medicine; and Julian Katz, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, MCP Hahnemann University

INTRODUCTION

Background:

The prevalence of hepatitis C virus (HCV) infection is increasing worldwide. The World Health Organization estimates that more than 170 million individuals throughout the world are infected with HCV. An estimated 1.8% of the population in the United States is positive for HCV antibodies; this rate corresponds to an estimated 3.9 million persons with HCV infection nationwide. Infection due to HCV accounts for 20% of all cases of acute hepatitis, an estimated 30,000 new acute infections, and 8,000-10,000 deaths each year in the United States.

Medical care costs associated with the treatment of HCV infection in the United States are estimated to be more than $600 million per year. Most patients infected with HCV have chronic liver disease, which may progress to cirrhosis and hepatocellular carcinoma. Chronic infection with HCV is one of the most important causes of chronic liver disease (see Image 1). Currently, chronic hepatitis C is the most common indication for orthotopic liver transplantation in the United States.

HCV is a spherical, enveloped, single-stranded RNA virus belonging to family Flaviviridae. In persons who are infected, HCV may produce approximately a trillion new viral particles each day in a steady state of viral replication. The RNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities and thus generates a large number of mutant viruses known as quasispecies. Viral quasispecies represent minor molecular variations with only 1-2% nucleotide heterogeneity. These quasispecies pose a major challenge with respect to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development.

Six major HCV genotypes and numerous subtypes have been identified based on molecular relatedness. Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. Genotypes 1, 2, and 3 have a worldwide distribution, while genotypes 4, 5, and 6 are localized to specific geographic locations. Genotype 1 is the most common genotype in the United States. HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype 1 also may be associated with more severe liver disease and a higher risk of hepatocellular carcinoma. Genotype 4 is the most prevalent genotype in Egypt, genotype 5 is found in South Africa, and genotype 6 is found in Southeast Asia.

HCV encodes a single polyprotein of 3011 amino acids that is processed into 10 structural and regulatory proteins (see Image 2). Structural components include the core and 2 envelope proteins, E1 and E2. Two regions of the E2 protein have an extremely high rate of mutation; these are designated hypervariable regions 1 and 2. Envelop protein E2 contains the binding site for CD-81, a receptor expressed on hepatocytes and B lymphocytes. HCV also encodes a virus-specific helicase, protease, and polymerase, all of which are critical in viral replication. These enzymes are attractive targets for antiviral therapy. Similarly, the untranslated regions at both ends of the viral RNA, 5′-UTR and 3′-UTR, are highly conserved. These sites are involved in critical stages of viral replication and may be logical targets for therapy.

Currently, HCV is predominantly transmitted by means of percutaneous exposure to infected blood. In developed countries, most new HCV infections are related to intravenous drug abuse. The screening of blood donors for HCV antibody since 1990 has decreased the risk of transfusion-associated HCV to less than 1 case in 103,000 transfused units. The risk may be even lower with the use of more sensitive assays with the polymerase chain reaction (PCR) to screen blood. These newer assays have decreased the window after infection, during which the virus may escape detection, to approximately 3 weeks.

HCV also may be transmitted by means of acupuncture, tattooing, and sharing razors. Needlestick injuries in the health care setting result in a 3% risk of HCV transmission. However, the prevalence of hepatitis C among health care workers is similar to that of the general population. Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope; dialysis; or surgery, including organ transplantation before 1992. Uncommon routes of transmission of HCV, ie, those that affect no more than 5% of the individuals at risk, include high-risk sexual activity and maternal-fetal transmission. Co-infection with human immunodeficiency virus type 1 (HIV-1) appears to increase the risk of both sexual and maternal-fetal transmission of HCV. Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10% of cases.

Pathophysiology:

The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells. In most persons infected with HCV, viremia persists, and this is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from more recent studies suggest that 50% or more of the hepatocytes may be infected with HCV.

Immunodeficiency associated with HIV infection accelerates the course of hepatitis C. In one Spanish series, as many as 25% of patients infected with HIV had cirrhosis within 15 years of infection with HCV, compared with only 6.5% of those who were HIV negative. Co-infection with the hepatitis B virus (HBV) also has been associated with increased severity of chronic hepatitis C and accelerated progression to cirrhosis. In addition, HBV co-infection seems to enhance the development of hepatocellular carcinoma.

Frequency:

• In the US: HCV infections account for approximately 30,000 new infections and 8,000-10,000 deaths each year in the United States. Of the new infections, 60% occur in persons who use intravenous drugs; fewer than 20% are acquired through sexual exposure; and 10% are due to other causes, including occupational or perinatal exposure and hemodialysis. The overall prevalence of anti-HCV antibodies in the United States is 1.8% of the population. Approximately 74% of individuals are positive for HCV RNA; this rate indicates that an estimated 3.9 million persons are infected with HCV and 2.7 million persons in the United States have chronic infection. Three fourths of these individuals are infected with HCV genotype 1.

• Internationally: More than 170 million individuals throughout the world are infected with HCV. The prevalence rates in healthy blood donors are 0.01-0.02% in the United Kingdom and northern Europe, 1-1.5% in southern Europe, and 6.5% in parts of equatorial Africa. Prevalence rates as high as 20% are reported in Egypt; these rates are attributed to the use of parenteral antischistosomal therapy.

Mortality/Morbidity: Hepatitis C is the major cause of chronic hepatitis in the United States. HCV infections account for 20% of all cases of acute hepatitis. It accounts for more than 40% of all referrals to active liver clinics.

• Severe progression of hepatitis C to cirrhosis occurs in approximately 20% of patients who have chronic infection. The rate and chance of progression varies with certain factors, including sex, alcohol use, concomitant hepatitis, age, and several other factors.

• Hepatocellular carcinoma develops in 1-4% of patients with cirrhosis each year. HCV is largely responsible for the recent increase in the incidence of hepatocellular carcinoma in the United States.

• In the United States, the number of deaths due to HCV-related complications has increased from fewer than 10,000 in 1992 to just fewer than 15,000 in 1999. This number is expected to increase in the future because of the current large pool of patients with chronic infections.

Race: In the United States, hepatitis C is more common among minority populations such as black persons and Hispanic persons than in other populations. Furthermore, genotype 1 is more prevalent in black persons in the United States than in other racial groups.

Sex: Females infected with HCV have somewhat better outcome than their male counterparts.

Age: In the United States, 65% of persons with HCV infection are aged 30-49 years. Those who acquire the infection at a younger age have a somewhat better prognosis than those who are infected later in life.

CLINICAL

History: The natural history of hepatitis C evolves over decades (see Image 3).

• Clinical manifestations after acute infection occur in only 20-30% of patients, usually within 7-8 weeks after exposure to HCV.

• Chronic subclinical infection with persistent HCV viremia is the most frequent outcome and occurs in 70-80% of patients.

Symptoms frequently are absent until the liver disease is advanced.

Spontaneous clearance of viremia in chronic infection is rare.

• Cirrhosis develops in 15-20% of individuals with chronic infections.

Its development may take as long as 30 years.

Once cirrhosis occurs, the risk of hepatocellular carcinoma is approximately 1-4% per year.

A more rapid disease progression is observed among individuals infected with HIV or HBV, those with alcoholism, males, and those who acquire the infection at an older age.

Compared with other patients infected with HCV, the incidence of cirrhosis in patients with alcoholism is increased 15-fold, and the incidence in those with HIV co-infection is increased 5-fold.

• Superinfection with hepatitis A virus in persons who are infected with HCV may result in severe acute or even fulminant hepatitis.

• Symptoms of hepatitis C include malaise, weakness, anorexia, and fatigue.

Physical:

Latently infected patients may have no abnormal findings upon examination. Others who have hepatitis, cirrhosis, or hepatocellular carcinoma may present with the following:

• Jaundice
• Yellowish discoloration of the eyes and urine
• Hepatomegaly (eg, hepatocellular carcinoma)
• Findings of portal hypertension (eg, ascites, spider angiomata)

Causes:

Hepatitis C is caused by a spherical, enveloped, single-stranded RNA virus belonging to the family Flaviviridae.

Differentials:

• Alcoholic Hepatitis
• Amebic Hepatic Abscesses
• Autoimmune Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis D
• Hepatitis E
• Hepatitis, Viral

Other Problems to be Considered:

• Drug-induced (ie, toxic) hepatitis

Work Up

Lab Studies:

Hepatitis C antibody test

• Anti-HCV serologic screening involves an enzyme immunoassay (EIA), including EIA-2 and EIA-3. Serologic assays for antibodies to HCV, ie, anti-HCV antibodies, are 97% specific. However, these assays cannot be used to distinguish an acute infection from a chronic infection.
• In 3 successive versions of EIA, sensitivity has increased progressively. With older tests, some HCV infections may have been missed 6-9 months after infection. The most recent third-generation EIA involves core protein and nonstructural proteins 3, 4, and 5; these can be used to detect antibodies within 4-10 weeks after the onset of infection.
• False-negative results for the presence of HCV antibody can occur in persons with compromised immune systems, such as those with HIV-1 infection, patients with renal failure, and those with HCV-associated essential mixed cryoglobulinemia.
• False-positive EIA results can occur in persons without risk factors and in those without signs of liver disease, such as blood donors or health care workers.

Recombinant immunoblot assay

• Recombinant immunoblot assay (RIBA-2) is used to confirm HCV infection.
• A positive immunoblot assay result is defined as the detection of antibodies against 2 or more antigens, and an indeterminate assay result is defined as the detection of antibodies against a single antigen.
• RIBA-2 is useful to confirm positive EIA results in low-risk populations.

HCV-RNA detection with polymerase chain reaction

• HCV-RNA assays with PCR can be used to detect infection within 1-3 weeks of exposure.
• Compared with other tests, qualitative HCV-RNA tests based on the PCR technique have a lower limit of detection of fewer than 100 copies of HCV RNA per milliliter.
• HCV-RNA PCR tests are useful in confirming viremia, assessing the treatment response, and examining patients with suspected false-negative results with antibody testing.
• HCV-RNA PCR assays are more than 90% sensitive and specific.

Viral load tests

• The viral load detected with quantitative assays can be used to predict the outcome of anti-HCV therapy but not the likelihood of disease progression.
• Three commercial tests to quantify the degree of viremia are currently available. They are described as follows:
  • Branched-chain DNA assay (Quantiplex HCV RNA, version 2.0)
  • Reverse-transcription PCR (Cobas Amplicor HCV monitor, version 2.0)
  • Reverse-transcription PCR (HCV SuperQuant)

Because viral RNA is unstable , serum samples should be frozen within 3 hours after they are obtained.

A single testing system should be used for serial monitoring of the viral load in each patient because the results may be test-dependent to some extent.

• Serum alanine aminotransferase test

• Viral genotyping

• A diagnostic algorithm for the evaluation of hepatitis C is shown in Image 4 (image currently unavailable).

• Pretreatment tests should include the following:
  • Anti-HCV antibody EIA
  • Genotyping
  • Quantitative HCV RNA assay: Reverse transcriptase PCR is more sensitive than bDNA testing
  • Determinations of ALT and aspartate aminotransferase (AST), bilirubin, and albumin levels
  • Screening for co-infection with HIV

• Patients should be closely monitored for treatment toxicity. Tests to help monitor drug toxicity include the following:
  • CBC count with differential and platelet counts
  • Renal function testing
  • Determination of glucose level
  • Determination of the activated partial thromboplastin time, prothrombin time, (including International Normalized Ratio), and baseline thyroid-stimulating hormone
  • Imaging Studies:

• Ultrasonography of the liver and biliary passages helps exclude other diagnostic possibilities.

Procedures:

• Liver biopsy

Histologic Findings:

Liver biopsy findings reveal lymphocytic infiltration, portal or bridging fibrosis, and moderate degrees of inflammation and necrosis. Regenerative nodules are noted in patients with cirrhosis. Findings of hepatocellular carcinoma may be present in some patients.

Treatment:

Medical Care:

• The goals of treatment of chronic HCV infection include the following:
  • Eradicate HCV.
  • Delay fibrosis and progression to cirrhosis.
  • Prevent hepatic decompensation and obviate liver transplantation.
  • Prevent hepatocellular carcinoma

• The virologic response to treatment is categorized in several ways, as follows:
  • The end-of-treatment response (ETR) refers to the absence of viremia at completion of therapy; ie, the serum HCV-RNA value is below the level of detection.
  • A sustained virologic response (SVR) indicates the persistent absence of serum HCV RNA for 6 months or longer after therapy.
  • Relapse is defined as an undetectable serum HCV-RNA level at the completion of therapy, with subsequent viremia.
  • A nonresponse is defined as a failure to eliminate HCV RNA from the serum during therapy.

• The treatment of hepatitis C has evolved over the years (see Image 5). It is discussed as follows:

• Treatment with IFN alfa 2b was reported to prevent chronic infection in 98% of a group of 44 German patients with acute hepatitis C.

• The study patients received 5 million U of IFN alfa 2b subcutaneously daily for 4 weeks and then 3 times per week for another 20 weeks. Therapy was well tolerated in all patients but one.

• This report is likely to alter the approach to treatment in patients acutely infected with HCV.

• Antiviral therapy of chronic hepatitis C currently is recommended for patients with elevated serum ALT levels who meet the following parameters:
  • They must be older than 18 years.
  • They must have positive findings with HCV EIA and HCV-RNA tests.
  • Liver biopsy findings must be consistent with a diagnosis of chronic hepatitis, although the diagnosis is not required.
  • They must not have active autoimmune disease.
  • No hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation are present.

• Pretreatment laboratory tests should be performed

• The following preparations of IFN currently are available for treatment of hepatitis C:
  • IFN alfa 2b (Intron-A; Schering-Plough, Kenilworth, NJ) is a recombinant IFN preparation.
  • IFN alfa 2a (Roferon; Hoffmann-La Roche, Basel, Switzerland) is a recombinant IFN preparation, differing from IFN alfa 2b by only a single amino acid residue.
  • IFN alfacon-1 (Infergens; Amgen, Thousand Oaks, Calif) or consensus IFN (CIFN) is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs.

• It has greater cytokine-induction, antiviral, antiproliferative, natural killer cell, and gene-induction activities than both IFN alfa 2a and IFN alfa 2b on an equal-mass basis.
• However, initial studies of the recommended CIFN dose of 9 mcg in IFN-naive patients with chronic hepatitis C have resulted in viral response rates similar to those of standard IFN-alfa monotherapy.

Regarding pegylated IFNs, recent developments in IFN technology have led to the development of long-lasting IFNs.

Polyethylene glycol (PEG) molecules are added to IFN.

These new pegylated IFNs have better sustained absorption, a slower rate of clearance, and a longer half-life than those of unmodified IFN.

They permit more convenient once-weekly dosing. The FDA has approved pegylated IFNs for use in the treatment of chronic hepatitis C

Pegylated IFNs have significantly improved the quality of life for patients who have a good response to therapy.

Two pegylated IFN preparations currently are available.

• PEG-IFN alfa 2b (PEG-Intron; Schering-Plough) consists of IFN alfa 2b attached to a single 12-kD PEG chain. PEG-IFN alfa 2b is excreted by the kidneys.

• PEG-IFN alfa 2a (PEGASYS; Hoffmann-La Roche) consists of IFN alfa 2a attached to a 40-kD branched PEG molecule. PEG-IFN alfa 2a is metabolized predominantly by the liver.

• Several reports have documented the improved sustained viral response with pegylated IFNs.

• Findings were 69% versus 28% (P = .001) at week 48 of therapy and 39% versus 19% (P = .001) at week 72 of therapy.

• Drug discontinuation in these treatment-naive patients and the frequencies of dose reduction were similar in the 2 treatment groups.

• The SVR rate was 30% after 48 weeks of therapy with 180 mcg, compared with 8% for patients treated with standard IFN alfa.

• Adverse effects did not significantly increase with the pegylated product.

The types and frequencies of adverse events and abnormal laboratory test results were similar among all groups.

The 180-mcg PEG-IFN alfa 2a dose appeared to be the optimal dose on the basis of the SVR and associated adverse-effect profile.

• They compared PEG-IFN alfa 2b (PEG-Intron) to IFN alfa 2b in the initial treatment of compensated chronic hepatitis C in a large cohort of 1219 patients.

• PEG-IFN alfa 2b maintained (at dose of 0.5 mcg/kg) or surpassed (at doses of 1 mcg/kg and 1.5 mcg/kg) the clinical efficacy of IFN alfa 2b (at the standard 3-times-weekly dose) while preserving its safety profile.

• Patients were assigned randomly to 3 groups as follows: (1) IFN alfa 2b, at 3 million U subcutaneously administered 3 times per week plus ribavirin at 1000-1200 mg/d orally administered; (2) PEG-IFN alfa 2b at 1.5 mcg/kg each week plus ribavirin 800 mg/d; and (3) PEG-IFN alfa 2b at 1.5 mcg/kg per week for 4 weeks then 0.5 mcg/kg per week plus ribavirin at 1000-1200 mg/d for 48 weeks.

• The SVR rate (see Image 6) was significantly higher in the higher-dose PEG-IFN group (274 of 511 patients [54%]) than in the lower-dose PEG-IFN (244 of 514 patients, [47%] P = .01) or IFN (235 of 505 patients, [47%] P = .01) groups.

• Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145 of 348 patients), 34% (118 of 349 patients), and 33% (114 of 343 patients).
• The rate for patients with genotype 2 and 3 infections was approximately 80% for all treatment groups.
• Adverse-effect profiles were similar among the treatment groups.
• Secondary analyses identified body weight as an important predictor of SVR. In this study, when the dose was optimized for the patient’s body weight, with a dose of more than 10.6 mg/kg of ribavirin daily, the SVR with IFN regimens was 61% for all genotypes, 48% for genotype 1, and 88% for genotypes 2 and 3.

• Influenzalike symptoms occur in more than 60% of patients.

• Other adverse effects include chronic fatigue and depression and mood dysfunction and depression.

• Short courses of IFN are relatively well tolerated. Increasing the duration of therapy from 6 months to 12 months increases the incidence of adverse effects.

• IFN therapy also may cause insomnia, rash and pruritus, anorexia, neutropenia, thrombocytopenia, and thyroid dysfunction.

• Patients may develop hemolytic anemia.
• Teratogenicity is a possibility. One should confirm negative pregnancy test results before initiating therapy. All patients, male and female, should be counseled about the risks and advised to use birth control.
• Patients may develop cough and dyspnea.
• Rash and pruritus has been described.
• Insomnia is an adverse effect of ribavirin therapy.
• Anorexia also is an adverse effect of ribavirin therapy.
• In clinical trials, as many as 20% of patients receiving combination therapy were unable to tolerate the regimen.
• Psychiatric illness or substance abuse should be addressed prior to treatment for HCV infection.
• The treatment of preexisting mood disorders before initiation of therapy for HCV infection is essential to increase the likelihood that the patient will comply with therapy.
• Interleukin-10 (IL-10) is a cytokine that down-regulates the proinflammatory response.

• Between 30% and 50% of persons infected with HIV are co-infected with HCV.

• Highly active antiretroviral therapy (HAART) is a combination therapy used in patients with HIV disease. HAART-associated immune recovery may increase HCV replication.

• Patients co-infected with HIV and HCV should be closely monitored during treatment for possible drug interactions.

• At week 24 of treatment, the patient should be evaluated for IFN-associated thyroid dysfunction.

Surgical Care:

Consultation with a surgeon may be necessary for patients in whom liver transplantation or hepatic resection for hepatoma is considered.

Consultations:

• An infectious diseases specialist should be consulted, as indicated.

• A gastroenterologist should be consulted, as indicated.

Diet:

No special diet is recommended.

(There is a diet written for people with Hep C, Cirrhosis, etc. located at: Hepatitis Diet

Activity:

No special restrictions are needed unless the patient has advanced liver disease with portal hypertension.

Medication:

Combination therapy with IFN alfa and the nucleoside analog ribavirin is the current standard of care in patients infected with HCV. Patients with HCV genotype 1 have a much less favorable response to therapy and are treated for 12 months, compared with patients infected with genotypes 2 and 3, in whom a 6-month course of therapy is sufficient. If viremia is present after 6 months, additional therapy has a negligible incremental benefit and treatment should be stopped in all patients regardless of the viral genotype. With HIV co-infection, all patients with a response to therapy at the end of 6 months should receive an additional 6 months of combination therapy regardless of the genotype. Patients with acute hepatitis C infection should be treated for 6 months.

Drug Category: Antivirals

Shorten the clinical course, prevent complications, prevent latent and/or subsequent recurrences, decrease transmission, and eliminate established latency.

Drug Name	Interferon alfa 2b (Intron-A) — Recombinant IFN preparation.
Adult Dose	3 million U SC 3 times/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <,70,000/mm3
Interactions	Theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	D – Unsafe in pregnancy
Precautions	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
Drug Name	Interferon alfa 2a (Roferon) — Recombinant IFN preparation.
Adult Dose	3 million U SC 3 times/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <,70,000/mm3
Interactions	Theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	D – Unsafe in pregnancy
Precautions	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
Drug Name	Interferon alfacon-1 (Infergens) — CIFN is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs.
Adult Dose	9 mcg SC 3 times/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <,70,000/mm3
Interactions	Theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	D – Unsafe in pregnancy
Precautions	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
Drug Name	Peginterferon alfa 2b (PEG-Intron) — Consists of IFN alfa 2b attached to a single 12-kD PEG chain. Excreted by the kidneys. Pegylated IFNs have sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN. Permit a more convenient once-weekly dosing. Has significantly improved quality of life for patients.
Adult Dose	1.5 mcg/kg SC qwk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <,70,000/mm3
Interactions	Theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	D – Unsafe in pregnancy
Precautions	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
Drug Name	Peginterferon alfa 2a (Pegasys) — Consists of IFN alfa 2a attached to a 40-kD branched PEG molecule. Predominantly metabolized by the liver.
Adult Dose	180 mcg SC qwk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <,70,000/mm3
Interactions	Theophylline may increase toxicity by reducing clearance; cimetidine may increase the antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	D – Unsafe in pregnancy
Precautions	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
Drug Name	Ribavirin (Rebetol) — Antiviral nucleoside analog. Chemical name is D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on the course of hepatitis C. When with IFN, significantly augments rate of sustained virologic response.
Adult Dose	10.6 mg/kg PO qd or divided bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pregnancy
Interactions	Decreases effects of zidovudine
Pregnancy	X – Contraindicated in pregnancy
Precautions	Hemolytic anemia (vulnerable individuals, eg, those with significant cardiovascular disease or underlying anemia should not take ribavirin); teratogenicity (confirm negative pregnancy test before therapy; both male and female patients should be counseled about risks and advised to use birth control); cough and dyspnea; rash and pruritus; insomnia; anorexia

Follow-Up

Further Inpatient Care:

• Severely ill patients with hepatitis due to HCV infection should be transferred to an intensive care unit for close observation and aggressive treatment.

Further Outpatient Care:

• Patients should be monitored closely for adverse effects and responses to therapy.

Transfer:

• Patients should be transferred to referral centers for liver transplantation, if indicated.

Deterrence/Prevention:

• Currently, no products are available to prevent hepatitis C infection.

• The development of immunoprophylaxis for this disease is proving to be difficult; an effective neutralizing immune response has not been demonstrated after HCV infection.

• Patients with hepatitis C should be advised to abstain from alcohol use.

• Patients with hepatitis C should be advised to use barrier protection during sexual intercourse.

• Screening high-risk patients and initiating appropriate treatment may curtail the incidence of cirrhosis and hepatocellular carcinoma.

Complications:

• Chronic infection develops in 70-80% of patients infected with HCV.

• Cirrhosis develops within 20 years of disease onset in 20% of those with chronic infection.

• Hepatocellular carcinoma develops in 1-4% of patients with cirrhosis each year. Hepatocellular carcinoma may develop on an average of 30 years after the onset of infection. It is more common in the presence of alcoholism, cirrhosis, and HBV co-infection.

• HCV is a well-recognized cause of a variety of manifestations. Among the most commonly reported are the following:

• The precise pathogenesis of these extrahepatic complications has not been determined, although most are the clinical expression of autoimmune phenomena.

Prognosis:

• Infection with HCV is self-limiting in only a small minority of those infected. Chronic infection develops in 70-80% of patients infected with HCV.

• Cirrhosis develops within 20 years of disease onset in 20% of those with chronic infection.

• Hepatocellular carcinoma develops in 1-4% of patients with cirrhosis each year after an average of 30 years. Hepatocellular carcinoma is more common in the presence of alcoholism, cirrhosis, and HBV co-infection.

• With the currently recommended therapy for chronic hepatitis C, which includes PEG IFN and ribavirin, cure rates are as high as 60%.

Patient Education:

• Patients with hepatitis C should be advised to abstain from alcohol use.

• Optimally, patients should use barrier protection during sexual intercourse.

• Patients with hepatitis C should not donate blood or organs.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to recommend appropriate therapy for hepatitis C may cause legal problems.

• Failure to monitor for adverse effects of therapy, especially depression due to IFN use, may cause legal problems.

• In pregnant patients, ribavirin may have teratogenic effects.

• Patients with acute infection appear to have an excellent chance of responding to 6 months of standard therapy. Patients stuck by a needle used on a person who is infected should have an HCV PCR performed immediately and then every 2 months for 6 months. If the viral infection is diagnosed, therapy can be instituted.

Special Concerns:

• Patients should be closely monitored for adverse effects of therapy.

Recommend that patients or their spouses not become pregnant while either is on therapy.

PICTURES

Picture 1. Hepatitis C. Causes of chronic liver disease.
Courtesy of the US Centers for Disease Control and Prevention, Atlanta, Ga.

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Picture 2. Hepatitis C viral genome.
Courtesy of Hepatitis Resource Network.

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Picture 3. Natural history of hepatitis C virus infection.

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Picture 4. Diagnostic algorithm for hepatitis C virus infection.

Click to view larger image (currently unavailable)

Picture 5. Evolution of the treatment for hepatitis C virus infection.

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Picture 6. Pegylated interferon alfa 2b plus ribavirin therapy for chronic hepatitis C.
From Manns et al: Lancet 2001 Sep 22; 358(9286): 958-65.

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BIBLIOGRAPHY

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