HEPC-info

INTRODUCTION

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 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.

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
The serum alanine aminotransferase (ALT) level may be elevated in patients with acute hepatitis C, and the ALT level is useful for helping monitor the effectiveness of therapy for HCV infection.
Because ALT levels may be normal or may fluctuate, a single normal value does not rule out active infection, progressive liver disease, or even cirrhosis. Similarly, the normalization of ALT levels with therapy is not a proof of cure.
Viral genotyping
Viral genotyping is essential in the treatment of patients infected with HCV. The genotype helps predict the outcome of therapy and helps determine the duration of therapy.
Currently, the only clinically relevant distinction is between genotype 1 and genotypes 2 and 3. Patients with genotype 1 infection usually are treated for 12 months, compared with a shorter period (eg, 6 mo) in patients with the other genotypes.

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
Liver biopsy before the initiation of treatment is not considered mandatory. However, liver biopsy is important for helping determine the activity of HCV-related liver disease.
Histologic evaluation of a liver biopsy sample and histologic staging remain the only reliable methods of predicting the prognosis and likelihood of disease progression. A scoring system for prognostic assessment takes into account the 2 cardinal features of liver injury, namely, inflammation and fibrosis.
Biopsy findings also may help rule out other concurrent causes of liver disease. Therefore, biopsy generally is recommended in the initial examination of persons with chronic HCV infection. However, some recommend biopsy only if the treatment does not result in sustained remission.
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:
Recombinant interferon (IFN) alfa 2b was the first drug approved by the US Food and Drug Administration (FDA) for use in the treatment of hepatitis C.
Approximately 40% of patients treated with 3 million U of IFN alfa 3 times a week had an initial response that was characterized by normalization of liver function test results and a loss of detectable HCV RNA.
Relapse occurs in most patients after therapy.
A sustained viral response occurs in only 6% in patients treated for 6 months and in 16% of those treated for 1 year with IFN alfa alone.
Combination therapy with IFN alfa and the nucleoside analog ribavirin has improved the SVR rate to 41%.
Patients with HCV genotype 1 have a much less favorable response to therapy and are treated for 12 months with IFN and ribavirin, compared with patients infected with genotypes 2 and 3, in whom a 6-month course of therapy is sufficient.
Fried et al noted that 5 million U of IFN alfa 2b daily for 24 weeks more rapidly decreased the HCV-RNA level and increased the initial and ETR rates when compared with a regimen of 3 million U of IFN alfa 2b 3 times a week in patients with chronic hepatitis C.
Jaeckel et al recently reported findings from a landmark study of treatment of acute hepatitis C infection, 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.

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.

IFN therapy may cause a variety of adverse effects, as follows:
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.
Ribavirin therapy may cause the following:
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.
IL-10 has a modulatory effect on hepatic fibrogenesis.
In a preliminary report, Nelson et al treated 24 patients with chronic hepatitis C in whom the disease had not previously responded to IFN-based therapy.
IL-10 had a salutary effect on hepatic inflammation and fibrosis.
Further studies are necessary to evaluate the therapeutic potential of IL-10 in patients with chronic hepatitis C.
Between 30% and 50% of persons infected with HIV are co-infected with HCV.

Co-infection is highest among those who use injection drugs, with a rate of approximately 90%.
The rate of co-infection among homosexual men is approximately 10%.
Co-infection with HIV both accelerates the clinical progression of hepatitis C and increases the risk of perinatal HCV transmission from 5% (range, 3-8%) to 17% (range, 7-36%).
Highly active antiretroviral therapy (HAART) is a combination therapy used in patients with HIV disease. HAART-associated immune recovery may increase HCV replication.
This recovery may represent an immune reconstitution phenomenon.
HAART-associated hepatotoxicity may complicate the treatment of HCV infection.
Patients co-infected with HIV and HCV should be closely monitored during treatment for possible drug interactions.
After IFN alfa 2b and ribavirin combination therapy is initiated, the CBC count and hemoglobin level should be checked regularly.
If warranted, the use of epoetin and granulocyte colony-stimulating factor may be considered.
At week 24 of treatment, the patient should be evaluated for IFN-associated thyroid dysfunction.
HCV-RNA levels should be monitored.
If the HCV-RNA level is undetectable , therapy should be continued for an additional 24 weeks regardless of the genotype.
HCV RNA is rechecked 6 months after treatment. If HCV RNA is detectable and the patient has mild liver disease, therapy may be stopped.
If HCV RNA is detectable and the patient has advanced fibrosis, maintenance IFN therapy may be considered.

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

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