Chronic Hepatitis C:

The most common chronic blood-borne infection in the United States is caused by hepatitis C virus (HCV), an RNA virus transmitted through blood-to-blood contact.¹ Approximately 4 million Americans are currently infected.^1-3 During the 1980s, as many as 230,000 new HCV infections were diagnosed each year.⁴ The development of antibody testing for HCV and routine screening of blood donations reduced this figure to about 25,000 new infections per year by 2001.⁴

However, the large burden of disease from the earlier years remains, and the morbidity and mortality associated with HCV are expected to increase over the next 2 decades.⁵ HCV-associated end-stage liver disease is the most frequent indication for liver transplantation in the western world.⁶

In this article, we identify risk factors for HCV infection and discuss which patients should be tested and treated.

HCV TRANSMISSION

In the past, the 2 most important modes of viral transmission weretransfusion of infected blood products and sharing of contaminated needles by injection drug users.⁴ Injection drug use accounts for about 60% of all new cases of hepatitis C in the United States.⁴ However, since 1992, when blood screening for HCV was introduced, the risk of contracting hepatitis C from a transfusion has been reduced to approximately 1 in 1.18 million donations.⁷ Patients who received transfusions before July 1992 remain at risk. Persons with hemophilia run a substantially higher risk: nearly 90% of patients who received factors made before 1987 have been infected with HCV.^4,8 Rigorous screening and viral inactivation procedures have virtually eliminated this mode of transmission.

Nosocomial transmission of HCV in the United States is relatively rare. Nevertheless, all health care personnel should be aware of the risks and should strictly observe universal precautions. At present, the rate of HCV infection among hospital workers (including surgeons) in the United States is similar to that in the general population, averaging 1% to 2%.⁴ Needlestick and sharps-related injuries remain a source of HCV infection. However, the incidence of HCV seroconversion after an incident is only about 1.8%.⁴ Moreover, the risk of transmission from infected health care workers to patients appears to be very low; only isolated cases have been reported.⁴

The risk of nosocomial transmission is highest in the hemodialysis unit, where the prevalence of HCV infection among patients undergoing long-term hemodialysis is 8.4% and among unit workers, 1.7%.⁹ Inadequate infection control has been cited as the most likely explanation for the increased prevalence in these units. However, there is no difference in the prevalence of the antibody against HCV (anti-HCV) at centers that reuse dialyzers on anti-HCV-positive patients compared with those that do not reuse dialyzers. Medical personnel in hemodialysis units should use gloves whenever they touch patients or equipment and should never allow patients to share instruments or medications.⁴

Although sexual contact is one of the most common modes of transmission for hepatitis B virus infection, HCV appears to be transmitted less readily via this route. A recent study showed no transmission of HCV during a 3-year follow-up of 600 spouses of patients with chronic hepatitis C.⁶ The CDC does not recommend any changes in sexual practices in long-term monogamous relationships in which one of the part- ners is infected with HCV.

Vertical transmission from HCV-positive mothers is also an important mode of disease transmission. Women infected with HCV have approximately a 5% to 6% risk of transmitting the virus to their infants. For infants born to women coinfected with HCV and HIV, the rate of HCV transmission is 14% from anti-HCV-positive mothers and 17% in mothers with documented HCV viremia.^4,10 Many studies have shown a failure of HCV transmission through breast-feeding, which has led to the assumption that this practice is safe in HCV-infected mothers.^11-13 However, the same cannot be said for those coinfected with HCV and HIV.

Less common modes of transmission include percutaneous exposure through tattooing and body piercing, and through the sharing of razor blades, toothbrushes, pedicure and manicure items, and other objects that might be exposed to blood.⁴ One study has suggested that HCV infection may also be transmitted via shared straws used in cocaine inhalation.¹⁴ However, the significance and extent of these modes of transmission remain unclear.

CLINICAL FEATURES OF INFECTION

Only a minority of patients with acute HCV infection experience significant illness or symptoms. Some may have nonspecific symptoms, such as general malaise, anorexia, and abdominal pain; some may have jaundice.

Chronic hepatitis C develops in approximately 60% to 85% of patients with acute HCV infection.^15-18 The rate of progression to chronic disease is slightly lower in children (55%). Children are also less likely to demonstrate progression of liver disease once they are infected.¹⁹ Spontaneous resolution of HCV infection, as demonstrated by the continued absence of HCV RNA and sustained normalization of serum alanine aminotransferase (ALT) levels, occurs in only 15% to 25% of patients, and only during the acute phase of infection.²⁰ Most patients with chronic hepatitis C are unaware of their disease and may remain asymptomatic for years or decades, presenting only once a complication develops.

Chronic HCV infection can lead to cirrhosis, liver failure, and hepatocellular carcinoma, all of which are potentially fatal. Within 20 years of the initial infection, cirrhosis develops in about 20% of patients with chronic hepatitis C.²¹ Alcohol use contributes to the development of cirrhosis in patients with HCV infection.²² One study has demonstrated that this may occur partly through enhanced viral replication.²³ Thus, patients with chronic HCV infection should be advised to avoid regular alcohol intake.

Patients with chronic HCV infection and liver disease are at increased risk for fulminant hepatitis A and B if they are susceptible to infection. Therefore, hepatitis A and/or B vaccines are strongly recommended for all patients infected with HCV. It is our practice to provide testing and counseling for hepatitis A and B virus infection to all HCV-infected patients.

TESTING PATIENTS AT RISK

Routinely test patients who have documented exposures, such as health care workers with needlestick injuries or other mucosal exposures to HCV-infected blood, and children born to HCV-positive women. Also offer HCV testing to patients who have other risk factors (Table). The CDC does not recommend routine HCV testing for health care workers without a history of needlestick injuries; nonsexual household contacts of persons infected with HCV; or the general population, including pregnant women with no risk factors for HCV infection.⁴

The usefulness of routine HCV screening in several groups of patients remains uncertain. These include patients who have received tissue (but not blood or organ) transplants, intranasal cocaine users who have never used injection drugs, persons with a history of tattooing or body piercing, those with long-term sex partners who are positive for HCV, and those with a history of multiple sex partners or sexually transmitted diseases.⁴ Nevertheless, many clinicians routinely screen the long-term sex partners of HCV-infected patients. In our practice, we screen all patients with risk factors for hepatitis A, B, and C and vaccinate susceptible patients against hepatitis A and/or B.

DIAGNOSIS

Diagnostic tests. The enzyme immunoassay (EIA) test is used for routine screening. Positive results usually indicate exposure to HCV but do not signify active infection. False-positive EIA results may be reported in certain patients, including those with autoimmune liver disease; confirmatory testing is necessary in these cases. The recombinant immunoblot assay was the first available confirmatory test. However, many clinicians now use techniques that directly measure viral RNA, such as the quantitative HCV RNA test.

Certain immunosuppressed patients, such as those with AIDS, may have false-negative EIA results. Confirmatory reverse transcription-polymerase chain reaction (RT-PCR) testing is recommended if clinical suspicion for HCV infection is high. The direct molecular detection of HCV RNA by RT-PCR is considered the gold standard for confirming the diagnosis of HCV infection and for assessing the antiviral response to therapy. RT-PCR assays may be qualitative or quantitative.

HCV genotypes. HCV has considerable sequence heterogeneity, which perhaps contributes to the high rates of chronic infection. The most frequently used system classifies HCV into 6 major groups, or genotypes (denoted by 1 to 6). These classifications exhibit a fairly distinct geographic distribution. More than 50 subtypes have also been identified (signified by lowercase letters a through e). Genotypes 1a and 1b are the most frequent in the United States and Western Europe.²⁴ Genotyping is vital because this information determines the duration of treatment and response to antiviral therapy. For instance, genotypes 2 and 3 are more susceptible to treatment than genotype 1.²⁵ Moreover, recent data show that in patients with cirrhosis, genotype 2 is a more favorable predictor of sustained virologic response than genotype 3.²⁶

Liver enzyme studies. ALT readings vary markedly in patients with hepatitis C and cannot be relied on for either diagnosis or assessment of liver damage. Although 60% to 70% of patients with chronic HCV infection have persistently elevated ALT levels, the remainder may have intermittently or persistently normal values.⁴ For this reason, a single normal ALT reading or even repeatedly normal readings do not exclude chronic disease.

Liver biopsy. Liver biopsy is the gold standard for staging liver disease, with results that range from mild or no fibrosis to cirrhosis. These results help experienced physicians guide treatment and evaluate the effectiveness of therapy.

Biopsy is helpful but not mandatory in the pretreatment staging of disease. The 2 main systems for grading liver biopsy specimens are the Knodell and METAVIR systems. The METAVIR system was specifically designed and validated for use in liver disease related to hepatitic C; it is the most commonly used. Fibrosis is graded on a scale of 0 to 4; a score of 4 indicates cirrhosis. The Knodell scoring system is also known as the histologic activity index (HAI); it has a wider range of scores.

TREATMENT

Patients with chronic hepatitis C who have persistently elevated ALT readings, detectable HCV RNA levels, and liver biopsy results (if available) that show portal or bridging fibrosis or at least moderate inflammation or necrosis have generally been considered prime candidates for therapy. Available treatments for HCV include traditional interferon alfa and pegylated interferon (peginterferon) plus ribavirin. The most recent data suggest that the optimal regimen is a 24- or 48-week course of peginterferon plus ribavirin based on HCV genotype.

Peginterferon is alpha interferon that has been modified chemically by the addition of a large inert molecule of polyethylene glycol. Pegylation changes the uptake, distribution, and excretion of interferon, thereby prolonging its half-life. This enhancement allows the drug to be given once weekly, whereas standard interferon must be given several times weekly. In addition, peginterferon is more active than standard interferon against HCV and yields higher sustained response rates without increasing the incidence of adverse effects. Because of its ease of administration and better efficacy, peginterferon has been supplanting standard interferon for the treatment of HCV.

The 2 types of peginterferon, peginterferon alfa-2a and peginterferon alfa-2b, are roughly equivalent in efficacy and safety but have different dosing regimens. Peginterferon alfa-2a is given subcutaneously in a fixed dosage of 180 µg/wk. Peginterferon alfa-2b is given subcutaneously in a weight-based dosage of 1.5 µg/kg/wk.

A 48-week course of combination therapy with peginterferon and ribavirin yields a sustained response rate of approximately 50% in genotype 1.²⁵ A 24-week course of therapy is sufficient for non-genotype 1 infection, for which the sustained response rate is about 80%. A response is considered "sustained" if HCV RNA remains undetectable for 6 months or more after cessation of therapy. The appropriate ribavirin dose is determined by weight for genotype 1, whereas a fixed dosage of ribavirin at 800 mg/d is adequate for non-genotype 1 infection.²⁵

SIDE EFFECTS AND CONTRAINDICATIONS

Both interferon and ribavirin can have serious side effects and are contraindicated for several groups of patients. These include patients who are allergic to either the medication itself or to the benzyl alcohol in which interferon is mixed; and those with significant cardiac disease, hemoglobinopathies, and autoimmune hepatitis. Inform patients about possible adverse effects and carefully monitor them throughout the course of treatment. The most common adverse effects associated with combination therapy are flu-like symptoms--such as headache, fatigue, myalgia, and fever--that have been traditionally associated with interferon therapy. The severity of these symptoms appears to lessen as treatment continues.

Severe psychiatric adverse effects have been reported in patients who have been treated with interferons. Use combination therapy with extreme caution in patients with preexisting psychiatric disorders who report a history of severe depression. Monitor all patients for evidence of depression and, in severe cases, stop treatment and seek psychiatric intervention. Mild to moderate depression and irritability can be treated successfully with selective serotonin reuptake inhibitors and other commonly prescribed antidepressants.²⁷

Interferon also causes generalized bone marrow suppression, although it is more likely to cause neutropenia than anemia. Peginterferons rarely cause clinically significant thrombocytopenia, with the exception of idiopathic thrombocytopenic purpura.

Ribavirin also has serious side effects. The combination of peginterferon and ribavirin is contraindicated in pregnant women, those who may become pregnant 6 months after therapy, and their male sexual partners. Significant teratogenic and embryocidal effects from ribavirin have been reported in animal studies. Perform pregnancy testing at regular intervals in women of childbearing age who are receiving combination therapy.

Hemolytic anemia has commonly been reported in patients treated with combination therapy. Regular monitoring of blood counts is recommended. Erythropoietin alfa ameliorates ribavirin-induced anemia, allows for maintenance of the ribavirin dose, and improves quality of life.¹⁰ Other adverse effects attributable to ribavirin include nausea, dry cough, chest pain, rash, dry skin, and pruritus.

References:

REFERENCES:

1.

National Institutes of Health. National Institutes of Health Consensus Development Conference panel statement management of hepatitis C.

Hepatology.

1997;26(suppl 1):2S-10S.

2.

McQuillan GM, Alter MJ, Moyer IA, et al. A population based serologic study of hepatitis C virus infection in the United States. In: Rizzetto M, Purcell RH, Gerin JL, Verme G, eds.

Viral Hepatitis and Liver Disease.

Turin, Italy: Edizioni Minerva Medica; 1997: 267-270.

3.

Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.

N Engl J Med.

1999;341:556-562.

4.

Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.

MMWR.

1998;47(RR-19):1-39.

5.

Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States.

Am J Public Health.

2000;90:1562-1569.

6.

Tahan V, Karaca C, Yildirim B, et al. Sexual trans-mission of HCV between spouses.

Am J Gastroenterol.

2005;100:821-824.

7.

Wang B, Schreiber GB, Glynn SA, et al. Does prevalence of transfusion-transmissible viral infection reflect corresponding incidence in United States blood donors?

Transfusion.

2005;45:1089-1096.

8.

Troisi CL, Hollinger FB, Hoots WK, et al. A multicenter study of viral hepatitis in a United States hemophilic population.

Blood.

1993;81:412-418.

9.

Tokars JI, Miller ER, Alter MJ, Arduino MJ. National surveillance of dialysis associated diseases in the United States, 1995.

ASAIO J.

1998;44:98-107.

10.

Pappalardo BL. Influence of maternal human immunodeficiency virus (HIV) co-infection on vertical transmission of hepatitis C virus (HCV): a meta-analysis.

Int J Epidemiol.

2003;32:727-734.

11.

Manzini P, Saracco G, Cerchier A, et al. Human immunodeficiency virus infection as risk factor for mother-to-child hepatitis C virus transmission: persistence of anti-hepatitis C virus in children is associated with the mother's anti-hepatitis C virus immunoblotting pattern.

Hepatology.

1995;21:328-332.

12.

Tovo PA, Palomba E, Ferraris G, et al. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Italian Study Group for HCV Infection in Children.

Clin Infect Dis.

1997;25: 1121-1124.

13.

Fischler B, Lindh G, Lindgren S, et al. Vertical transmission of hepatitis C virus infection.

Scand J Infect Dis.

1996;28:353-356.

14.

Judd A, Hutchinson S, Wadd S, et al. Prevalence of, and risk factors for, hepatitis C virus infection among recent initiates to injecting in London and Glasgow: cross sectional analysis.

J Viral Hepat.

2005;12:655-662.

15.

Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team.

N Engl J Med.

1992;327:1899-1905.

16.

Barrera JM, Bruguera M, Ercilla MG, et al. Persistent hepatitis C viremia after acute self-limit-ing posttransfusion hepatitis C.

Hepatology.

1995;3:639-644.

17.

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;29:908-914.

18.

Seeff L, Miller R, Rabkin C, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults.

Ann Intern Med.

2000;132:105-111.

19.

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;341:866-870.

20.

Lauer GM, Walker BD. Hepatitis C virus infection.

N Engl J Med.

2001;345:41-52.

21.

Seeff LB. Natural history of chronic hepatitis C.

Hepatology.

2002;36(suppl 1):S35-S46.

22.

Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histological and clinical progression of hepatitis C infection.

Hepatology.

1998;28: 805-809.

23.

Oshita M, Hayashi N, Kasahara A, et al. Increased serum hepatitis C virus RNA levels among alcoholic patients with chronic hepatitis C.

Hepatology.

1994;20:1115-1120.

24.

Wong JB, Bennett WG, Koff RS, et al. Pretreatment evaluation of chronic hepatitis C: risks, benefits, and costs.

JAMA.

1998;280:2088-2093.

25.

Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of the effect of treatment duration and ribavirin dose.

Ann Intern Med.

2004;140:346-355.

26.

Lee SS, Bain VG, Peltekian K, et al. Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice.

Aliment Pharmacol Ther.

2006;23:397-408.

27.

Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study.

Gastroenterology.

2004;126: 1302-1311.