Hepatitis C virus (HCV) infection is a worldwide pandemic. Up to 300 million persons are infected-5 times the number infected with HIV.1 As many as 4 million Americans test positive for HCV,2 and it is now the most common cause of chronic viral hepatitis and cirrhosis in this country, as well as the leading indication for liver transplantation. In the United States, the prevalence of HCV infection is highest among men aged 20 to 40 years and among African Americans.
In this article, we identify the risk factors for infection and discuss which patients should be tested and which should be treated. We also describe how to make optimal use of the latest treatment options, including strategies to manage the adverse effects of therapy.
NATURAL HISTORY OF THE DISEASE
Chronic hepatitis C develops in most persons who are infected with HCV. Spontaneous clearance of the virus occurs in only 15% to 25% of patients, almost always within the first 6 months of infection. Most acute infections are asymptomatic, and in the past, HCV infection was often not recognized until decompensated liver disease developed.
The natural history of the disease varies. Cirrhosis develops in about 15% to 20% of those infected and can result in severe complications and death. Alcohol consumption accelerates the progression to fibrosis or cirrhosis; thus, many health care providers recommend complete abstinence for patients with HCV infection.3 Increased awareness of risk factors has led to earlier detection of HCV infection, before advanced liver disease occurs.
WHO IS AT RISK?
Risk factors. Most patients contracted HCV between 1970 and 1989, before screening tests of blood and blood products became available. Hepatitis C is transmitted parenterally; commonly accepted risk factors are listed in Table 1. Other possible risk factors that have been suggested include:
- Intranasal cocaine use.
- Low socioeconomic status.
- Maternal-infant transmission.
- Extensive body piercing or tattooing.
- A history of incarceration.
Reasons for some of these associations are not clear, but many suspect that undisclosed intravenous drug use is frequently a factor.
Despite rigorous screening measures to prevent contamination of blood products, new cases of HCV infection continue to appear. These are associated mainly with intravenous drug use.
Transmission. Some investigators have detected HCV-RNA in almost all body fluids; however, it is found most frequently and at the highest concentration in blood. The presence of HCV-RNA does not always indicate infectivity; in fact, HCV is inactive in bile-and, therefore, stool.4 Some investigators-but not others5-have also detected HCV-RNA in saliva. In any event, contact with the saliva of infected persons is a very inefficient mode of transmission.Although the likelihood of transmission through household or casual contact is highly unlikely, caution patients with HCV infection not to share razors or toothbrushes and to keep wounds covered.
A key concern for patients is whether they can transmit the disease to their sex partners. HCV infection may be transmitted by sexual intercourse, but this is rare; sexual transmission is thought to be responsible for less than 3% of cases. Breaks in the mucosal barrier, such as those that occur with traumatic intercourse or with genital ulcers, may enhance transmission.4 In addition, patients who are coinfected with HIV appear to transmit HCV to their partners more readily.4
The CDC recommends no changes in sexual practices for patients with HCV infection who are in monogamous relationships. It is recommended, however, that their partners be screened for HCV.2For patients with HCV infection who are not in monogamous relationships, recommend the routine use of condoms with each sexual contact, to prevent both transmission of HCV and acquisition of other sexually transmitted diseases.
Improved screening of the blood supply in the United States has dramatically reduced the risk of contracting HCV infection through transfusion; however, this is still a concern in countries that do not screen their blood supply for HCV.
Suspect HCV infection if any of the risk factors in Table 1 are present-even if the patient has normal liver enzyme levels. Patients may be reluctant to admit to risk factors other than blood transfusion, especially during an initial office visit. An effective approach is simply to give patients a list of risk factors, and to ask whether they consider themselves at risk-without having them specify why.
Once you have determined the patient is at risk for HCV infection, order an enzyme-linked immunosorbent assay to test for HCV antibody. Keep in mind that results may not be positive until 4 to 6 weeks after exposure; thus, a patient with acute hepatitis may test negative. Results may also be negative in patients who are immunosuppressed or receiving hemodialysis. In these patients, a test for HCV-RNA by polymerase chain reaction (PCR) is required to make the diagnosis.
After HCV infection has been diagnosed, rule out other causes of liver disease and assess liver function. Recommended tests include:
- Complete blood cell count with differential.
- Measurement of prothrombin time and thyroid-stimulating hormone level.
- Iron studies to assess for possible hemochromatosis.
- Hepatitis B surface antigen test.
- HIV test.
In patients with a family history of liver disease or with early progression to cirrhosis, determination of alpha1-antitrypsin phenotype and ceruloplasmin levels and an antinuclear antibody test with quantitation may be indicated.
ASSESSING DISEASE SEVERITY
Severity of disease can be assessed only by liver biopsy, which remains the gold standard for determining the activity of HCV-related disease. Liver biopsy can be used to assess the degree of inflammation, stage of fibrosis, and presence of cirrhosis (Figures 1, 2, and 3).It is the only reliable predictor of prognosis; liver enzyme levels do not correlate with disease severity and cannot be used for prognosis. Liver biopsy is also helpful in uncovering other causes of liver disease, which may complicate the course of HCV infection.1 Although not absolutely necessary before beginning treatment, liver biopsy provides information that is highly useful in making therapeutic decisions.
WHICH PATIENTS TO TREAT
The treatment of HCV infection is complex, and guidelines change frequently. All patients with hepatitis C are potential candidates for therapy if they have no contraindications. We encourage primary care practitioners who have patients with newly diagnosed infection to consult with a specialist who is active in the treatment of hepatitis C.
Absolute contraindications to interferon therapy include current psychosis or a history of psychosis, severe depression, current alcohol or intravenous drug use, neutropenia or thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and organ transplantation (other than liver). Relative contraindications include most autoimmune disorders and uncontrolled diabetes.
Absolute contraindications to ribavirin therapy include pregnancy or unwillingness to use effective contraception, renal insufficiency, anemia, hemoglobinopathies, and severe heart disease. Relative contraindications are uncontrolled hypertension and ischemic heart disease.
For patients who have no contraindications, the decision to treat is based on the severity of the disease (determined by liver biopsy results), age, and pretreatment probability of a response. Ultimately, the decision should be made by the patient, after he or she has been counseled about all aspects of treatment, including side effects and expected efficacy rates.
Several parameters predict a favorable response to therapy, including6:
- Infection with genotype 2 or 3 (rather than genotype 1).
- Low viral load. (Obtain HCV-RNA quantitation by PCR in any patient who is a candidate for therapy to confirm viremia as well as to establish a baseline before the start of treatment.)
- No fibrosis or only portal fibrosis.
- Female sex.
- Age less than 40 years at the time of treatment.
The presence of fewer than 4 of these factors decreases the odds of a sustained response; the presence of 4 or 5 of these factors increases the odds.
Recommend antiviral therapy to patients with aggressive disease on liver biopsy (eg, stage 2 to 4 fibrosis). Those with minimal disease can be given the option of waiting for safer, more efficacious medications or starting treatment now. The younger the patient, the more aggressive the approach, because the risk of progression over time is greater. For example, younger patients who have favorable pretreatment parameters, no contraindications to therapy, and aggressive biopsy-proven liver disease are obvious candidates for treatment. Similar patients with mild disease may opt for treatment or may wait for other, more effective therapies in the future. Repeat liver biopsy at 4- to 5-year intervals if the patient chooses not to be treated.
The absence of fibrosis after 25 or more years of infection suggests a good prognosis, and treatment may not be required. Patients older than 65 years who do not have fibrosis may not benefit from antiviral therapy, especially if concurrent illnesses and/or less favorable pretreatment parameters are present.
The goal of antiviral therapy is to achieve a sustained viral response (SVR), defined as no detectable virus in the serum 6 months after antiviral therapy is completed. Recent advances in hepatitis C therapy now allow clearance of the infection in more than half of patients treated.
Combination therapy with standard interferon and ribavirin. Because the sustained response to interferon monotherapy is low (5% to 15%), this treatment is of historic interest only. The advent of combination therapy with interferon plus ribavirin, an oral nucleoside analogue, led to marked improvements in efficacy. Approximately 50% of patients who received combination therapy achieved undetectable levels of HCV-RNA during treatment, and SVR occurred in about 41%.7 However, genotype 1 (both 1a and 1b), the most common type of HCV in the United States and Western Europe, is also the least responsive to treatment. Only 29% of patients infected with genotype 1 achieved an SVR after 1 year of interferon-ribavirin combination therapy.7 In contrast, response rates of up to 66% have been seen in those infected with genotype 2 or 3.
Pegylated interferon. The rapid rate of HCV replication and the short half-life (6 hours) of conventional interferon limit the efficacy of this therapy. To improve the pharmacokinetics of interferon, researchers attached a large molecule-polyethylene glycol (PEG)-to increase its half-life. While the concentration of conventional interferon peaks and then declines rapidly after subcutaneous administration, the serum concentration of pegylated interferon increases gradually and does not peak until about 24 hours after injection. This allows for a more even rate of drug delivery.
Pegylation alsoreduces the renal clearance of interferon. A major advantage of pegylated interferon is that its longer half-life allows for once-weekly dosing-in contrast to conventional interferon, which must be injected 3 times per week.
Two pegylated interferons have been developed: peginterferon alfa-2a and peginterferon alfa-2b. Peginterferon alfa-2b is currently approved by the FDA for the treatment of HCV infection; approval of peginterferon alfa-2a is pending. Because of the smaller size of the PEG molecule in pegylated interferon alfa-2b, this product is dosed by weight; pegylated interferon alfa-2a is administered in a fixed dose.
Both pegylated interferons are superior to standard interferon monotherapy in the treatment of HCV infection in patients with all viral genotypes and in African Americans, who are thought to respond poorly to standard interferon. During treatment, viremia resolved in 69% of patients who received peginterferon alfa-2a but in only 28% of those who received standard interferon alfa-2a monotherapy. An SVR was achieved by 39% of patients in the peginterferon alfa-2a group but in only 19% of those treated with standard interferon alfa-2a.8 A trial comparing peginterferon alfa-2b with standard interferon alfa-2b yielded similar results.9
However, the efficacy of pegylated interferon monotherapy is less than that of combination therapy with standard interferon and ribavirin. For this reason, use pegylated interferon monotherapy only in patients who cannot tolerate ribavirin.
Combination therapy with pegylated interferon and ribavirin. Peginterferon alfa-2b (1.5 µg/kg/wk), in combination with ribavirin (800 mg/d), resulted in higher rates of SVR than the combination of standard interferon and ribavirin (Table 2).10 Peginterferon alfa-2a (180 µg/wk) in combination with ribavirin (1000 to 1200 mg/d) yielded similar results.11 Based on the outcome of these and other studies, the FDA approved the combination of peginterferon alfa-2b and ribavirin (800 mg/d) for the treatment of patients with HCV infection. Pegylated interferon in combination with ribavirin is currently the treatment of choice for patients with recently diagnosed HCV infection.
Recent studies suggest that dosing ribavirin by weight, avoiding unnecessary dose reductions or interruption, and increasing patient compliance may raise the rate of SVR to 61%.11 In the future, weight-based ribavirin dosing together with pegylated interferon may become the standard of care.
Duration of treatment. Treat patients infected with genotype 1 for 48 weeks to maximize the likelihood of an SVR. Patients who fail to clear the virus by week 24 of therapy (as confirmed by positive results on a qualitative HCV-RNA PCR assay) have less than a 2% chance of achieving SVR; consider discontinuing treatment at that point.
Patients infected with genotype 2 or 3 who have no fibrosis on biopsy and who are able to take the recommended doses of peginterferon and ribavirin (ie, no dose reductions) only need to be treated for 24 weeks.
MANAGING SIDE EFFECTS OF THERAPY
Adequate management of adverse effects is essential to successful therapy. Table 3 lists effective strategies for minimizing these effects.
Adverse effects associated with interferon. The side-effect profile of the pegylated interferons is similar to that of regular interferon. Adverse effects were seen in 42% of patients who received peginterferon and ribavirin, compared with 34% of those who received standard interferon and ribavirin.10 However, flu-like symptoms and depression were seen more often in patients who received standard interferon than in those who received pegylated interferon.12
Flu-like symptoms are among the most common complaints of patients undergoing interferon therapy. Most experience myalgia, fatigue, headache, and malaise; some also have fever and rigors. Because interferon raises the body temperature, hydration is extremely important in ameliorating flu-like symptoms. Fortunately, these symptoms tend to lessen after the first few weeks of therapy.
Neuropsychiatric disturbances are also frequent complications of interferon therapy; depression (which can be severe and can lead to suicide), insomnia, irritability, and anxiety are seen most often. Because they can dramatically affect the quality of life of both patients and their families, neuropsychiatric disturbancesare the most common reason for discontinuation of therapy. They result in discontinuation in 2% to 9% of treatment-naive patients and in 3% of relapsers who are re-treated.13
The prevalence of psychiatric disorders is thought to be greater among persons with untreated HCV infection than in the general population, which poses a dilemma for those who wish to be treated.14 Patients with severe depression, a history of suicidal ideation or attempts, manic-depressive disorder, or other severe psychiatric illness are not candidates for therapy.
Involvement of the family is key to early detection and management of psychiatric symptoms; family members may notice irritability, depression, and other symptoms before the patient does.
Injection site reactions are another phenomenon seen with interferon therapy. These usually consist of only localized erythema and are generally a mild inconvenience, not a treatment-limiting event.10
Pegylated interferon alfa-2b is a pregnancy category C medication. Standard interferon alfa-2b has also been shown to have abortifacient effects in experimental animals. Do not use either product in pregnant women.
Adverse effects associated with ribavirin. Ribavirin-associated dermatologic side effects include diffuse or localized rash and pruritus. GI side effects, such as nausea and dyspepsia, often occur as a result of ribavirin therapy.
The teratogenic effects associated with ribavirin necessitate the use of effective contraception during treatment and for 6 months afterward. Counsel patients to practice contraception even if only the male partner is receiving therapy. Unwillingness to use reliable contraception is an absolute contraindication to treatment with ribavirin.
Hematologic adverse effects. Bone marrow suppression caused by interferon and ribavirin-induced hemolytic anemia are common occurrences. A decrease in hemoglobin levels of at least 2 g/dL is common. This gradually stabilizes during the first 4 to 8 weeks of therapy as a result of reticulocytosis. Absolute neutropenia may also be seen during treatment. This side effect is more common in patients treated with pegylated interferon (up to 20% of such patients). Cytopenias are especially common in patients with cirrhosis; however, a recent study found that ribavirin and interferon can be used safely in patients with well-compensated cirrhosis, provided they are closely monitored.15
Careful monitoring of hematologic parameters is required, especially at the beginning of treatment. Obtain a complete blood cell count with differential weekly or biweekly for the first 4 to 6 weeks of therapy and monthly thereafter. Because ribavirin-associated anemia may be severe, use caution when treating patients with preexisting anemia or heart disease. Some authorities consider these to be contraindications to therapy.1 Management of neutropenia is also critical to successful therapy.
ADHERENCE TO THERAPY
Because treatment is long and difficult, extensive patient support greatly enhances adherence. Counsel patients regarding all side effects before therapy is started. Educated patients are more likely to be emotionally prepared for these side effects and therefore more likely to complete the prescribed course of medication. Also impress upon patients the importance of compliance with follow-up visits for monitoring.
A good office library of patient-oriented videotapes, brochures, and manufacturer-sponsored support materials is extremely helpful. Physician extenders and telephone "hot lines" are also valuable in helping patients cope with side effects of treatment. The Box lists other resources for patients.
Offer re-treatment with peginterferon and ribavirin to patients in whom previous interferon monotherapy failed, or who responded to combination therapy with standard interferon and ribavirin but then relapsed.
Base the decision to re-treat patients who failed to clear the virus during standard interferon and ribavirin therapy on the severity of their disease and their tolerance of previous therapy.
Observe-rather than re-treat-patients who had mild disease on liver biopsy and who tolerated previous treatment poorly. Re-treat patients who had fibrosis or cirrhosis on liver biopsy-unless they did not tolerate previous therapy. The likelihood of achieving an SVR with peginterferon and ribavirin therapy in previous nonresponders is currently unknown.
1. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41-52.
2. 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):20-25.
3. Herrera JL, Roveda KP. Hepatitis C: what recent advances in therapy mean for your patients. Consultant. 1999;39:436-447.
4. Thomas DL. Hepatitis C: epidemiologic quandaries. Clin Liv Dis. 2001;5:955-968.
5. Fried MW, Shindo M, Fong TL, et al. Absence of HCV RNA from saliva and semen in patients with chronic hepatitis C. Gastroenterology. 1992;102: 1306-1308.
6. Poynard T, McHutchinson J, Goodman Z, et al, for the ALGOVIRC Project Group. Is an “à la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first-line treatment in patients with chronic hepatitis C? Hepatology. 2000;31:211-218.
7. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis. 1999;19:57-65.
8. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343:1666-1672.
9. Glue P, Rouzier-Panis R, Raffanel C, et al. A doseranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. Hepatology. 2000;32: 647-653.
10. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958-965.
11. Fried MW. Pegylated (40 kDa) interferon alfa-2a (PEGASYS) in combination with ribavirin: efficacy and safety results from a phase III randomized, actively- controlled multicenter study. Gastroenterology. 2001;120:A55. Abstract.
12. Fried MW. Advances in therapy for chronic hepatitis C. Clin Liv Dis. 2001;5:1009-1023.
13. Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis. 1999;19(suppl 1):67-75.
14. Zdilar D, Franco-Bronson K, Buchler N, et al. Hepatitis C, interferon alfa, and depression. Hepatology. 2000;31:1207-1211.
15. Heathcote EJ, Shiffman ML, Cooksley GE, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med. 2000;343:1673-1680.