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Hepatitis C virus is a leading cause of chronic liver disease, with over 170 million people infected worldwide. It is also the leading indication for liver transplantation. Complications from chronic hepatitis C infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma. As a result, treatment strategies to prevent such complications have been widely researched, although many questions remain unanswered. To date, the standard therapy for chronic hepatitis C infection is the combination of peginterferon and ribavirin. Treatment strategies differ based on factors such as genotype and liver biopsy results. Other strategies must be considered for special groups, such as patients with acute hepatitis C infection, hepatitis C/human immunodeficiency virus (HIV) coinfection, and prior nonresponse to interferon or relapse after its use. The goal of therapy is to achieve a sustained virologic response (ie, no detectable hepatitis C ribonucleic acid 6 months after completion of therapy). The substantial adverse effects associated with both interferon alfa and ribavirin often make it difficult for patients to continue with their therapies.
Hepatitis C is transmitted through contact with blood and blood products. The leading risk factor for hepatitis C infection today is injection drug use (Table 1).
Viral infections in short-term injection drug users the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses.
Other potential modes of transmission, although less common, include occupational exposure, sexual transmission, intranasal cocaine use, tattooing, body piercing, and maternal-infant spread.
Viral hepatitis in health care personnel at The Johns Hopkins Hospital. The seroprevalence of and risk factors for hepatitis B virus and hepatitis C virus infection.
Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women.
Commercial tattooing as a potentially important source of hepatitis C infection. Clinical epidemiology of 626 consecutive patients unaware of their hepatitis C serologic status.
Recipients of therapeutic blood products before 1992, when screening became possible with the availability of serological markers, are also considered to be at risk of chronic hepatitis C infection.
Centers for Disease Control and Prevention Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.
Positive enzyme immunoassay test results should be confirmed with either a recombinant immunoblot assay or hepatitis C ribonucleic acid (RNA) measurement.
Centers for Disease Control and Prevention Centers for Disease Control and Prevention. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus.
Hepatitis C RNA measurement, which is considered the “gold standard” for the diagnosis of hepatitis C, has the advantage over the recombinant immunoblot assay of not only confirming an exposure to hepatitis C but also determining ongoing viral replication. Patients with a positive enzyme immunoassay but a negative hepatitis C RNA assay may have cleared the infection, may have hepatitis C RNA that is below the level of detection, or may never have been exposed to hepatitis C (false positive). A recombinant immunoblot assay would confirm that the enzyme immunoassay is a true positive. Referral to a hepatologist for counseling, education, and treatment consideration should be considered for any patient who is found to have hepatitis C.
Table 1Risk factors for hepatitis C infection
Injection drug use
Recipient of clotting factor before 1987
Intranasal cocaine use
Sex with multiple partners
Body piercing
Long-term hemodialysis
Occupational exposure (eg, needle stick)
Perinatal transmission
Blood transfusion or organ transplantation before 1992
Adapted from Centers for Disease Control and Prevention.
Centers for Disease Control and Prevention Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.
Hepatitis C is an uncommon cause of acute hepatitis in the United States. Hepatitis A is responsible for 40% to 55% of acute hepatitis, and hepatitis B is responsible for another 30% to 35%; hepatitis C accounts for only 12% to 16% of acute infections.
Chronic hepatitis C is difficult to assess, because it is frequently subclinical, so many patients are not even aware that they are infected. Patients with chronic hepatitis C are at risk of cirrhosis and hepatocellular carcinoma.
There are 6 genotypes and numerous subtypes of hepatitis C based on RNA sequence diversity of the genome. Genotypes 1 and 2 are found worldwide, genotype 3 mostly in South and Southeast Asia, genotype 4 predominantly in Africa and the Middle East, genotype 5 mostly in South Africa, and genotype 6 mainly in Hong Kong and Vietnam. In the United States, genotype 1 accounts for more than 70% of all infections.
Genotype should be assessed in patients who are being considered for treatment. The genotype predicts the likelihood of achieving a sustained virologic response and determines how long treatment should be continued.
International Hepatitis Interventional Therapy Group (IHIT) Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.
The ALGOVIRC Project Group Is an “a la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C?.
Hepatitis Interventional Therapy Group A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.
A liver biopsy is recommended to assess the severity of liver disease and the need for antiviral therapy. Liver biopsy is optional in patients with genotype 2 and 3 due to the high likelihood of viral response.
Repeat biopsies can also be useful to evaluate the progression of the disease in patients who have opted against treatment or in patients who did not respond to their initial therapy and are considering another course of therapy. Regardless of the alanine aminotransferase levels, liver biopsy should be performed when the results will influence whether treatment is recommended.
The objective of therapy is to eradicate the virus and prevent potential complications from chronic hepatitis C infection. The risk of chronic disease in infected patients is greater than 80%.
; among these cirrhotic patients, there is a 30% risk of developing decompensated liver disease after a decade, and a 1% to 2% yearly risk of developing hepatocellular carcinoma.
Efficacy of the treatment is assessed by measurements of hepatitis C RNA viral load (Table 2). The goal is to achieve a sustained virologic response, defined by the continued absence of hepatitis C RNA 6 months after the completion of treatment. The likelihood of achieving a sustained virological response can be predicted at 3 months (Figure 2). If the hepatitis C RNA does not drop by at least 2 logs at 3 months after initiating therapy, treatment should be discontinued, because the likelihood of a sustained virologic response is only 0% to 3%
; these patients are termed nonresponders, in whom treatment strategies may need to be reconsidered (see below). Ongoing studies are assessing whether the early virologic response could be less than 12 weeks. Relapsers are patients who had undetectable hepatitis C RNA levels during therapy but levels that became detectable when therapy was discontinued.
Table 2Classifications of treatment responses to hepatitis C therapy
Early virologic response
Absence of hepatitis C ribonucleic acid or at least a 2-log decrease in ribonucleic acid within 12 weeks of initiating treatment for hepatitis C
End of treatment response
Absence of hepatitis C ribonucleic acid at the completion of treatment
Sustained virologic response
Persistent absence of hepatitis C ribonucleic acid 6 months after the completion of therapy
In the absence of contraindications (Table 3), treatment is recommended for patients who are at increased risk of developing cirrhosis, generally defined by a measurable hepatitis C RNA level and liver biopsy showing portal or bridging fibrosis along with at least moderate inflammation and necrosis.
Table 3Absolute contraindications to hepatitis C therapy
Active psychiatric illnesses, such as major depression, schizophrenia, or bipolar disorder that is not controlled
Having undergone renal, heart, or lung transplant
Comorbid conditions known to be exacerbated by interferon and ribavirin therapy, such as autoimmune hepatitis
Untreated hyperthyroidism
Severe concurrent disease such as severe hypertension, heart failure, considerable coronary artery disease, poorly controlled diabetes mellitus, severe chronic obstructive pulmonary disease
Known hypersensitivity to drugs used to treat hepatitis C
The past decade has seen a steady improvement in therapies against hepatitis C. In the mid-1990s, monotherapy with interferon glycoproteins with antiviral and immunomodulatory activity,
The addition of ribavirin (a guanosine nucleoside analog that is able to inhibit the replication of viruses) to interferon in the late 1990s was associated with an increase in sustained virologic response to approximately 30%.
International Hepatitis Interventional Therapy Group (IHIT) Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.
Realizing the importance of sustained interferon levels, the interferon product was pegylated, a process by which polyethylene glycol is covalently attached to a protein to increase its half-life, thereby resulting in better response rates (Table 4). Currently, the standard of care for the treatment of hepatitis C is the combination of peginterferon and ribavirin (Table 5), with a monthly cost of approximately $1200 for peginterferon and $1100 for ribavirin.
Table 4Likelihood of sustained virologic response in different patient population settings
PEGASYS International Study Group Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.
Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin an open-label series.
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
The most common adverse effects associated with interferon include fatigue and flu-like symptoms (Table 6); interferon can also cause neutropenia and thrombocytopenia. With ribavirin, dose-dependent and reversible hemolytic anemia is the most prominent adverse effect,
whereas the most serious potential adverse effect is teratogenicity. Two forms of contraception must be used during therapy and for 6 months following treatment cessation.
Table 6Selected common adverse effects reported with interferon and ribavirin*
The decision of whether to continue antiviral treatment depends on the severity of adverse effects, their effect on quality of life, and the degree of underlying histologic damage. Peginterferon and ribavirin should be discontinued if the hemoglobin level is less than 8.5 g/dL, the white blood cell count is less than 1 × 109/L, the absolute neutrophil count is less than 0.5 × 109/L, and/or platelet count is less than 50 × 109/L.
Treatment
Acute hepatitis C
Most patients with acute hepatitis C are asymptomatic, thus making it difficult to identify those with de novo infection. Hepatitis C RNA is detectable as early as 1 to 2 weeks following exposure,
Due to the difficulty of identifying acute hepatitis C infection, only 1 randomized, prospective trial has assessed the treatment of acute disease. Various studies demonstrate excellent sustained virologic responses with earlier treatment.
In the only controlled study of acute hepatitis C, patients were randomized to interferon monotherapy starting 8 weeks (early intervention) or 1 year (late intervention) after infection. The sustained virologic response was 100% with early intervention but only 53% with late intervention.
These aggregate data suggest that the sustained virologic response is higher when treatment is instituted no more than 3 months after infection, although it may be prudent to wait 12 weeks to allow for spontaneous resolution. Although the optimal dose and duration of treatment of acute hepatitis C is unclear, patients may benefit from 6 months of interferon therapy. Other options include peginterferon, with and without ribavirin.
Currently, the best treatment for acute hepatitis C is a 6-month course of peginterferon and ribavirin (doses in Table 5). Although most studies used interferon in the treatment of acute hepatitis C, peginterferon is more convenient to use. Moreover, the addition of ribavirin to peginterferon is associated with a greater probability of a virologic response without a concomitant exacerbation of adverse effects.
Chronic hepatitis C
Elevated aminotransferase levels
Several studies have compared the safety and efficacy of peginterferon and ribavirin with standard interferon and ribavirin for the treatment of chronic hepatitis C in patients with elevated aminotransferase levels.
PEGASYS International Study Group Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.
PEGASYS International Study Group Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.
Predictors of poor sustained virologic response include genotype 1, high viral load, increased body weight, and substantial fibrosis (bridging fibrosis and cirrhosis).
For example, the sustained virologic response for patients with genotype 1 with peginterferon and ribavirin is between 42% and 56%. For patients with genotypes 2 and 3, the sustained virologic response is between 75% and 84%. In patients with genotype 1 and a high viral load, the sustained virologic response is between 26% and 42%. With low viral load, the sustained virologic response was between 52% and 56%. In patients with bridging fibrosis and cirrhosis, the sustained virologic response is between 29% and 43%.
Treatment of patients with compensated cirrhosis must be tempered by the fact that many patients are already thrombocytopenic before starting therapy, and many may be at risk of further decompensation when therapy is instituted. Patients with decompensated liver disease tolerate interferon poorly and have a higher incidence of adverse events
By 2015, the number of nonresponders to either interferon/ribavirin or peginterferon/ribavirin seeking retreatment is expected to outgrow the number of patients who are seeking initial therapy. The primary goal of retreatment is to achieve a sustained virologic response. Secondary goals include the prevention of progressive histologic diseases, the regression of fibrosis, a decrease in the risk of hepatocellular carcinoma, and, potentially, a reduction of the risk of hepatic decompensation. The sustained virologic response in interferon/ribavirin nonresponders retreated with peginterferon/ribavirin is between 4% and 12%.
Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial of prior nonresponders to intereron monotherapy or combination therapy and in combination therapy relapsers: Final results.
Unfortunately, retreatment options are limited, and their efficacy is low. Options in nonresponders may include peginterferon maintenance therapy or interferon alfacon-1 used in combination with ribavirin. When retreating nonresponders to interferon or interferon/ribavirin, early virologic response is often assessed at 20 to 24 weeks rather than at 12 weeks.
Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
In preliminary studies, the results from using interferon alfacon-1 and ribavirin appear promising in nonresponders to interferon/ribavirin and peginterferon/ribavirin.
However, larger trials are needed before this approach is used routinely in clinical practice.
HIV/hepatitis C coinfection
The human immunodeficiency virus and hepatitis C have similar modes of transmission, so rates of coinfection are higher. Several studies have shown that approximately 25% to 30% of all patients infected with HIV in the United States and Europe are also infected with hepatitis C,
Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS) the effect of coinfection on survival.
Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus a cross-sectional analysis of the US adult AIDS Clinical Trials Group.
Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus a cross-sectional analysis of the US adult AIDS Clinical Trials Group.
Response rates to interferon-based therapy appear to be slightly lower in patients with HIV/hepatitis C coinfection compared with patients infected with hepatitis C. As seen in hepatitis C alone, the combination of peginterferon and ribavirin is associated with a higher sustained virologic response than is standard interferon and ribavirin; the sustained virologic response ranged from 27% to 44% with the peginterferon/ribavirin group compared with 11% to 12% with the standard interferon/ribavirin groups.
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
For patients with genotype 1, the sustained virologic response ranges from 14% to 29% with peginterferon and ribavirin and from 44% to 73% for patients with genotypes 2 and 3.
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
Similarly, the response rates in patients with genotypes 2, 3 and 5 were also analyzed together. With treatment for hepatitis C, HIV RNA levels do not appreciable increase. CD4 counts decrease during treatment but return to baseline after completion of therapy. However, the adverse effects of treatment for hepatitis C treatment in HIV coinfected patients lead to high rates of discontinuing therapy.
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
Although the 5-year survival rate for transplant recipients with hepatitis C is similar to other patients, more recent data suggest decreased long-term survival.
Moreover, accelerated recurrent hepatitis C infection after transplantation can rapidly result in development of cirrhosis and decompensated disease. Efforts to treat recurrent disease have been hampered by the limited efficacy and adverse effects of current therapies. The combination of interferon and ribavirin has been associated with a sustained virologic response rate of approximately 20%
Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.
Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin an open-label series.
Hepatitis C: development of new drugs and clinical trials: promises and pitfalls: summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003.
: therapies directed against specific hepatitis C targets (polymerase and protease inhibitors, antisense nucleotides), immunomodulators (histamine, chloride matrix and thymosin alfa), vaccines, alternative interferons (oral interferon alfa, purified multisubtype human interferon alfa, interferon omega and interferon gamma), alternative interferon delivery systems (fusion protein interferon alfa-albumin and transfersome containing interferon alfa), and ribavirin prodrugs and L isomers. However, no new drugs are expected on the market for several years, and interferon is likely to remain the core of any regimen that becomes available.
Acknowledgments
We thank Joshua Marehbian, Ian Cown, and Lisette Peralta for editorial assistance.
Viral hepatitis in health care personnel at The Johns Hopkins Hospital. The seroprevalence of and risk factors for hepatitis B virus and hepatitis C virus infection.
Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women.
Commercial tattooing as a potentially important source of hepatitis C infection. Clinical epidemiology of 626 consecutive patients unaware of their hepatitis C serologic status.
International Hepatitis Interventional Therapy Group (IHIT)
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.
Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial of prior nonresponders to intereron monotherapy or combination therapy and in combination therapy relapsers: Final results.
Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.
Hepatitis C: development of new drugs and clinical trials: promises and pitfalls: summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003.
Treatment using peginterferon and ribavirin in all settings, except in acute hepatitis C, in which interferon was used with or without ribavirin.
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